Small nerve fiber loss and damage (SNFLD) is a frequent complication of sarcoidosis that is associated with autonomic dysfunction and sensory abnormalities, including pain syndromes that severely ...degrade the quality of life. SNFLD is hypothesized to arise from the effects of immune dysregulation, an essential feature of sarcoidosis, on the peripheral and central nervous systems. Current therapy of sarcoidosis-associated SNFLD consists primarily of immune suppression and symptomatic treatment; however, this treatment is typically unsatisfactory. ARA 290 is a small peptide engineered to activate the innate repair receptor that antagonizes inflammatory processes and stimulates tissue repair. Here we show in a blinded, placebo-controlled trial that 28 d of daily subcutaneous administration of ARA 290 in a group of patients with documented SNFLD significantly improves neuropathic symptoms. In addition to improved patient-reported symptom-based outcomes, ARA 290 administration was also associated with a significant increase in corneal small nerve fiber density, changes in cutaneous temperature sensitivity, and an increased exercise capacity as assessed by the 6-minute walk test. On the basis of these results and of prior studies, ARA 290 is a potential disease-modifying agent for treatment of sarcoidosis-associated SNFLD.
Objective. The N‐methyl‐D‐Aspartate (NMDA) receptor has been proposed as a primary target for the treatment of neuropathic pain. The aim of the present study was to perform a meta‐analysis ...evaluating the effects of (individual) NMDA receptor antagonists on neuropathic pain, and the response (sensitivity) of individual neuropathic pain disorders to NMDA receptor antagonist therapy.
Design. PubMed (including MEDLINE), EMBASE and CENTRAL were searched up to October 26, 2009 for randomized placebo controlled trials (RCTs) on neuropathic pain. The methodological quality of the included trials was independently assessed by two authors using the Delphi list. Fixed or random effects model were used to calculate the summary effect size using Hedges' g.
Setting. NA.
Patients. The patients used for the study were neuropathic pain patients.
Interventions. The interventions used were NMDA receptor antagonists.
Outcome measurements. The outcome of measurements was the reduction of spontaneous pain.
Results. Twenty‐eight studies were included, meeting the inclusion criteria. Summary effect sizes were calculated for subgroups of studies evaluating ketamine IV in complex regional pain syndrome (CRPS), oral memantine in postherptic neuralgia and, respectively, ketamine IV, and oral memantine in postamputation pain. Treatment with ketamine significantly reduced pain in postamputation pain (pooled summary effect size: −1.18 confidence interval (CI) 95% −1.98, −0.37, P = 0.004). No significant effect on pain reduction could be established for ketamine IV in CRPS (−0.65 CI 95% −1.47, 0.16, P = 0.11) oral memantine in postherptic neuralgia (0.03 CI 95% −0.51, 0.56, P = 0.92) and for oral memantine in postamputation pain (0.38 CI 95% −0.21, 0.98, P = 0.21).
Conclusions. Based on this systematic review, no conclusions can yet be made about the efficacy of NMDA receptor antagonists on neuropathic pain. Additional RCTs in homogenous groups of pain patients are needed to explore the therapeutic potential of NMDA receptor antagonists in neuropathic pain.
Glucuronidation is a major detoxification pathway for endogenous and exogenous compounds in mammals that results in the intracellular formation of polar metabolites, requiring specialized ...transporters to cross biological membranes. By using morphine as a model aglycone, we demonstrate that multidrug resistance protein 3 (MRP3/ABCC3), a protein present in the basolateral membrane of polarized cells, transports morphine-3-glucuronide (M3G) and morphine-6-glucuronide in vitro. Mrp3(-/-)mice are unable to excrete M3G from the liver into the bloodstream, the major hepatic elimination route for this drug. This results in increased levels of M3G in liver and bile, a 50-fold reduction in the plasma levels of M3G, and in a major shift in the main disposition route for morphine and M3G, predominantly via the urine in WT mice but via the feces in Mrp3(-/-)mice. The pharamacokinetics of injected morphine-glucuronides are altered as well in the absence of Mrp3, and this results in a decreased antinociceptive potency of injected morphine-6-glucuronide.
To compare the costs of a strategy of patient controlled remifentanil versus epidural analgesia for pain relief in labour.
We performed a multicentre randomised controlled trial in 15 hospitals in ...the Netherlands, the RAVEL trial. Costs were analysed from a health care perspective alongside the RAVEL trial.
Pregnant women of intermediate to high risk beyond 32 weeks gestation who planned vaginal delivery.
Women were randomised before the onset of labour, to receive either patient controlled remifentanil or epidural analgesia when pain relief was requested during labour.
Primary outcome for effectiveness was satisfaction with pain relief, expressed as the area under the curve (AUC). A higher AUC represents higher satisfaction with pain relief. Here, we present an economic analysis from a health care perspective including costs from the start of labour to ten days postpartum. Health-care utilization was documented in the Case Report Forms and by administering an additional questionnaire.
The costs in the patient controlled remifentanil group (n = 687) and in the epidural group (n = 671) were €2900 versus €3185 respectively (mean difference of -€282 (95% CI -€611 to €47)). The (non-significant) higher costs in the epidural analgesia group could be mainly attributed to higher costs of neonatal admission.
From an economic perspective, there is no preferential pain treatment in labouring intermediate to high risk women. Since patient controlled remifentanil is not equivalent to epidural analgesia with respect to AUC for satisfaction with pain relief we recommend epidural analgesia as the method of choice. However, if appropriately counselled on effect and side effects there is, from an economic perspective, no reason to deny women patient controlled remifentanil.
The value of understanding patients' illness experience and social contexts for advancing medicine and clinical care is widely acknowledged. However, methodologies for rigorous and inclusive data ...gathering and integrative analysis of biomedical, cultural, and social factors are limited. In this paper, we propose a digital strategy for large-scale qualitative health research, using
(as a state of being, a communication mode or context, and a set of imaginative, expressive, and game-like activities) as a research method for recursive learning and action planning. Our proposal builds on Gregory Bateson's cybernetic approach to knowledge production. Using chronic pain as an example, we show how pragmatic, structural and cultural constraints that define the relationship of patients to the healthcare system can give rise to conflicted messaging that impedes inclusive health research. We then review existing literature to illustrate how different types of play including games, chatbots, virtual worlds, and creative art making can contribute to research in chronic pain. Inspired by Frederick Steier's application of Bateson's theory to designing a science museum, we propose DiSPORA (Digital Strategy for Play-Oriented Research and Action), a virtual citizen science laboratory which provides a framework for delivering health information, tools for play-based experimentation, and data collection capacity, but is flexible in allowing participants to choose the mode and the extent of their interaction. Combined with other data management platforms used in epidemiological studies of neuropsychiatric illness, DiSPORA offers a tool for large-scale qualitative research, digital phenotyping, and advancing personalized medicine.
Background:
Due the increasing need for storage of carbon dioxide (CO
2
) more individuals are prone to be exposed to high concentrations of CO
2
accidentally released into atmosphere, with ...deleterious consequences.
Methods:
We tested the effect of increasing CO
2
concentrations in humans (6–12%) and rats (10–50%) at varying inhalation times (10–60 min). In humans, a continuous positive airway pressure helmet was used to deliver the gas mixture to the participants. Unrestrained rats were exposed to CO
2
in a transparent chamber. In both species regular arterial blood gas samples were obtained. After the studies, the lungs of the animals were examined for macroscopic and microscopic abnormalities.
Results:
In humans, CO
2
concentrations of 9% inhaled for >10 min, and higher concentrations inhaled for <10 min were poorly or not tolerated due to exhaustion, anxiety, dissociation or acidosis (pH < 7.2), despite intact oxygenation. In rats, concentrations of 30% and higher were associated with CO
2
narcosis, epilepsy, poor oxygenation and, at 50% CO
2
, spontaneous death. Lung hemorrhage and edema were observed in the rats at inhaled concentrations of 30% and higher.
Conclusion:
This study provides essential insight into the occurrence of physiological changes in humans and fatalities in rats after acute exposure to high levels of CO
2
. Humans tolerate 9% CO
2
and retain their ability to function coherently for up to 10 min. These data support reconsideration of the current CO
2
levels (<7.5%) that pose a risk to exposed individuals (<7.5%) as determined by governmental agencies to ≤9%.
Abstract
Editor’s Perspective
What We Already Know about This Topic
The nociception level index (Medasense Biometrics Ltd., Ramat Gan, Israel), is a reliable measure of moderate to intense noxious ...stimulation during anesthesia and surgery
What This Article Tells Us That Is New
In a randomized trial in patients having major abdominal surgery, compared to standard practice, nociception level-guided analgesia resulted in 30% less intraoperative remifentanil consumption
Background
The multidimensional index of nociception, the nociception level, outperforms blood pressure and heart rate in detection of nociceptive events during anesthesia. We hypothesized that nociception level–guided analgesia reduces opioid consumption and suboptimal anesthesia events such as low blood pressure and use of vasoactive medication.
Methods
In this single-blinded randomized study, 80 American Society of Anesthesiologists class I–III adult patients of either sex, scheduled for major abdominal procedures under remifentanil/propofol anesthesia by target-controlled infusion, were included. During the procedure nociception level, noninvasive blood pressure, and heart rate were monitored. Patients were randomized to receive standard clinical care or nociception level–guided analgesia. In the nociception level–guided group, remifentanil concentration was reduced when index values were less than 10 or increased when values were above 25 for at least 1 min, in steps of 0.5 to 1.0 ng/ml. Propofol was titrated to bispectral index values between 45 and 55. The primary outcomes of the study were remifentanil and propofol consumption and inadequate anesthesia events.
Results
Compared with standard care, remifentanil administration was reduced in nociception level–guided patients from (mean ± SD) 0.119 ± 0.033 to 0.086 ± 0.032 μg · kg-1 · min-1 (mean difference, 0.039 μg · kg-1 · min-1; 95% CI, 0.025–0.052 μg · kg-1 · min-1; P < 0.001). Among nociception level–guided patients, 2 of 40 (5%) experienced a hypotensive event (mean arterial pressure values less than 55 mm Hg) versus 11 of 40 (28%) patients in the control group (relative risk, 0.271; 95% CI, 0.08–0.77; P = 0.006). In the nociception level–guided group, 16 of 40 (40%) patients received vasoactive medication versus 25 of 40 (63%) patients in the standard care group (relative risk, 0.64; 95% CI, 0.40–0.99; P = 0.044).
Conclusions
Nociception level-guided analgesia during major abdominal surgery resulted in 30% less remifentanil consumption.
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