- Anesthesia for Liver Transplantation
- Perioperative Recovery
Boards, Advisory Committees, Professional Organizations
Appointments and Promotions Committee, Stanford University School of Medicine (2014 - Present)
Board Certification: Anesthesia, Swiss Medical Federation (FMH), (1993)
Residency:University of Bern - Switzerland (1994) Switzerland
Residency:Regionalspital Burgdorf (1990) Switzerland
Medical Education:Berne University School of Medicine (1987) Switzerland
Current Research and Scholarly Interests
Our laboratory's current transformative research efforts focus on studying immune health in the context of surgery and anesthesia. Our interest stems from previous work elucidating the modulation of inflammatory responses by anesthetic and analgesic drugs.
The aim of studying immunity in patients undergoing surgery is to identify immune phenotypes predictive of aversive postoperative outcomes including protracted recovery and infection. Our major working hypotheses are that 1) specific immune phenotypes will predict the risk for developing postoperative complications, 2) immune phenotyping will lead to the discovery of mechanisms aggravating or alleviating such risk, and 3) gained knowledge will allow devising immune-modulatory strategies mitigating such risk. Mass cytometry (CyTOF), proteomics, and functional ex-vivo immune assays are the major molecular tools for the systems-based numerical and functional exploration of the circulating immune system.
Detection of Immune Changes as a Result of Surgical Trauma in Human Subject
Surgical trauma triggers a massive inflammatory response. Over time, both the innate and adaptive branches of the immune system are affected by surgical trauma. The purpose of this study to characterize the cellular and molecular mechanisms immune response to surgical trauma. Additionally, detailed information about patients' recovery profile will be recorded over a period of 6 weeks, with the eventual goal of linking immune responses to recovery profiles.
Human Mesenchymal Stem Cells For Acute Respiratory Distress Syndrome (START)
This is a Phase 2, randomized, double-blind, placebo-controlled, multi-center study to assess the safety and efficacy of a single dose of Allogeneic Bone Marrow-derived Human Mesenchymal Stem Cells infusion in patients with Acute Respiratory Distress Syndrome (ARDS). This study is the extension of the Phase 1 pilot study (NCT01775774). Patients will be randomized to receive Human Mesenchymal Stem Cells infusion or placebo in a 2:1 allocation. Patients will be followed daily for adverse events through day 28, death or hospital discharge, whichever occurs first. Vital status will be collected at 6 and 12 months after study enrollment.
Reevaluation Of Systemic Early Neuromuscular Blockade
This study evaluates whether giving a neuromuscular blocker (skeletal muscle relaxant) to a patient with acute respiratory distress syndrome will improve survival. Half of the patients will receive a neuromuscular blocker for two days and in the other half the use of neuromuscular blockers will be discouraged .
A Human In-vivo Model for the Detection of Inflammatory and Nociceptive Biomarkers
This study aims to establish a novel approach assisting the rational development of analgesic and anti-inflammatory drugs. In a first step we will test in healthy human volunteers whether proteins mediating inflammation and pain can be detected in an experimentally induced inflammatory skin lesion. Fluids that will be used to detect such proteins will be collected from the inflamed skin site via small porous catheters. We wish to establish the expression pattern of different proteins and correlate it with various tests assessing pain.
Stanford is currently not accepting patients for this trial. For more information, please contact Martin Angst, (650) 498 - 5109.
Assess Safety and Efficacy of ELAD (Extracorporeal Liver Assist System) in Subjects With Alcohol-Induced Liver Failure
The primary objective of the study is to evaluate safety and efficacy of ELAD® with respect to overall survival (OS) of subjects with a clinical diagnosis of alcohol-induced liver decompensation (AILD) up to at least Study Day 91, with follow-up Protocol VTI-208E providing additional survival data up to a maximum of 5 years that will be included, as available, through VTI-208 study termination (after the last surviving enrolled subject completes Study Day 91). Secondary objectives are to determine the proportion of survivors at Study Days 28 and 91. Exploratory objectives are to evaluate the ability of ELAD to stabilize liver function, measured using the Model for End Stage Liver Disease (MELD)-based time to progression (TTP) up to Study Day 91, and the proportion of progression-free survivors (PFS) up to Study Days 28 and 91. Progression is defined as death or the first observed increase of at least 5 points from End of Study Day 1 MELD score (for both the ELAD and Control groups) until at least 24 hours after the ELAD Treatment Period is ended (end of Day 7 for Controls) and up to both End of Study Days 28 and 91 following Randomization.
Stanford is currently not accepting patients for this trial.
Effects of a Peripheral Nerve Block on Biomarkers of Pain and Inflammation
The purpose of this study is to determine the effect of a local anesthetic nerve block on markers of inflammation and pain after a sunburn. This is important because it may provide information regarding the way that nerve blocks help with the treatment of pain and in particular provide preemptive analgesia.
Stanford is currently not accepting patients for this trial. For more information, please contact Martha Tingle, (650) 724 - 2742.
Evaluation of Immune Signaling Networks in Healthy Human Volunteers
The purpose of this study is to better understand whether and to what extent the activity of immune cells in blood varies over time under normal conditions as assessed in healthy subjects. Results of this study will provide the foundation for helping us evaluate changes in immune cell activities in response to surgery and drugs used in anesthesia. The overall purpose of our research is to understand immune health in the context of anesthesia and surgery.
Stanford is currently not accepting patients for this trial.
Evaluation of Propranolol's Effect on Pain and Inflammation.
Previous studies have shown that the beta-adrenergic system plays a role in processing pain and the expression of hyperalgesia. Recent studies have investigated the analgesic effects, and potential anti-hyperalgesic effects (using a model of opioid induced (OIH) hyperalgesia) of propranolol, a beta adrenergic antagonist. We plan to further investigate the analgesic effects, and the potential anti inflammatory effects, of propranolol and compare those effects to alfentanil, an opioid of known effect, and placebo
Stanford is currently not accepting patients for this trial. For more information, please contact Martha Tingle, (650) 724 - 2742.
Heritability of Opioid Effects: A Twin Study
Proposed twin study will test to what degree inter-individual differences in pain sensitivity and amount of pain relief in response to opioid therapy are inherited or alternatively, are due to environmental factors. This knowledge is important to guide future studies trying to explain such inter-individual differences. For example, finding that differences are largely due to environmental factors would discourage genomic studies and emphasize epidemiological studies.
Stanford is currently not accepting patients for this trial. For more information, please contact Martha Tingle, (650) 724 - 2742.
Hypertonic Saline as Therapy for Pediatric Concussion
This single center, blinded, randomized controlled trial evaluated the use of hypertonic saline versus normal saline as therapy for the symptoms of pediatric concussion post head injury. The study hypothesis was that hypertonic saline would improve symptoms of pediatric concussion following head injury as measured on the self-reported Wong Baker Faces Pain Scale as compared to normal saline. The null hypothesis was that there would be no difference in change of reported pain in either group.
Stanford is currently not accepting patients for this trial.
Immune-modulation Effects of an Arginine Rich Nutritional Supplement in Surgical Patients
The primary objective of this study is to characterize the immune-modulatory effects of arginine-rich nutritional supplements in patients undergoing surgery. Numerical and functional changes of all circulating immune cells will be assessed with mass cytometry.
Stanford is currently not accepting patients for this trial. For more information, please contact Julian Silva, MA, 650-724-9341.
Optimization of Time-of-Flight Mass Cytometry (CyTOF) Analysis for Evaluation of Immune Changes Following Surgery
Surgical trauma triggers a massive inflammatory response. Over time, both the innate and adaptive branches of the immune system are affected by surgical trauma. The purpose of this study is to use a single cell flow cytometry approach to characterize the cellular and molecular mechanisms involved in the inflammatory response to surgical trauma.
Stanford is currently not accepting patients for this trial.
Study of Experimental Models of Pain and Inflammation.
The experimental pain model studied in this proposal show characteristics of an inflamed wound with a pro-inflammatory response. This study will help discover candidate genetic and/or proteomic pain biomarkers that could provide objective and mechanism based tests to diagnose, monitor or quantify pain. We also hope to determine the measurable effects of a known non-steroidal anti-inflammatory drug (NSAID) on biomarkers of pain and inflammation.
Stanford is currently not accepting patients for this trial. For more information, please contact Martin Angst, (650) 498 - 5109.
- Independent Studies (5)
Postdoctoral Research Mentor
GateFinder: Projection-based Gating Strategy Optimization for Flow and Mass Cytometry.
Bioinformatics (Oxford, England)
High-parameter single-cell technologies can reveal novel cell populations of interest, but studying or validating these populations using lower-parameter methods remains challenging.Here we present GateFinder, an algorithm that enriches high-dimensional cell types with simple, stepwise polygon gates requiring only two markers at a time. A series of case studies of complex cell types illustrates how simplified enrichment strategies can enable more efficient assays, reveal novel biomarkers, and clarify underlying biology.The GateFinder algorithm is implemented as a free and open-source package for BioConductor: https://firstname.lastname@example.org or email@example.com.Supplementary data are available at Bioinformatics online.
View details for DOI 10.1093/bioinformatics/bty430
View details for PubMedID 29850785
Best Practices for Postoperative Brain Health: Recommendations From the Fifth International Perioperative Neurotoxicity Working Group.
Anesthesia and analgesia
As part of the American Society of Anesthesiology Brain Health Initiative goal of improving perioperative brain health for older patients, over 30 experts met at the fifth International Perioperative Neurotoxicity Workshop in San Francisco, CA, in May 2016, to discuss best practices for optimizing perioperative brain health in older adults (ie, >65 years of age). The objective of this workshop was to discuss and develop consensus solutions to improve patient management and outcomes and to discuss what older adults should be told (and by whom) about postoperative brain health risks. Thus, the workshop was provider and patient oriented as well as solution focused rather than etiology focused. For those areas in which we determined that there were limited evidence-based recommendations, we identified knowledge gaps and the types of scientific knowledge and investigations needed to direct future best practice. Because concerns about perioperative neurocognitive injury in pediatric patients are already being addressed by the SmartTots initiative, our workshop discussion (and thus this article) focuses specifically on perioperative cognition in older adults. The 2 main perioperative cognitive disorders that have been studied to date are postoperative delirium and cognitive dysfunction. Postoperative delirium is a syndrome of fluctuating changes in attention and level of consciousness that occurs in 20%-40% of patients >60 years of age after major surgery and inpatient hospitalization. Many older surgical patients also develop postoperative cognitive deficits that typically last for weeks to months, thus referred to as postoperative cognitive dysfunction. Because of the heterogeneity of different tools and thresholds used to assess and define these disorders at varying points in time after anesthesia and surgery, a recent article has proposed a new recommended nomenclature for these perioperative neurocognitive disorders. Our discussion about this topic was organized around 4 key issues: preprocedure consent, preoperative cognitive assessment, intraoperative management, and postoperative follow-up. These 4 issues also form the structure of this document. Multiple viewpoints were presented by participants and discussed at this in-person meeting, and the overall group consensus from these discussions was then drafted by a smaller writing group (the 6 primary authors of this article) into this manuscript. Of course, further studies have appeared since the workshop, which the writing group has incorporated where appropriate. All participants from this in-person meeting then had the opportunity to review, edit, and approve this final manuscript; 1 participant did not approve the final manuscript and asked for his/her name to be removed.
View details for DOI 10.1213/ANE.0000000000003841
View details for PubMedID 30303868
Oxytocin and Migraine Headache
2017; 57: 64-75
This article reviews material presented at the 2016 Scottsdale Headache Symposium. This presentation provided scientific results and rationale for the use of intranasal oxytocin for the treatment of migraine headache. Results from preclinical experiments are reviewed, including in vitro experiments demonstrating that trigeminal ganglia neurons possess oxytocin receptors and are inhibited by oxytocin. Furthermore, most of these same neurons contain CGRP, the release of which is inhibited by oxytocin. Results are also presented which demonstrate that nasal oxytocin inhibits responses of trigeminal nucleus caudalis neurons to noxious stimulation using either noxious facial shock or nitroglycerin infusion. These studies led to testing the analgesic effect of intranasal oxytocin in episodic migraineurs-studies which did not meet their primary endpoint of pain relief at 2 h, but which were highly informative and led to additional rat studies wherein inflammation was found to dramatically upregulate the number of oxytocin receptors available on trigeminal neurons. This importance of inflammation was supported by a series of in vivo rat behavioral studies, which demonstrated a clear craniofacial analgesic effect when a pre-existing inflammatory injury was present. The significance of inflammation was further solidified by a small single-dose clinical study, which showed analgesic efficacy that was substantially stronger in chronic migraine patients that had not taken an anti-inflammatory drug within 24 h of oxytocin dosing. A follow-on open label study examining effects of one month of intranasal oxytocin dosing did show a reduction in pain, but a more impressive decrease in the frequency of headaches in both chronic and high frequency episodic migraineurs. This study led to a multicountry double blind, placebo controlled study studying whether, over 2 months of dosing, "as needed" dosing of intranasal oxytocin by chronic and high frequency migraineurs would reduce the frequency of their headaches compared to a 1-month baseline period. This study failed to meet its primary endpoint, due to an extraordinarily high placebo rate in the country of most of the patients (Chile), but was also highly informative, showing strong results in other countries and strong post hoc indications of efficacy. The results provide a strong argument for further development of intranasal oxytocin for migraine prophylaxis.
View details for DOI 10.1111/head.13082
View details for Web of Science ID 000401012800005
View details for PubMedID 28485846
Human umbilical cord plasma proteins revitalize hippocampal function in aged mice
2017; 544 (7651): 488-?
Ageing drives changes in neuronal and cognitive function, the decline of which is a major feature of many neurological disorders. The hippocampus, a brain region subserving roles of spatial and episodic memory and learning, is sensitive to the detrimental effects of ageing at morphological and molecular levels. With advancing age, synapses in various hippocampal subfields exhibit impaired long-term potentiation, an electrophysiological correlate of learning and memory. At the molecular level, immediate early genes are among the synaptic plasticity genes that are both induced by long-term potentiation and downregulated in the aged brain. In addition to revitalizing other aged tissues, exposure to factors in young blood counteracts age-related changes in these central nervous system parameters, although the identities of specific cognition-promoting factors or whether such activity exists in human plasma remains unknown. We hypothesized that plasma of an early developmental stage, namely umbilical cord plasma, provides a reservoir of such plasticity-promoting proteins. Here we show that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice. Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appears in the brain after systemic administration and increases synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma. We find that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for previously unknown roles for TIMP2 in normal hippocampal function. Our findings reveal that human cord plasma contains plasticity-enhancing proteins of high translational value for targeting ageing- or disease-associated hippocampal dysfunction.
View details for DOI 10.1038/nature22067
View details for Web of Science ID 000400051900045
View details for PubMedID 28424512
Multicenter Systems Analysis of Human Blood Reveals Immature Neutrophils in Males and During Pregnancy.
Journal of immunology
2017; 198 (6): 2479-2488
Despite clear differences in immune system responses and in the prevalence of autoimmune diseases between males and females, there is little understanding of the processes involved. In this study, we identified a gene signature of immature-like neutrophils, characterized by the overexpression of genes encoding for several granule-containing proteins, which was found at higher levels (up to 3-fold) in young (20-30 y old) but not older (60 to >89 y old) males compared with females. Functional and phenotypic characterization of peripheral blood neutrophils revealed more mature and responsive neutrophils in young females, which also exhibited an elevated capacity in neutrophil extracellular trap formation at baseline and upon microbial or sterile autoimmune stimuli. The expression levels of the immature-like neutrophil signature increased linearly with pregnancy, an immune state of increased susceptibility to certain infections. Using mass cytometry, we also find increased frequencies of immature forms of neutrophils in the blood of women during late pregnancy. Thus, our findings show novel sex differences in innate immunity and identify a common neutrophil signature in males and in pregnant women.
View details for DOI 10.4049/jimmunol.1601855
View details for PubMedID 28179497
A Proteomic Clock of Human Pregnancy.
American journal of obstetrics and gynecology
Early detection of maladaptive processes underlying pregnancy-related pathologies is desirable, as it will enable targeted interventions ahead of clinical manifestations. The quantitative analysis of plasma proteins features prominently among molecular approaches used to detect deviations from normal pregnancy. However, derivation of proteomic signatures sufficiently predictive of pregnancy-related outcomes has been challenging. An important obstacle hindering such efforts were limitations in assay technology, which prevented the broad examination of the plasma proteome.The recent availability of a highly-multiplexed platform affording the simultaneous measurement of 1,310 plasma proteins opens the door for a more explorative approach. The major aim of this study was to examine whether analysis of plasma collected during gestation of term pregnancy would allow identifying a set of proteins that tightly track gestational age. Establishing precisely-timed plasma proteomic changes during term pregnancy is a critical step in identifying deviations from regular patterns due to fetal and maternal maladaptations. A second aim was to gain insight into functional attributes of identified proteins, and link such attributes to relevant immunological changes.Pregnant women participated in this longitudinal study. In two subsequent subsets of 21 (training cohort) and 10 (validation cohort) women, specific blood specimens were collected during the first (7-14 wks), second (15-20 wks), and third (24-32 wks) trimesters, and 6 wks post-partum for analysis with a highly-multiplexed aptamer-based platform. An elastic net algorithm was applied to infer a proteomic model predicting gestational age. A bootstrapping procedure and piece-wise regression analysis was used to extract the minimum number of proteins required for predicting gestational age without compromising predictive power. Gene ontology analysis was applied to infer enrichment of molecular functions among proteins included in the proteomic model. Changes in abundance of proteins with such functions were linked to immune features predictive of gestational age at the time of sampling in pregnancies delivering at term.An independently validated model consisting of 74 proteins strongly predicted gestational age (p = 3.8x10-14, R = 0.97). The model could be reduced to eight proteins without losing its predictive power (p = 1.7x10-3, R = 0.91). The three top ranked proteins were glypican 3, chorionic somatomammotropin hormone, and granulins. Proteins activating the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway were enriched in the proteomic model, chorionic somatomammotropin hormone being the top ranked protein. Abundance of chorionic somatomammotropin hormone strongly correlated with STAT5 signaling activity in CD4 T cells, the endogenous cell-signaling event most predictive of gestational age.Results indicate that precisely timed changes in the plasma proteome during term pregnancy mirror a "proteomic clock". Importantly, the combined use of several plasma proteins was required for accurate prediction. The exciting promise of such a "clock" is that deviations from its regular chronological profile may assist in the early diagnoses of pregnancy-relate pathologies and point to underlying pathophysiology. Functional analysis of the proteomic model generated the novel hypothesis that somatomammotropin hormone may critically regulate T-cell function during pregnancy.
View details for DOI 10.1016/j.ajog.2017.12.208
View details for PubMedID 29277631
An immune clock of human pregnancy.
2017; 2 (15)
The maintenance of pregnancy relies on finely tuned immune adaptations. We demonstrate that these adaptations are precisely timed, reflecting an immune clock of pregnancy in women delivering at term. Using mass cytometry, the abundance and functional responses of all major immune cell subsets were quantified in serial blood samples collected throughout pregnancy. Cell signaling-based Elastic Net, a regularized regression method adapted from the elastic net algorithm, was developed to infer and prospectively validate a predictive model of interrelated immune events that accurately captures the chronology of pregnancy. Model components highlighted existing knowledge and revealed previously unreported biology, including a critical role for the interleukin-2-dependent STAT5ab signaling pathway in modulating T cell function during pregnancy. These findings unravel the precise timing of immunological events occurring during a term pregnancy and provide the analytical framework to identify immunological deviations implicated in pregnancy-related pathologies.
View details for DOI 10.1126/sciimmunol.aan2946
View details for PubMedID 28864494
- Deep Immune Profiling in Trauma and Sepsis: Flow Is the Way to Go! Critical care medicine 2017; 45 (9): 1577–78
- Risky Business: Meeting the Structural Needs of Transdisciplinary Science. The Journal of pediatrics 2017; 191: 255–58
Deep Immune Profiling of an Arginine-Enriched Nutritional Intervention in Patients Undergoing Surgery.
Journal of immunology (Baltimore, Md. : 1950)
Application of high-content immune profiling technologies has enormous potential to advance medicine. Whether these technologies reveal pertinent biology when implemented in interventional clinical trials is an important question. The beneficial effects of preoperative arginine-enriched dietary supplements (AES) are highly context specific, as they reduce infection rates in elective surgery, but possibly increase morbidity in critically ill patients. This study combined single-cell mass cytometry with the multiplex analysis of relevant plasma cytokines to comprehensively profile the immune-modifying effects of this much-debated intervention in patients undergoing surgery. An elastic net algorithm applied to the high-dimensional mass cytometry dataset identified a cross-validated model consisting of 20 interrelated immune features that separated patients assigned to AES from controls. The model revealed wide-ranging effects of AES on innate and adaptive immune compartments. Notably, AES increased STAT1 and STAT3 signaling responses in lymphoid cell subsets after surgery, consistent with enhanced adaptive mechanisms that may protect against postsurgical infection. Unexpectedly, AES also increased ERK and P38 MAPK signaling responses in monocytic myeloid-derived suppressor cells, which was paired with their pronounced expansion. These results provide novel mechanistic arguments as to why AES may exert context-specific beneficial or adverse effects in patients with critical illness. This study lays out an analytical framework to distill high-dimensional datasets gathered in an interventional clinical trial into a fairly simple model that converges with known biology and provides insight into novel and clinically relevant cellular mechanisms.
View details for DOI 10.4049/jimmunol.1700421
View details for PubMedID 28794234
Mapping the Fetomaternal Peripheral Immune System at Term Pregnancy.
Journal of immunology
Preterm labor and infections are the leading causes of neonatal deaths worldwide. During pregnancy, immunological cross talk between the mother and her fetus is critical for the maintenance of pregnancy and the delivery of an immunocompetent neonate. A precise understanding of healthy fetomaternal immunity is the important first step to identifying dysregulated immune mechanisms driving adverse maternal or neonatal outcomes. This study combined single-cell mass cytometry of paired peripheral and umbilical cord blood samples from mothers and their neonates with a graphical approach developed for the visualization of high-dimensional data to provide a high-resolution reference map of the cellular composition and functional organization of the healthy fetal and maternal immune systems at birth. The approach enabled mapping of known phenotypical and functional characteristics of fetal immunity (including the functional hyperresponsiveness of CD4(+) and CD8(+) T cells and the global blunting of innate immune responses). It also allowed discovery of new properties that distinguish the fetal and maternal immune systems. For example, examination of paired samples revealed differences in endogenous signaling tone that are unique to a mother and her offspring, including increased ERK1/2, MAPK-activated protein kinase 2, rpS6, and CREB phosphorylation in fetal Tbet(+)CD4(+) T cells, CD8(+) T cells, B cells, and CD56(lo)CD16(+) NK cells and decreased ERK1/2, MAPK-activated protein kinase 2, and STAT1 phosphorylation in fetal intermediate and nonclassical monocytes. This highly interactive functional map of healthy fetomaternal immunity builds the core reference for a growing data repository that will allow inferring deviations from normal associated with adverse maternal and neonatal outcomes.
View details for PubMedID 27793998
View details for PubMedCentralID PMC5125527
Oxytocin receptor: Expression in the trigeminal nociceptive system and potential role in the treatment of headache disorders.
2016; 36 (10): 943-950
Our studies investigated the location of oxytocin receptors in the peripheral trigeminal sensory system and determined their role in trigeminal pain.Oxytocin receptor expression and co-localization with calcitonin gene-related peptide was investigated in rat trigeminal ganglion using immunohistochemistry. Enzyme-linked immunosorbent assay was used to determine the effects of facial electrocutaneous stimulation and adjuvant-induced inflammation of the temporomandibular joint on oxytocin receptor expression in the trigeminal ganglion. Finally, the effects of oxytocin on capsaicin-induced calcitonin gene-related peptide release from dural nociceptors were investigated using isolated rat dura mater.Oxytocin receptor immunoreactivity was present in rat trigeminal neurons. The vast majority of oxytocin receptor immunoreactive neurons co-expressed calcitonin gene-related peptide. Both electrocutaneous stimulation and adjuvant-induced inflammation led to a rapid upregulation of oxytocin receptor protein expression in trigeminal ganglion neurons. Oxytocin significantly and dose-dependently decreased capsaicin-induced calcitonin gene-related peptide release from dural nociceptors.Oxytocin receptor expression in calcitonin gene-related peptide containing trigeminal ganglion neurons, and the blockade of calcitonin gene-related peptide release from trigeminal dural afferents suggests that activation of these receptors may provide therapeutic benefit in patients with migraine and other primary headache disorders.
View details for DOI 10.1177/0333102415618615
View details for PubMedID 26590611
Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations
2016; 157 (9): 1851-1871
There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for "precision medicine" or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain.
View details for DOI 10.1097/j.pain.0000000000000602
View details for Web of Science ID 000386014700003
View details for PubMedID 27152687
- In Reply. Anesthesiology 2016; 124 (6): 1414-1415
Patient-specific Immune States before Surgery Are Strong Correlates of Surgical Recovery
2015; 123 (6): 1241-1255
Recovery after surgery is highly variable. Risk-stratifying patients based on their predicted recovery profile will afford individualized perioperative management strategies. Recently, application of mass cytometry in patients undergoing hip arthroplasty revealed strong immune correlates of surgical recovery in blood samples collected shortly after surgery. However, the ability to interrogate a patient's immune state before surgery and predict recovery is highly desirable in perioperative medicine.To evaluate a patient's presurgical immune state, cell-type-specific intracellular signaling responses to ex vivo ligands (lipopolysaccharide, interleukin [IL]-6, IL-10, and IL-2/granulocyte macrophage colony-stimulating factor) were quantified by mass cytometry in presurgical blood samples. Selected ligands modulate signaling processes perturbed by surgery. Twenty-three cell surface and 11 intracellular markers were used for the phenotypic and functional characterization of major immune cell subsets. Evoked immune responses were regressed against patient-centered outcomes, contributing to protracted recovery including functional impairment, postoperative pain, and fatigue.Evoked signaling responses varied significantly and defined patient-specific presurgical immune states. Eighteen signaling responses correlated significantly with surgical recovery parameters (|R| = 0.37 to 0.70; false discovery rate < 0.01). Signaling responses downstream of the toll-like receptor 4 in cluster of differentiation (CD) 14 monocytes were particularly strong correlates, accounting for 50% of observed variance. Immune correlates identified in presurgical blood samples mirrored correlates identified in postsurgical blood samples.Convergent findings in pre- and postsurgical analyses provide validation of reported immune correlates and suggest a critical role of the toll-like receptor 4 signaling pathway in monocytes for the clinical recovery process. The comprehensive assessment of patients' preoperative immune state is promising for predicting important recovery parameters and may lead to clinical tests using standard flow cytometry.
View details for DOI 10.1097/ALN.0000000000000887
View details for Web of Science ID 000365483600009
View details for PubMedID 26655308
View details for PubMedCentralID PMC4681408
Implementing Mass Cytometry at the Bedside to Study the Immunological Basis of Human Diseases: Distinctive Immune Features in Patients with a History of Term or Preterm Birth
CYTOMETRY PART A
2015; 87A (9): 817-829
Single-cell technologies have immense potential to shed light on molecular and biological processes that drive human diseases. Mass cytometry (or Cytometry by Time Of Flight mass spectrometry, CyTOF) has already been employed in clinical studies to comprehensively survey patients' circulating immune system. As interest in the "bedside" application of mass cytometry is growing, the delineation of relevant methodological issues is called for. This report uses a newly generated dataset to discuss important methodological considerations when mass cytometry is implemented in a clinical study. Specifically, the use of whole blood samples versus peripheral blood mononuclear cells (PBMCs), design of mass-tagged antibody panels, technical and analytical implications of sample barcoding, and application of traditional and unsupervised approaches to analyze high-dimensional mass cytometry datasets are discussed. A mass cytometry assay was implemented in a cross-sectional study of 19 women with a history of term or preterm birth to determine whether immune traits in peripheral blood differentiate the two groups in the absence of pregnancy. Twenty-seven phenotypic and 11 intracellular markers were simultaneously analyzed in whole blood samples stimulated with lipopolysaccharide (LPS at 0, 0.1, 1, 10, and 100 ng mL(-1) ) to examine dose-dependent signaling responses within the toll-like receptor 4 (TLR4) pathway. Complementary analyses, grounded in traditional or unsupervised gating strategies of immune cell subsets, indicated that the prpS6 and pMAPKAPK2 responses in classical monocytes are accentuated in women with a history of preterm birth (FDR<1%). The results suggest that women predisposed to preterm birth may be prone to mount an exacerbated TLR4 response during the course of pregnancy. This important hypothesis-generating finding points to the power of single-cell mass cytometry to detect biologically important differences in a relatively small patient cohort. © 2015 International Society for Advancement of Cytometry.
View details for DOI 10.1002/cyto.a.22720
View details for Web of Science ID 000360590500009
- Intraoperative Use of Remifentanil for TIVA: Postoperative Pain, Acute Tolerance, and Opioid-Induced Hyperalgesia JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA 2015; 29: S16-S22
- Editorial comment: challenges in the perioperative management of the patient receiving extended-release naltrexone. A & A case reports 2014; 3 (11): 145-?
Clinical recovery from surgery correlates with single-cell immune signatures.
Science translational medicine
2014; 6 (255): 255ra131-?
Delayed recovery from surgery causes personal suffering and substantial societal and economic costs. Whether immune mechanisms determine recovery after surgical trauma remains ill-defined. Single-cell mass cytometry was applied to serial whole-blood samples from 32 patients undergoing hip replacement to comprehensively characterize the phenotypic and functional immune response to surgical trauma. The simultaneous analysis of 14,000 phosphorylation events in precisely phenotyped immune cell subsets revealed uniform signaling responses among patients, demarcating a surgical immune signature. When regressed against clinical parameters of surgical recovery, including functional impairment and pain, strong correlations were found with STAT3 (signal transducer and activator of transcription), CREB (adenosine 3',5'-monophosphate response element-binding protein), and NF-κB (nuclear factor κB) signaling responses in subsets of CD14(+) monocytes (R = 0.7 to 0.8, false discovery rate <0.01). These sentinel results demonstrate the capacity of mass cytometry to survey the human immune system in a relevant clinical context. The mechanistically derived immune correlates point to diagnostic signatures, and potential therapeutic targets, that could postoperatively improve patient recovery.
View details for DOI 10.1126/scitranslmed.3009701
View details for PubMedID 25253674
- Analgesic and sympatholytic effects of low-dose intrathecal clonidine compared with bupivacaine: a doseresponse study in female volunteers BRITISH JOURNAL OF ANAESTHESIA 2013; 111 (2): 256-?
Changes resembling complex regional pain syndrome following surgery and immobilization.
journal of pain
2013; 14 (5): 516-524
The study of complex regional pain syndrome (CRPS) in humans is complicated by inhomogeneities in available study cohorts. We hoped to characterize early CRPS-like features in patients undergoing hand surgery. Forty-three patients were recruited from a hand surgery clinic that had elective surgeries followed by cast immobilization. On the day of cast removal, patients were assessed for vasomotor, sudomotor, and trophic changes, and edema and pain sensitization using quantitative sensory testing. Pain intensity was assessed at the time of cast removal and after 1 additional month, as was the nature of the pain using the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS). Skin biopsies were harvested for the analysis of expression of inflammatory mediators. We identified vascular and trophic changes in the surgical hands of most patients. Increased sensitivity to punctate, pressure, and cold stimuli were observed commonly as well. Moreover, levels of IL-6, TNF-alpha, and the mast cell marker tryptase were elevated in the skin of hands ipsilateral to surgery. Moderate-to-severe pain persisted in the surgical hands for up to 1 month after cast removal. Exploratory analyses suggested interrelationships between the physical, quantitative sensory testing, and gene expression changes and pain-related outcomes.This study has identified CPRS-like features in the limbs of patients undergoing surgery followed by immobilization. Further studies using this population may be useful in refining our understanding of CRPS mechanisms and treatments for this condition.
View details for DOI 10.1016/j.jpain.2013.01.004
View details for PubMedID 23453564
Bayesian methods to determine performance differences and to quantify variability among centers in multi-center trials: the IHAST trial
BMC MEDICAL RESEARCH METHODOLOGY
To quantify the variability among centers and to identify centers whose performance are potentially outside of normal variability in the primary outcome and to propose a guideline that they are outliers.Novel statistical methodology using a Bayesian hierarchical model is used. Bayesian methods for estimation and outlier detection are applied assuming an additive random center effect on the log odds of response: centers are similar but different (exchangeable). The Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) is used as an example. Analyses were adjusted for treatment, age, gender, aneurysm location, World Federation of Neurological Surgeons scale, Fisher score and baseline NIH stroke scale scores. Adjustments for differences in center characteristics were also examined. Graphical and numerical summaries of the between-center standard deviation (sd) and variability, as well as the identification of potential outliers are implemented.In the IHAST, the center-to-center variation in the log odds of favorable outcome at each center is consistent with a normal distribution with posterior sd of 0.538 (95% credible interval: 0.397 to 0.726) after adjusting for the effects of important covariates. Outcome differences among centers show no outlying centers. Four potential outlying centers were identified but did not meet the proposed guideline for declaring them as outlying. Center characteristics (number of subjects enrolled from the center, geographical location, learning over time, nitrous oxide, and temporary clipping use) did not predict outcome, but subject and disease characteristics did.Bayesian hierarchical methods allow for determination of whether outcomes from a specific center differ from others and whether specific clinical practices predict outcome, even when some centers/subgroups have relatively small sample sizes. In the IHAST no outlying centers were found. The estimated variability between centers was moderately large.
View details for DOI 10.1186/1471-2288-13-5
View details for Web of Science ID 000316227900001
View details for PubMedID 23324207
View details for PubMedCentralID PMC3599203
- In reply. Anesthesiology 2013; 118 (1): 230-231
Postoperative Subcutaneous Instillation of Low-Dose Ketorolac But Not Hydromorphone Reduces Wound Exudate Concentrations of Interleukin-6 and Interleukin-10 and Improves Analgesia Following Cesarean Delivery
JOURNAL OF PAIN
2013; 14 (1): 48-56
The objectives of this study were to test the effects of low-dose ketorolac and hydromorphone added to continuous local anesthetic wound instillation on surgical-site inflammatory mediators, postoperative pain, and opioid consumption. Sixty healthy women undergoing cesarean delivery were enrolled in this randomized, double-blinded study. Patients were randomized to receive a subcutaneous wound instillation of bupivacaine .5% at 10 mg/hour (active control), bupivacaine .5% with ketorolac .6 mg/hour, or bupivacaine .5% with hydromorphone .04 mg/hour for 48 hours postcesarean. Wound exudate was sampled at 4, 24, and 48 hours postcesarean and assayed for interleukins IL-1β, IL-2, IL-6, IL-8, IL-10, and IL-12, tumor necrosis factor (TNF-α), interferon (INF-γ), and granulocyte-macrophage colony stimulating factor (GM-CSF). The addition of ketorolac to bupivacaine significantly decreased IL-6 (P = .012) and IL-10 (P = .005) compared to plain bupivacaine. Ketorolac, but not hydromorphone, was associated with a decrease in pain (P = .018) and analgesic use (P = .020) following cesarean delivery. Our results are compatible with the view that significant analgesics effects are mediated through local modulation of inflammatory events. Low-dose ketorolac administered into surgical wounds exert significant anti-inflammatory and analgesic effects and may be a valuable analgesic alternative to systemic nonsteroidal anti-inflammatories (NSAIDs) but with potentially fewer side effects.This article demonstrates that low-dose ketorolac administered into wounds modulates local inflammatory events, decreases postoperative pain, and reduces opioid consumption. These results suggest that administration of NSAIDs into surgical wounds may be an analgesic alternative to higher systemic dosing of NSAIDs.
View details for DOI 10.1016/j.jpain.2012.10.002
View details for Web of Science ID 000314081100006
View details for PubMedID 23218935
- Collecting And Measuring Wound Exudate Biochemical Mediators In Surgical Wounds JOVE-JOURNAL OF VISUALIZED EXPERIMENTS 2012
Analgesic tolerance without demonstrable opioid-induced hyperalgesia: a double-blinded, randomized, placebo-controlled trial of sustained-release morphine for treatment of chronic nonradicular low-back pain
2012; 153 (8): 1583-1592
Although often successful in acute settings, long-term use of opioid pain medications may be accompanied by waning levels of analgesic response not readily attributable to advancing underlying disease, necessitating dose escalation to attain pain relief. Analgesic tolerance, and more recently opioid-induced hyperalgesia, have been invoked to explain such declines in opioid effectiveness over time. Because both phenomena result in inadequate analgesia, they are difficult to distinguish in a clinical setting. Patients with otherwise uncomplicated low-back pain were titrated to comfort or dose-limiting side effects in a prospective, randomized, double-blind, placebo-controlled clinical trial using sustained-release morphine or weight-matched placebo capsules for 1 month. A total of 103 patients completed the study, with an average end titration dose of 78 mg morphine/d. After 1 month, the morphine-treated patients developed tolerance to the analgesic effects of remifentanil, but did not develop opioid-induced hyperalgesia. On average, these patients experienced a 42% reduction in analgesic potency. The morphine-treated patients experienced clinically relevant improvements in pain relief, as shown by a 44% reduction in average visual analogue scale pain levels and a 31% improvement in functional ability. The differences in visual analogue scale pain levels (P = .003) and self-reported disability (P = .03) between both treatment groups were statistically significant. After 1 month of oral morphine therapy, patients with chronic low-back pain developed tolerance but not opioid-induced hyperalgesia. Improvements in pain and functional ability were observed.
View details for DOI 10.1016/j.pain.2012.02.028
View details for Web of Science ID 000306240100011
View details for PubMedID 22704854
Pain sensitivity and opioid analgesia: A pharmacogenomic twin study
2012; 153 (7): 1397-1409
Opioids are the cornerstone medication for the management of moderate to severe pain. Unfortunately, vast inter-individual differences in dose requirements complicate their effective and safe clinical use. Mechanisms underlying such differences are incompletely understood, are likely multifactorial, and include genetic and environmental contributions. While accumulating evidence suggests that variants of several genes account for some of the observed response variance, the relative contribution of these factors remains unknown. This study used a twin paradigm to provide a global estimate of the genetic and environmental contributions to inter-individual differences in pain sensitivity and analgesic opioid effects. Eighty one monozygotic and 31 dizygotic twin pairs successfully underwent a computer-controlled infusion with the μ-opioid agonist alfentanil in a single occasion, randomized, double-blind and placebo-controlled study design. Pain sensitivity and analgesic effects were assessed with experimental heat and cold pressor pain models along with important covariates including demographic factors, depression, anxiety, and sleep quality. Significant heritability was detected for cold pressor pain tolerance and opioid-mediated elevations in heat and cold pressor pain thresholds. Genetic effects accounted for 12-60% of the observed response variance. Significant familial effects accounting for 24-32% of observed variance were detected for heat and cold pressor pain thresholds and opioid-mediated elevation in cold pressor pain tolerance. Significant covariates included age, gender, race, education, and anxiety. Results provide a strong rationale for more detailed molecular genetic studies to elucidate mechanisms underlying inter-individual differences in pain sensitivity and analgesic opioid responses. Such studies will require careful consideration of the studied pain phenotype.
View details for DOI 10.1016/j.pain.2012.02.022
View details for Web of Science ID 000305423700014
View details for PubMedID 22444188
View details for PubMedCentralID PMC3377769
Aversive and Reinforcing Opioid Effects A Pharmacogenomic Twin Study
2012; 117 (1): 22-37
The clinical utility of opioids is limited by adverse drug effects including respiratory depression, sedation, nausea, and pruritus. In addition, abuse of prescription opioids is problematic. Gaining a better understanding of the genetic and environmental mechanisms contributing to an individual's susceptibility to adverse opioid effects is essential to identify patients at risk.A classic twin study paradigm provided estimates for the genetic and familial (genetic and/or shared environment) contribution to acute adverse and affective opioid responses, all secondary outcomes of a larger dataset. One hundred twenty-one twin pairs were recruited in a single occasion, randomized, double-blind, and placebo-controlled study. The μ-opioid receptor agonist alfentanil and saline placebo were administered as target-controlled infusions under carefully monitored laboratory conditions. Measured outcomes included respiratory depression, sedation, nausea, pruritus, drug liking, and drug disliking. Demographic information was collected, and aspects of mood and sleep were evaluated.Significant heritability was detected for respiratory depression (30%), nausea (59%), and drug disliking (36%). Significant familial effects were detected for sedation (29%), pruritus (38%), dizziness (32%), and drug liking (26%). Significant covariates included age, sex, race, ethnicity, education, mood, and depression. Covariates affected sedation, pruritus, drug liking and disliking, and dizziness.This study demonstrates that large-scale efforts to collect quantitative and well-defined opioid response data are not only feasible but also produce data that are suitable for genetic analysis. Genetic, environmental, and demographic factors work together to control adverse and reinforcing opioid responses, but contribute differently to specific responses.
View details for Web of Science ID 000305672800007
View details for PubMedID 22713632
View details for PubMedCentralID PMC3428265
Sensitivity of gait parameters to the effects of anti-inflammatory and opioid treatments in knee osteoarthritis patients
JOURNAL OF ORTHOPAEDIC RESEARCH
2012; 30 (7): 1118-1124
The study aim was to address the need for objective markers of pain-modifying interventions by testing the hypothesis that selective gait measures of knee joint loading can distinguish differences between non-steroidal anti-inflammatory (NSAID), analgesic treatment (opioid-receptor agonist), and placebo in patients medial knee osteoarthritis (OA). A randomized, single-blind washout, double-blind treatment, double-dummy cross-over trial using three treatment arms placebo, opioid (Oxycodone), and NSAID (Celecoxib) in medial compartment knee OA patients. Six patients with Kellgren-Lawrence radiographic severity grades of 2 or 3 completed six testing sessions (gait and pain assessment) at 2-week intervals. A significant increase was found in the knee total reaction moment and vertical ground reaction force (GRF) for Celecoxib compared to placebo (p=0.005, p=0.003), but not for Oxycodone compared to placebo (p=0.20, p=0.27) treatments. Walking speed was significantly higher for the Celecoxib and Oxycodone compared to placebo treatment (p=0.041 and p=0.031, respectively). Self-reported function (WOMAC scores) was not different among treatments (p>0.05). The changes in total reaction moments and GRFs for only the NSAID suggest that greater increases in joint loading occurs when joint inflammation is treated in addition to pain. The total knee reaction moment, representing the magnitude of the extrinsic moment, appears to be a sensitive marker, more so than self-reported metrics, for evaluating knee OA treatment effects.
View details for DOI 10.1002/jor.22037
View details for Web of Science ID 000303810000016
View details for PubMedID 22179861
Integrative Approach to Pain Genetics Identifies Pain Sensitivity Loci across Diseases
PLOS COMPUTATIONAL BIOLOGY
2012; 8 (6)
Identifying human genes relevant for the processing of pain requires difficult-to-conduct and expensive large-scale clinical trials. Here, we examine a novel integrative paradigm for data-driven discovery of pain gene candidates, taking advantage of the vast amount of existing disease-related clinical literature and gene expression microarray data stored in large international repositories. First, thousands of diseases were ranked according to a disease-specific pain index (DSPI), derived from Medical Subject Heading (MESH) annotations in MEDLINE. Second, gene expression profiles of 121 of these human diseases were obtained from public sources. Third, genes with expression variation significantly correlated with DSPI across diseases were selected as candidate pain genes. Finally, selected candidate pain genes were genotyped in an independent human cohort and prospectively evaluated for significant association between variants and measures of pain sensitivity. The strongest signal was with rs4512126 (5q32, ABLIM3, P = 1.3×10⁻¹⁰) for the sensitivity to cold pressor pain in males, but not in females. Significant associations were also observed with rs12548828, rs7826700 and rs1075791 on 8q22.2 within NCALD (P = 1.7×10⁻⁴, 1.8×10⁻⁴, and 2.2×10⁻⁴ respectively). Our results demonstrate the utility of a novel paradigm that integrates publicly available disease-specific gene expression data with clinical data curated from MEDLINE to facilitate the discovery of pain-relevant genes. This data-derived list of pain gene candidates enables additional focused and efficient biological studies validating additional candidates.
View details for DOI 10.1371/journal.pcbi.1002538
View details for Web of Science ID 000305965300012
View details for PubMedID 22685391
View details for PubMedCentralID PMC3369906
Modulation of remifentanil-induced postinfusion hyperalgesia by the beta-blocker propranolol in humans
2012; 153 (5): 974-981
Acute and chronic exposure to opioids has been associated with hyperalgesia in both animals and humans. A genetic analysis of opioid-induced hyperalgesia in mice linked the β(2)-adrenergic receptor to mechanical sensitization after opioid exposure. In humans, expansion of the area of mechanical hyperalgesia surrounding an experimentally induced lesion after the cessation of remifentanil infusion is a commonly used model of opioid hyperalgesia (remifentanil-induced postinfusion hyperalgesia, RPH). The purpose of our translational study was to test the hypothesis that the β-adrenergic receptor antagonist propranolol modulates the expression of RPH in humans. This double-blinded, randomized, placebo-controlled, crossover study was performed in 10 healthy human volunteers. During test sessions, intracutaneous electrical stimulation was used to generate areas of secondary mechanical hyperalgesia. The area of this sensitization was measured before, during, and after remifentanil infusion. Heat pain sensitivity was also followed. During one test session, subjects received propranolol infusion. We observed an average increase in the areas of secondary mechanical hyperalgesia to 141% of the baseline in subjects infused with remifentanil and placebo (P=0.00040). However, when remifentanil infusion was combined with propranolol, the area of secondary hyperalgesia after terminating remifentanil was not significantly different than the area before beginning the opioid infusion (P=0.13). Thermal hyperalgesia was not observed after remifentanil infusion. Propranolol infusion at the selected dose had minor hemodynamic effects. Concomitant infusion of propranolol with remifentanil prevented the expression of RPH. β-adrenergic receptor blockade may be a useful pharmacological strategy for preventing hyperalgesia in patients exposed to opioids.
View details for DOI 10.1016/j.pain.2012.01.014
View details for Web of Science ID 000302996200010
View details for PubMedID 22365565
Sex Differences in Reported Pain Across 11,000 Patients Captured in Electronic Medical Records
JOURNAL OF PAIN
2012; 13 (3): 228-234
Clinically recorded pain scores are abundant in patient health records but are rarely used in research. The use of this information could help improve clinical outcomes. For example, a recent report by the Institute of Medicine stated that ineffective use of clinical information contributes to undertreatment of patient subpopulations--especially women. This study used diagnosis-associated pain scores from a large hospital database to document sex differences in reported pain. We used de-identified electronic medical records from Stanford Hospital and Clinics for more than 72,000 patients. Each record contained at least 1 disease-associated pain score. We found over 160,000 pain scores in more than 250 primary diagnoses, and analyzed differences in disease-specific pain reported by men and women. After filtering for diagnoses with minimum encounter numbers, we found diagnosis-specific sex differences in reported pain. The most significant differences occurred in patients with disorders of the musculoskeletal, circulatory, respiratory and digestive systems, followed by infectious diseases, and injury and poisoning. We also discovered sex-specific differences in pain intensity in previously unreported diseases, including disorders of the cervical region, and acute sinusitis (P = .01, .017, respectively). Pain scores were collected during hospital encounters. No information about the use of pre-encounter over-the-counter medications was available. To our knowledge, this is the largest data-driven study documenting sex differences of disease-associated pain. It highlights the utility of electronic medical record data to corroborate and expand on results of smaller clinical studies. Our findings emphasize the need for future research examining the mechanisms underlying differences in pain.This article highlights the potential of electronic medical records to conduct large-scale pain studies. Our results are consistent with previous studies reporting pain differences between sexes and also suggest that clinicians should pay increased attention to this idea.
View details for DOI 10.1016/j.jpain.2011.11.002
View details for Web of Science ID 000301612900003
View details for PubMedID 22245360
Collecting and measuring wound exudate biochemical mediators in surgical wounds.
Journal of visualized experiments : JoVE
We describe a methodology by which we are able to collect and measure biochemical inflammatory and nociceptive mediators at the surgical wound site. Collecting site-specific biochemical markers is important to understand the relationship between levels in serum and surgical wound, determine any associations between mediator release, pain, analgesic use and other outcomes of interest, and evaluate the effect of systemic and peripheral drug administration on surgical wound biochemistry. This methodology has been applied to healthy women undergoing elective cesarean delivery with spinal anesthesia. We have measured wound exudate and serum mediators at the same time intervals as patient's pain scores and analgesics consumption for up to 48 hours post-cesarean delivery. Using this methodology we have been able to detect various biochemical mediators including nerve growth factor (NGF), prostaglandin E2 (PG-E2) substance P, IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, TNFα, INFγ, G-CSF, GM-CSF, MCP-1 and MIP-1β. Studies applying this human surgical wound bioassay have found no correlations between wound and serum cytokine concentrations or their time-release profile (J Pain. 2008; 9(7):650-7).(1) We also documented the utility of the technique to identify drug-mediated changes in wound cytokine content.
View details for DOI 10.3791/50133
View details for PubMedID 23117346
Necessity and Risks of Arterial Blood Sampling in Healthy Volunteer Studies
2012; 51 (10): 629-638
Arterial blood sampling is necessary when drugs such as the fast-acting opioid analgesic remifentanil exhibit relevant differences between arterial and venous blood concentrations. Arterial cannulation is generally considered to be clinically safe and has thus become a standard procedure in pharmacokinetic-pharmacodynamic assessments. However, rare cases of arterial occlusions have to be considered in risk-benefit assessments of arterial sampling in pharmacokinetic studies, especially when including healthy volunteers. In an actual case, arterial occlusion requiring surgical repair was caused by a factor V Leiden thrombophilia associated genetic variant F5 1691G>A (rs6025) and aggravated by a hypoplastic radial artery. Neither risk factor had been identified prior to enrolment by routine laboratory tests such as the prothrombin time (international normalized ratio), partial thromboplastin time and the clinical Allen's test of arterial function. Re-assessment of the necessity of arterial sampling showed that none of the potential alternatives, target concentrations of computerized infusions or venous concentrations during non-steady-state and steady-state conditions could provide the arterial concentrations. Relying on venous concentrations may result in erroneous pharmacodynamic parameters. Accurate pharmacokinetic-pharmacodynamic studies relying on precisely measured blood concentrations require serial sampling techniques during both steady-state and non-steady-state conditions. However, as illustrated by the presented case, incidents involving the generally safe procedure of arterial sampling are possible, although rare. To further minimize the risks, screening of subjects for prothrombotic risks and careful assessment of the suitability of the artery should be considered in pharmacokinetic studies requiring arterial cannulation.
View details for DOI 10.1007/s40262-012-0001-1
View details for Web of Science ID 000309248300001
View details for PubMedID 23018527
Selective nociceptor activation in volunteers by infrared diode laser
Two main classes of peripheral sensory neurons contribute to thermal pain sensitivity: the unmyelinated C fibers and thinly myelinated Aδ fibers. These two fiber types may differentially underlie different clinical pain states and distinctions in the efficacy of analgesic treatments. Methods of differentially testing C and Aδ thermal pain are widely used in animal experimentation, but these methods are not optimal for human volunteer and patient use. Thus, this project aimed to provide psychophysical and electrophysiological evidence that whether different protocols of infrared diode laser stimulation, which allows for direct activation of nociceptive terminals deep in the skin, could differentially activate Aδ or C fiber thermonociceptors in volunteers.Short (60 ms), high intensity laser pulses (SP) evoked monomodal "pricking" pain which was not enhanced by topical capsaicin, whereas longer, lower power pulses (LP) evoked monomodal "burning" pain which was enhanced by topical capsaicin. SP also produced cortical evoked EEG potentials consistent with Aδ mediation, the amplitude of which was directly correlated with pain intensity but was not affected by topical capsaicin. LP also produced a distinct evoked potential pattern the amplitude of which was also correlated with pain intensity, which was enhanced by topical capsaicin, and the latency of which could be used to estimate the conduction velocity of the mediating nociceptive fibers.Psychophysical and electrophysiological data were consistent with the ability of short high intensity infrared laser pulses to selectively produce Aδ mediated pain and of longer pulses to selectively produce C fiber mediated thermal pain. Thus, the use of these or similar protocols may be useful in developing and testing novel therapeutics based on the differential molecular mechanisms underlying activation of the two fiber types (e.g., TRPV1, TRPV2, etc). In addition, these protocol may be useful in determining the fiber mediation of different clinical pain types which may, in turn be useful in treatment choice.
View details for DOI 10.1186/1744-8069-7-18
View details for Web of Science ID 000289115700001
View details for PubMedID 21426575
The Endogenous Opioid System Is Not Involved in Modulation of Opioid-Induced Hyperalgesia
JOURNAL OF PAIN
2011; 12 (1): 108-115
Some recent studies suggested a role of the endogenous opioid system in modulating opioid-induced hyperalgesia (OIH). In order to test this hypothesis, we conducted a prospective randomized, placebo-controlled, 2-way crossover study in healthy human volunteers. We utilized a well-established model of inducing OIH after a brief exposure to the μ-opioid agonist remifentanil using intradermal electrical stimulation. Patients were exposed to a randomized 90-minute infusion of remifentanil or saline placebo during 2 separate occasions. Development of OIH was quantified using changes in the average radius of the area of secondary hyperalgesia generated by electrical pain stimulation. A 23.6% (20.2) increase in area of secondary hyperalgesia over baseline was observed in the postinfusion period of the remifentanil session, demonstrating development of OIH (P = .03). In order to test endogenous opioid system modulation of OIH, patients were given a 1-time bolus of naloxone, which had no effect on the size of the hyperalgesic lesion in either the remifentinal or placebo session. These results suggested that the endogenous opioid system did not appear to modulate OIH.Experimental evidence suggested that the endogenous opioid system did not significantly affect opioid-induced hyperalgesia. Consequently, this study suggested that alternative mechanisms such as pronociceptive stimulation and neuroplastic changes might be responsible for expression of OIH.
View details for DOI 10.1016/j.jpain.2010.05.006
View details for Web of Science ID 000286549700013
View details for PubMedID 20864417
The Role of Interleukin-1 in Wound Biology. Part I: Murine In Silico and In Vitro Experimental Analysis
ANESTHESIA AND ANALGESIA
2010; 111 (6): 1525-1533
Wound healing is a multistep, complex process that involves the coordinated action of multiple cell types. Conflicting results have been obtained when conventional methods have been used to study wound biology. Therefore, we analyzed the wound response in a mouse genetic model.We analyzed inflammatory mediators produced within incisional wounds induced in 16 inbred mouse strains. Computational haplotype-based genetic analysis of inter-strain differences in the level of production of 2 chemokines in wounds was performed. An in vitro experimental analysis system was developed to investigate whether interleukin (IL)-1 could affect chemokine production by 2 different types of cells that are present within wounds.The level of 2 chemokines, keratinocyte-derived chemokine (KC) and macrophage inflammatory protein 1α, exhibited very large (75- and 463-fold, respectively) interstrain differences within wound tissue across this inbred strain panel. Genetic variation within Nalp1, an inflammasome component that regulates IL-1 production, correlated with the interstrain differences in KC and macrophage inhibitory protein 1α production. Consistent with the genetic correlation, IL-1β was shown to stimulate KC production by murine keratinocyte and fibroblast cell lines in vitro.Genetic variation within Nalp1 could contribute to interstrain differences in wound chemokine production by altering the amount of IL-1 produced.
View details for DOI 10.1213/ANE.0b013e3181f5ef5a
View details for Web of Science ID 000284973300032
View details for PubMedID 20889942
Continuous Subcutaneous Instillation of Bupivacaine Compared to Saline Reduces Interleukin 10 and Increases Substance P in Surgical Wounds After Cesarean Delivery
ANESTHESIA AND ANALGESIA
2010; 111 (6): 1452-1459
Recent evidence suggests that locally delivered local anesthetics may exert tissue-damaging effects such as chondrolysis after intraarticular injection. Alteration of the inflammatory response is a potential mechanism for local anesthetic-induced tissue toxicity. In this study, we tested the effects of continuous local anesthetic infiltration on the release of inflammatory and nociceptive mediators in skin wounds after cesarean delivery.Thirty-eight healthy women undergoing cesarean delivery with spinal anesthesia were enrolled in this study, and were randomized to receive subcutaneous surgical wound infiltration with bupivacaine 5 mg/mL or saline at 2 mL/h for 24 hours after cesarean delivery. Wound exudate was sampled at 1, 3, 5, 7, and 24 hours after cesarean delivery using a subcutaneous wound drain technique. Cytokines, chemokines, substance P, prostaglandin E(2), and nerve growth factor were assayed using multiplex Bio-Plex® (Bio-Rad, Hercules, CA) and enzyme-linked immunosorbent assays.Bupivacaine wound infusion resulted in a significant decrease of interleukin 10 and increase of substance P in wounds compared with saline infusion (area under the 24-hour concentration-time curve; P < 0.001). No statistically significant differences were detected for other cytokines, nerve growth factor, and prostaglandin E(2).This study demonstrates that the continuous administration of clinically used doses of bupivacaine into wounds affects the local composition of wound mediators. Observed changes in interleukin 10 are compatible with a disruption of antiinflammatory mechanisms. Whether such modulation combined with the release of the proinflammatory mediator substance P results in an overall proinflammatory wound response will require future studies of wound healing.
View details for DOI 10.1213/ANE.0b013e3181f579de
View details for Web of Science ID 000284973300020
View details for PubMedID 20861424
The Role of Interleukin-1 in Wound Biology. Part II: In Vivo and Human Translational Studies
ANESTHESIA AND ANALGESIA
2010; 111 (6): 1534-1542
In the accompanying paper, we demonstrate that genetic variation within Nalp1 could contribute to interstrain differences in wound chemokine production through altering the amount of interleukin (IL)-1 produced. We further investigate the role of IL-1 in incisional wound biology and its effect on wound chemokine production in vivo and whether this mechanism could be active in human subjects.A well-characterized murine model of incisional wounding was used to assess the in vivo role of IL-1 in wound biology. The amount of 7 different cytokines/chemokines produced within an experimentally induced skin incision on a mouse paw and the nociceptive response was analyzed in mice treated with an IL-1 inhibitor. We also investigated whether human IL-1β or IL-1α stimulated the production of chemokines by primary human keratinocytes in vitro, and whether there was a correlation between IL-1β and chemokine levels in 2 experimental human wound paradigms.Administration of an IL-1 receptor antagonist to mice decreased the nociceptive response to an incisional wound, and reduced the production of multiple inflammatory mediators, including keratinocyte-derived chemokine (KC) and macrophage inhibitory protein (MIP)-1α, within the wounds. IL-1α and IL-1β stimulated IL-8 and GRO-α (human homologues of murine keratinocyte-derived chemokine) production by primary human keratinocytes in vitro. IL-1β levels were highly correlated with IL-8 in human surgical wounds, and at cutaneous sites of human ultraviolet B-induced sunburn injury.IL-1 plays a major role in regulating inflammatory mediator production in wounds through a novel mechanism; by stimulating the production of multiple cytokines and chemokines, it impacts clinically important aspects of wound biology. These data suggest that administration of an IL-1 receptor antagonist within the perioperative period could decrease postsurgical wound pain.
View details for DOI 10.1213/ANE.0b013e3181f691eb
View details for Web of Science ID 000284973300033
View details for PubMedID 20889944
Effect of a Preemptive Femoral Nerve Block on Cytokine Release and Hyperalgesia in Experimentally Inflamed Skin of Human Volunteers
REGIONAL ANESTHESIA AND PAIN MEDICINE
2010; 35 (6): 514-519
Tissue injury is associated with the local release of inflammatory and nociceptive mediators and the development of hyperalgesia. It is unclear whether interrupting neuronal signaling using regional anesthetic techniques at the time of the injury modifies local nociceptive and inflammatory processes. The aim of this study was to determine whether a peripheral nerve block at the time of tissue injury could modify the development of wound hyperalgesia and the local release of inflammatory and nociceptive mediators.Twelve healthy volunteers participated in this controlled, crossover, randomized study. A femoral nerve block or a sham block was established before inducing an experimental UVB burn on the thigh. Twenty-four hours later, the interstitial wound fluid was sampled, and mechanical and heat pain thresholds were assessed. Wound fluid concentrations of an array of cytokines, chemokines, nerve growth factor, prostaglandin E2, and substance P were determined.Skin inflammation was associated with the release of inflammatory and nociceptive mediators and resulted in significant tissue hyperalgesia (P < 0.001). However, the presence of a fully established peripheral nerve block at the time of tissue injury did not alter the development of hyperalgesia after regression of the block. Similarly, the presence of a peripheral nerve block did not modify the release of inflammatory or nociceptive mediators.These findings suggest that a preemptive, single-shot peripheral nerve block minimally affects wound hyperalgesia and inflammation. Continuous nerve block techniques may be better suited to alter nociceptive and inflammatory events in wounds beyond the duration of the block.
View details for DOI 10.1097/AAP.0b013e3181faa107
View details for Web of Science ID 000284301300008
View details for PubMedID 20975465
The Analgesic and Antihyperalgesic Effects of Transcranial Electrostimulation with Combined Direct and Alternating Current in Healthy Volunteers
ANESTHESIA AND ANALGESIA
2010; 111 (5): 1301-1307
Transcranial electrostimulation (TES) has been reported to produce clinically significant analgesia, but randomized and double-blind studies are lacking. We investigated the analgesic and antihyperalgesic effects of TES in validated human experimental pain models.In 20 healthy male subjects we evaluated the analgesic and antihyperalgesic effects of TES(60Hz) and TES(100Hz) to heat and mechanical pain in experimentally induced ultraviolet B skin sunburns and in normal skin. Previous animal studies in our laboratory predicted that TES(60Hz) would provide significant analgesia, and TES(100Hz) was a suitable active control. The study was conducted in a double-blind, randomized, 2-way cross-over fashion. TES was administered for 35 minutes. Quantitative sensory testing evaluating heat and mechanical pain thresholds was conducted before TES, during TES, and 45 minutes after TES.TES (TES(60Hz) > TES(100Hz)) evoked rapidly developing, significant thermal and mechanical antihyperalgesic effects in the ultraviolet B lesion, and attenuated thermal pain in unimpaired skin. No long-lasting analgesic and antihyperalgesic effects of a single TES treatment were demonstrated in this study.TES produces significant, frequency-dependent antihyperalgesic and analgesic effects in humans. The characteristics of the TES effects indicate a high likelihood of its ability to modulate both peripheral sensitization of nociceptors and central hyperexcitability.
View details for DOI 10.1213/ANE.0b013e3181e3697e
View details for Web of Science ID 000283675000034
View details for PubMedID 20530614
Opioid Pharmacogenomics Using a Twin Study Paradigm: Methods and Procedures for Determining Familial Aggregation and Heritability
TWIN RESEARCH AND HUMAN GENETICS
2010; 13 (5): 412-425
Opioids are the cornerstone medication for the treatment of moderate to severe pain. However, analgesic opioid requirements and the propensity to suffer from aversive opioid effects, including fatal respiratory depression and addiction, vary widely among patients. The factors underlying the substantial response variance remain largely unknown and need clarification for using opioids more effectively in appropriately selected patients. This ongoing study takes advantage of the twin paradigm to estimate the genetic and environmental contributions to inter-individual differences in opioid responses. Evidence of significant heritability will justify more detailed and extensive genomic studies. The enrollment target is 80 monozygotic and 45 dizygotic twin pairs who undergo a target-controlled infusion of the opioid alfentanil and saline placebo in sequential but randomized order. In a laboratory-type setting, well-defined pharmacodynamic endpoints are measured to quantify pain sensitivity, analgesic opioid effects, and aversive opioid effects including respiratory depression, sedation and reinforcing affective responses. First results obtained in 159 participants provide evidence for the feasibility and utility of this interventional study paradigm to estimate familial aggregation and heritability components of relevant drug effects. Areas highlighted in this report include recruitment strategies, required infrastructure and personnel, selection of relevant outcome measures, drug infusion algorithm minimizing pharmacokinetic variability, and considerations for optimizing data quality and quantity without hampering feasibility. Applying the twin paradigm to complex and potentially harmful studies comprehensively characterizing pharmacological response profiles is without much precedent. Methods and first results including heritability estimates for heat and cold pain sensitivity should be of interest to investigators considering similar studies.
View details for Web of Science ID 000283001300002
View details for PubMedID 20874462
Opioid Pharmacotherapy for Chronic Non-Cancer Pain in the United States: A Research Guideline for Developing an Evidence-Base
JOURNAL OF PAIN
2010; 11 (9): 807-829
This document reports the consensus of an interdisciplinary panel of research and clinical experts charged with reviewing the use of opioids for chronic noncancer pain (CNCP) and formulating guidelines for future research. Prescribing opioids for chronic noncancer pain has recently escalated in the United States. Contrasting with increasing opioid use are: 1) The lack of evidence supporting long-term effectiveness; 2) Escalating misuse of prescription opioids including abuse and diversion; and 3) Uncertainty about the incidence and clinical salience of multiple, poorly characterized adverse drug events (ADEs) including endocrine dysfunction, immunosuppression and infectious disease, opioid-induced hyperalgesia and xerostomia, overdose, falls and fractures, and psychosocial complications. Chief among the limitations of current evidence are: 1) Sparse evidence on long-term opioid effectiveness in chronic pain patients due to the short-term time frame of clinical trials; 2) Insufficiently comprehensive outcome assessment; and 3) Incomplete identification and quantification of ADEs. The panel called for a strategic interdisciplinary approach to the problem domain in which basic scientists and clinicians cooperate to resolve urgent issues and generate a comprehensive evidence base. It offered 4 recommendations in 3 areas: 1) A research strategy for studying the effectiveness of long-term opioid pharmacotherapy; 2) Improvements in evidence-generation methodology; and 3) Potential research topics for generating new evidence.Prescribing opioids for CNCP has outpaced the growth of scientific evidence bearing on the benefits and harms of these interventions. The need for a strong evidence base is urgent. This guideline offers a strategic approach to creating a comprehensive evidence base to guide safe and effective management of CNCP.
View details for DOI 10.1016/j.jpain.2010.02.019
View details for Web of Science ID 000282033900001
View details for PubMedID 20430701
- Ketamine for Managing Perioperative Pain in Opioid-dependent Patients with Chronic Pain A Unique Indication? ANESTHESIOLOGY 2010; 113 (3): 514-515
Perioperative Hypothermia (33 degrees C) Does Not Increase the Occurrence of Cardiovascular Events in Patients Undergoing Cerebral Aneurysm Surgery Findings from the Intraoperative Hypothermia for Aneurysm Surgery Trial
2010; 113 (2): 327-342
Perioperative hypothermia has been reported to increase the occurrence of cardiovascular complications. By increasing the activity of sympathetic nervous system, perioperative hypothermia also has the potential to increase cardiac injury and dysfunction associated with subarachnoid hemorrhage.The Intraoperative Hypothermia for Aneurysm Surgery Trial randomized patients undergoing cerebral aneurysm surgery to intraoperative hypothermia (n = 499, 33.3 degrees +/- 0.8 degrees C) or normothermia (n = 501, 36.7 degrees +/- 0.5 degrees C). Cardiovascular events (hypotension, arrhythmias, vasopressor use, myocardial infarction, and others) were prospectively followed until 3-month follow-up and were compared in hypothermic and normothermic patients. A subset of 62 patients (hypothermia, n = 33; normothermia, n = 29) also had preoperative and postoperative (within 24 h) measurement of cardiac troponin-I and echocardiography to explore the association between perioperative hypothermia and subarachnoid hemorrhage-associated myocardial injury and left ventricular function.There was no difference between hypothermic and normothermic patients in the occurrence of any single cardiovascular event or in composite cardiovascular events. There was no difference in mortality (6%) between groups, and there was only a single primary cardiovascular death (normothermia). There was no difference between hypothermic and normothermic patients in postoperative versus preoperative left ventricular regional wall motion or ejection fraction. Compared with preoperative values, hypothermic patients had no postoperative increase in cardiac troponin-I (median change 0.00 microg/l), whereas normothermic patients had a small postoperative increase (median change + 0.01 microg/l, P = 0.038).In patients undergoing cerebral aneurysm surgery, perioperative hypothermia was not associated with an increased occurrence of cardiovascular events.
View details for DOI 10.1097/ALN.0b013e3181dfd4f7
View details for Web of Science ID 000280363900011
View details for PubMedID 20571361
Identification of a complex between fibronectin and aggrecan G3 domain in synovial fluid of patients with painful meniscal pathology
2010; 43 (10-11): 808-814
We previously described a panel of four cytokines biomarkers in knee synovial fluid for acute knee pain associated with meniscal pathology. The cytokine biomarkers included interferon gamma (IFN-gamma), interleukin 6 (IL-6), monocyte chemotactic protein 1 (MCP-1), and macrophage inflammatory protein-1 beta (MIP-1beta). Validation studies using other immunologic techniques confirmed the presence of IL-6, MCP-1 and MIP-1beta, but not IFN-gamma. Therefore we sought the identity of the IFN-gamma signal in synovial fluid.Knee synovial fluid was collected from patients with an acute, painful meniscal injury, as well as asymptomatic volunteers. A combination of high-pressure chromatography, mass spectrometry and immunological techniques were used to enrich and identify the protein components representing the IFN-gamma signal.A protein complex of fibronectin and the aggrecan G3 domain was identified in the synovial fluid of patients with a meniscal tear and pain that was absent in asymptomatic controls. This protein complex correlated to the IFN-gamma signal. A novel enzyme-linked immunosorbent assay (ELISA) was developed to specifically identify the complex in synovial fluid.We have identified a protein complex of fibronectin and aggrecan G3 domain that is a candidate biomarker for pain associated with meniscal injury.
View details for DOI 10.1016/j.clinbiochem.2010.04.069
View details for Web of Science ID 000279133100003
View details for PubMedID 20460120
- Intrathecal Cyclooxygenase Inhibitors in Humans Don't Throw in the Towel! ANESTHESIOLOGY 2010; 112 (5): 1082-1083
Cytokine evaluation in individuals with low back pain using discographic lavage
2010; 10 (3): 212-218
The pathophysiology underlying degenerative disc disease and its implication in painful syndromes remain unclear. However, spine magnetic resonance imaging (MRI) can demonstrate changes in disc water content and the annulus; provocative discography purportedly identifies degenerate discs causing serious low back pain; and biochemical assays have identified local inflammatory markers. No study to date has correlated pain on disc injection during discography evaluation with relevant MRI findings and biochemical markers.The purpose of this study was to correlate concordant pain on during discography to biochemical markers obtained by disc lavage and MRI findings.This is a Phase 1 Diagnostic Test Assessment Cohort Study (Sackett and Haynes).The patient sample included 21 symptomatic patients with suspected discogenic pain and three Phase 1 control subjects.The outcome measures included discography pain scores, MRI degenerative grades, and immunoreactivity to various inflammatory cytokine concentrations present in disc lavage samples.Twenty-one symptomatic patients with lumbar degenerative disc disease and three control subjects underwent discography, MRI, and biochemical analysis of disc lavage fluid. Lumbar MRI was scored for Pfirrmann grading of the lumbar discs, and annular disruption was identified by nuclear disc lavage. Disc lavage samples were analyzed for biochemical markers by high-sensitivity immunoassay.Eighty-three discs from 24 patients were studied: 67 discs from 21 patients with axial back pain (suspected discogenic pain group) and 16 discs from 3 scoliosis patients without back pain (Phase 1 control subjects). Among the biochemical markers surveyed, interferon gamma (IFN-gamma) immunoreactivity was most consistently identified in patients with axial back pain. Discs with annular disruption and concordant pain reproduction at a visual analog scale of 7 to 10/10 had greater IFN-gamma immunoreactivity than those without this finding (p=.003); however, at least some IFN-gamma immunoreactivity was found in all but one disc in the symptomatic group.Among the potential inflammatory markers tested in this Phase 1 study, IFN-gamma immunoreactivity was most commonly elevated in discogram "positive" discs but absent in asymptomatic controls. However, this marker was also frequently elevated in degenerative but "negative" discography discs. From these findings, Phase 2 and Phase 3 validity studies are reasonable to pursue. Phase 4 utility studies may be performed concurrently to assess this method's predictive value in outcome studies.
View details for DOI 10.1016/j.spinee.2009.12.007
View details for Web of Science ID 000208284600006
View details for PubMedID 20207331
Selective Antagonism of Opioid-Induced Ventilatory Depression by an Ampakine Molecule in Humans Without Loss of Opioid Analgesia
CLINICAL PHARMACOLOGY & THERAPEUTICS
2010; 87 (2): 204-211
Ventilatory depression is a significant risk associated with the use of opioids. We assessed whether opioid-induced ventilatory depression can be selectively antagonized by an ampakine without reduction of analgesia. In 16 healthy men, after a single oral dose of 1,500 mg of the ampakine CX717, a target concentration of 100 ng/ml alfentanil decreased the respiratory frequency by only 2.9 +/- 33.4% as compared with 25.6 +/- 27.9% during placebo coadministration (P < 0.01).Blood oxygenation and the ventilatory response to hypercapnic challenge also showed significantly smaller decreases with CX717 than with placebo. In contrast, CX717 did not affect alfentanil-induced analgesia in either electrical or heat-based experimental models of pain. Both ventilatory depression and analgesia were reversed with 1.6 mg of naloxone. These results support the use of ampakines as selective antidotes in humans to counter opioid-induced ventilatory depression without affecting opioid-mediated analgesia.
View details for DOI 10.1038/clpt.2009.194
View details for Web of Science ID 000274140200018
View details for PubMedID 19907420
No Association between Intraoperative Hypothermia or Supplemental Protective Drug and Neurologic Outcomes in Patients Undergoing Temporary Clipping during Cerebral Aneurysm Surgery Findings from the Intraoperative Hypothermia for Aneurysm Surgery Trial
2010; 112 (1): 86-101
Although hypothermia and barbiturates improve neurologic outcomes in animal temporary focal ischemia models, the clinical efficacy of these interventions during temporary occlusion of the cerebral vasculature during intracranial aneurysm surgery (temporary clipping) is not established.A post hoc analysis of patients from the Intraoperative Hypothermia for Aneurysm Surgery Trial who underwent temporary clipping was performed. Univariate and multivariate logistic regression methods were used to test for associations between hypothermia, supplemental protective drug, and short- (24-h) and long-term (3-month) neurologic outcomes. An odds ratio more than 1 denotes better outcome.Patients undergoing temporary clipping (n = 441) were assigned to intraoperative hypothermia (33.3 degrees +/- 0.8 degrees C, n = 208) or normothermia (36.7 degrees +/- 0.5 degrees C, n = 233), with 178 patients also receiving supplemental protective drug (thiopental or etomidate) during temporary clipping. Three months after surgery, 278 patients (63%) had good outcome (Glasgow Outcome Score = 1). Neither hypothermia (P = 0.847; odds ratio = 1.043, 95% CI = 0.678-1.606) nor supplemental protective drug (P = 0.835; odds ratio = 1.048, 95% CI = 0.674-1.631) were associated with 3-month Glasgow Outcome Score. The effect of supplemental protective drug did not significantly vary with temperature. The effects of hypothermia and protective drug did not significantly vary with temporary clip duration. Similar findings were made for 24-h neurologic status and 3-month Neuropsychological Composite Score.In the Intraoperative Hypothermia for Aneurysm Surgery Trial, neither systemic hypothermia nor supplemental protective drug affected short- or long-term neurologic outcomes of patients undergoing temporary clipping.
View details for Web of Science ID 000273314200016
View details for PubMedID 19952722
Epidural Interferon Gamma-Immunoreactivity A Biomarker for Lumbar Nerve Root Irritation
2009; 34 (21): 2311-2317
Prospective observational cohort.Correlate epidural inflammatory cytokines with the clinical response to epidural steroid injection in patients with lumbar nerve root irritation.Some back pain syndromes are thought to be associated with activation of inflammatory pathways and others may be associated with primary mechanical derangements. Human studies providing detailed evidence for the primary inflammatory causation, which may be best treated with anti-inflammatory strategies, are lacking. There are currently no accurate diagnostic tests to predict the response to epidural steroid injection or surgical intervention in back pain and sciatica syndromes. METHODS.: Forty-seven consecutive patients with lumbar degenerative changes and low back and/or leg pain were prospectively enrolled. An epidural lavage was performed, followed by injection of marcaine/depo-medrol. Subjects scored their pain before and 3 months after the procedure. The immunoreactivity of an array of cytokines was measured in lavage samples and compared with clinical response to the therapeutic injection. Ten subjects underwent repeat epidural lavage sampling 3 months after the steroid injection.Interferon gamma (IFNgamma) was the most consistently detected cytokine. IFNgamma-immunoreactivity also highly correlated with reported reduction of pain 3-months after the epidural steroid injection. In subjects reporting significant pain relief (>50%) from the injection, mean [IFNgamma] was significantly greater compared with patients experiencing no significant relief. The IFNgamma-immunoreactivity in repeat lavage samples decreased to trace residual concentrations in patients who reported pain relief from the steroid injection.The presence of epidural IFNgamma-immunoreactivity corresponding to >10 pg/mL predicted significant pain relief after epidural steroid injection with >95% accuracy. These results suggest that IFNgamma may be part of a biochemical cascade triggering pain in sciatica; IFNgamma-immunoreactivity may aid as a biomarker for predicting the response to steroid therapy and/or surgical intervention, and may serve as a future therapeutic target.
View details for DOI 10.1097/BRS.0b013e3181af06b6
View details for Web of Science ID 000270382600011
View details for PubMedID 19934811
PERIOPERATIVE FEVER AND OUTCOME IN SURGICAL PATIENTS WITH ANEURYSMAL SUBARACHNOID HEMORRHAGE
2009; 64 (5): 897-908
We examined the incidence of perioperative fever and its relationship to outcome among patients enrolled in the Intraoperative Hypothermia for Aneurysm Surgery Trial.One thousand patients with initial World Federation of Neurological Surgeons grades of I to III undergoing clipping of intracranial aneurysms after subarachnoid hemorrhage were randomized to intraoperative normothermia (36 degrees C-37 degrees C) or hypothermia (32.5 degrees C-33.5 degrees C). Fever (> or =38.5 degrees C) and other complications (including infections) occurring between admission and discharge (or death) were recorded. Functional and neuropsychologic outcomes were assessed 3 months postoperatively. The primary outcome variable for the trial was dichotomized Glasgow Outcome Scale (good outcome versus all others).Fever was reported in 41% of patients. In 97% of these, fever occurred in the postoperative period. The median time from surgery to first fever was 3 days. All measures of outcome were worse in patients who developed fever, even in those without infections or who were World Federation of Neurological Surgeons grade I. Logistic regression analyses were performed to adjust for differences in preoperative factors (e.g., age, Fisher grade, initial neurological status). This demonstrated that fever continued to be significantly associated with most outcome measures, even when infection was added to the model. An alternative stepwise model selection process including all fever-related measures from the preoperative and intraoperative period (e.g., hydrocephalus, duration of surgery, intraoperative blood loss) resulted in the loss of significance for dichotomized Glasgow Outcome Scale, but significant associations between fever and several other outcome measures remained. After adding postoperative delayed ischemic neurological deficits to the model, only worsened National Institutes of Health Stroke Scale score, Barthel Activities of Daily Living index, and discharge destination (home versus other) remained independently associated with fever.These findings suggest that fever is associated with worsened outcome in surgical subarachnoid hemorrhage patients, although, because the association between fever and the primary outcome measure for the trial is dependent on the covariates used in the analysis (particularly operative events and delayed ischemic neurological deficits), we cannot rule out the possibility that fever is a marker for other events. Only a formal trial of fever treatment or prevention can address this issue.
View details for DOI 10.1227/01.NEU.0000341903.11527.2F
View details for Web of Science ID 000265661100034
View details for PubMedID 19404150
No evidence for the development of acute tolerance to analgesic, respiratory depressant and sedative opioid effects in humans
2009; 142 (1-2): 17-26
It is widely accepted that chronic opioid therapy is associated with the development of pharmacological tolerance. More controversial is the question as to whether acute opioid administration can result in "acute tolerance." The aim of this double-blind, placebo-controlled study in thirty-six healthy human volunteers was to examine whether a 3-h intravenous infusion delivering two different but clinically relevant doses of the mu-opioid receptor agonist remifentanil would result in tolerance to analgesic, respiratory depressant and/or sedative opioid effects. The blood remifentanil concentration versus opioid effect relationship was determined before and after the 3-h infusion. Tolerance was inferred if the potency of remifentanil was significantly lower after the 3-h infusion. Opioid analgesia was assessed with the aid of the cold pressor test and models of electrical and heat pain. Respiratory depression was assessed by measuring arterial pCO2 and minute ventilation. Subjective sedation scores were assessed on a visual analogue scale. Mixed effects modeling was used to relate the steady-state blood remifentanil concentration to each pharmacodynamic assessment. Neither dose of remifentanil produced detectable tolerance to any of the measured opioid effects following a 3-h infusion. The study was adequately powered to detect a decrease in potency of 5-24% for analgesia, 20-48% for respiratory depression, and 32% for sedative effects. These results suggest that short-term administration of clinically useful doses of remifentanil is not associated with the development of significant tolerance to analgesic, respiratory depressant, or sedative opioid effects.
View details for DOI 10.1016/j.pain.2008.11.001
View details for Web of Science ID 000264275800008
View details for PubMedID 19135798
Effect of Nitrous Oxide Use on Long-term Neurologic and Neuropsychological Outcome in Patients Who Received Temporary Proximal Artery Occlusion during Cerebral Aneurysm Clipping Surgery
2009; 110 (3): 563-573
The authors explored the relationship between nitrous oxide use and neurologic and neuropsychological outcome in a population of patients likely to experience intraoperative cerebral ischemia: those who had temporary cerebral arterial occlusion during aneurysm clipping surgery.A post hoc analysis of a subset of the data from the Intraoperative Hypothermia for Aneurysm Surgery Trial was conducted. Only subjects who had temporary arterial occlusion during surgery were included in the analysis. Metrics of short-term and long-term (i.e., 3 months after surgery) outcome were evaluated via both univariate and multivariate logistic regression analysis. An odds ratio (OR) greater than 1.0 denotes a worse outcome in patients receiving nitrous oxide.The authors evaluated 441 patients, of which 199 received nitrous oxide. Patients receiving nitrous oxide had a greater risk of delayed ischemic neurologic deficits (i.e., the clinical manifestation of vasospasm) (OR, 1.78, 95% confidence interval [CI], 1.08-2.95; P = 0.025). However, at 3 months after surgery, there was no difference in any metric of gross neurologic outcome: Glasgow Outcome Score (OR, 0.67; CI, 0.44-1.03; P = 0.065), Rankin Score (OR, 0.74; CI, 0.47-1.16; P = 0.192), National Institutes of Health Stroke Scale (OR, 1.02; CI, 0.66-1.56; P = 0.937), or Barthel Index (OR, 0.69; CI, 0.38-1.25; P = 0.22). The risk of impairment on at least one test of neuropsychological function was reduced in those who received nitrous oxide (OR, 0.56; CI, 0.36-0.89; P = 0.013).In this patient population, use of nitrous oxide was associated with an increased risk for the development of delayed ischemic neurologic deficits; however, there was no evidence of detriment to long-term gross neurologic or neuropsychological outcome.
View details for Web of Science ID 000263734900018
View details for PubMedID 19212259
View details for PubMedCentralID PMC2735401
Determining heat and mechanical pain threshold in inflamed skin of human subjects.
Journal of visualized experiments : JoVE
In a previous article in the Journal of Visualized Experiments we have demonstrated skin microdialysis techniques for the collection of tissue-specific nociceptive and inflammatory biochemicals in humans. In this article we will show pain-testing paradigms that are often used in tandem with microdialysis procedures. Combining pain tests with microdialysis provides the critical link between behavioral and biochemical data that allows identifying key biochemicals responsible for generating and propagating pain. Two models of evoking pain in inflamed skin of human study participants are shown. The first model evokes pain with aid of heat stimuli. Heat evoked pain as described here is predominantly mediated by small, non-myelinated peripheral nociceptive nerve fibers (C-fibers). The second model evokes pain via punctuated pressure stimuli. Punctuated pressure evoked pain is predominantly mediated by small, myelinated peripheral nociceptive nerve fibers (A-delta fibers). The two models are mechanistically distinct and independently examine nociceptive processing by the two major peripheral nerve fiber populations involved in pain signaling. Heat pain is evoked with aid of the TSA II, a commercially available thermo-sensory analyzer (Medoc Advanced Medical Systems, Durham, NC). Stimulus configuration and delivery is handled with aid of specific software. Thermodes vary in size and shape but in principle consist of a metal plate that can be heated or cooled at various rates and for different periods of time. Algorithms assessing heat-evoked pain are manifold. In the experiments shown here, study participants are asked to indicate at what point they start experiencing pain while the thermode in contact with skin is heated at a predetermined rate starting at a temperature that does not evoke pain. The thermode temperature at which a subject starts experiencing pain constitutes the heat pain threshold. Mechanical pain is evoked with punctuated probes. Such probes are commercially available from several manufacturers (von Frey hairs). However, the accuracy of von Frey hairs has been criticized and many investigators use custom made punctuated pressure probes. In the experiments shown here eight custom-made punctuated probes of different weights are applied in consecutive order, a procedure called up-down algorithm, to identify perceptional deflection points, i.e., a change from feeling no pain to feeling pain or vice versa. The average weight causing a perceptional deflection constitutes the mechanical pain threshold.
View details for DOI 10.3791/1092
View details for PubMedID 19229176
Cytokine profile in human skin in response to experimental inflammation, noxious stimulation, and administration of a COX-inhibitor: A microdialysis study
2008; 139 (1): 15-27
Animal studies have documented a critical role for cytokines in cell signaling events underlying inflammation and pain associated with tissue injury. While clinical reports indicate an important role of cytokines in inflammatory pain, methodological limitations have made systematic human studies difficult. This study examined the utility of a human in vivo bioassay combining microdialysis with multiplex immunoassay techniques for measuring cytokine arrays in tissue. The first experiment measured cytokines in interstitial fluid collected from non-inflamed and experimentally inflamed skin (UVB). The effects of noxious heat on cytokine release were also assessed. The second experiment examined whether anti-hyperalgesic effects of the COX-inhibitor ibuprofen were associated with decreased tissue levels of the pro-inflammatory cytokines IL-1 beta and IL-6. In the first experiment, inflammation significantly increased IL-1 beta, IL-6, IL-8, IL-10, G-CSF, and MIP-1 beta. Noxious heat but not experimental inflammation significantly increased IL-7 and IL-13. In the second experiment, an oral dose of 400 and 800 mg ibuprofen produced similar anti-hyperalgesic effects suggesting a ceiling effect. Tissue levels of IL-1 beta and IL-6 were not affected after the 400mg dose but decreased significantly (44+/-32% and 38+/-13%) after the 800 mg dose. These results support the utility of explored method for tracking cytokines in human tissue and suggest that anti-hyperalgesic and anti-inflammatory effects of ibuprofen are at least partially dissociated. The data further suggest that high clinical doses of ibuprofen exert anti-inflammatory effects by down-regulating tissue cytokine levels. Explored human bioassay is a promising tool for studying the pathology and pharmacology of inflammatory and chronic pain conditions.
View details for DOI 10.1016/j.pain.2008.02.028
View details for Web of Science ID 000260159200003
View details for PubMedID 18396374
Local and systemic release of cytokines, nerve growth factor, prostaglandin E2, and substance P in incisional wounds and serum following cesarean delivery
JOURNAL OF PAIN
2008; 9 (7): 650-657
The objectives of this study were to test the feasibility of measuring inflammatory and nociceptive biochemical mediators at the surgical site and to evaluate the relationship between wound and serum levels as well as determine any associations between mediator release, pain, and analgesic consumption after cesarean delivery. Twenty healthy women undergoing elective cesarean delivery with spinal anesthesia were enrolled. Wound exudate and serum mediators, pain scores, and analgesic consumption were measured at 1, 6, 24, and 48 hours after cesarean. In wound exudate, 19 of 20 mediators were reliably detected including interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, tumor necrosis factor-alpha, interferon-gamma, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1 (MIP-1beta), nerve growth factor (NGF), prostaglandin E2 (PG-E2), and substance P. Wound PG-E2 and various cytokines peaked early, whereas NGF showed a more delayed release. There were no correlations between the concentration versus time profile of wound and serum cytokines. Analgesic consumption during the first 24 hours after surgery was negatively correlated with IL-1beta, IL-6, and G-CSF in the wound exudate. This study demonstrates the feasibility of collecting and measuring nociceptive and inflammatory mediators in surgical wounds at specific time points. The lack of significant correlations between wound and serum levels emphasizes the importance of determining site-specific release if localized pathologies are to be studied.This study demonstrates the feasibility of measuring real-time nociceptive and inflammatory mediators in surgical wounds. Our findings confirm the lack of correlation between wound and serum levels of many pro-inflammatory and anti-inflammatory cytokines and nerve growth factor.
View details for DOI 10.1016/j.jpain.2008.02.004
View details for Web of Science ID 000257640100010
View details for PubMedID 18394968
Opioid-induced hyperalgesia in humans - Molecular mechanisms and clinical considerations
CLINICAL JOURNAL OF PAIN
2008; 24 (6): 479-496
Opioid-induced hyperalgesia (OIH) is most broadly defined as a state of nociceptive sensitization caused by exposure to opioids. The state is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain may actually become more sensitive to certain painful stimuli. The type of pain experienced may or may not be different from the original underlying painful condition. Although the precise molecular mechanism is not yet understood, it is generally thought to result from neuroplastic changes in the peripheral and central nervous systems that lead to sensitization of pronociceptive pathways. OIH seems to be a distinct, definable, and characteristic phenomenon that may explain loss of opioid efficacy in some cases. Clinicians should suspect expression of OIH when opioid treatment effect seems to wane in the absence of disease progression, particularly if found in the context of unexplained pain reports or diffuse allodynia unassociated with the pain as previously observed. This review highlights the important mechanistic underpinnings and clinical ramifications of OIH and discusses future research directions and the latest clinical evidence for modulation of this potentially troublesome clinical phenomenon.
View details for Web of Science ID 000257198800003
View details for PubMedID 18574358
Chronic morphine administration enhances nociceptive sensitivity and local cytokine production after incision
The chronic use of opioids prior to surgery leads to lowered pain thresholds and exaggerated pain levels after these procedures. Several mechanisms have been proposed to explain this heightened sensitivity commonly termed opioid-induced hyperalgesia (OIH). Most of these proposed mechanisms involve plastic events in the central or peripheral nervous systems. Alterations in the abundance of peripheral mediators of nociception have not previously been explored.In these experiments mice were treated with saline (control) or ascending daily doses of morphine to generate a state of OIH followed by hind paw incision. In other experiments morphine treatment was initiated at the time of incision. Both mechanical allodynia and peri-incisional skin cytokine levels were measured. Myeloperoxidase (MPO) assays were used to determine neutrophil activity near the wounds. The cytokine production inhibitor pentoxifylline was used to determine the functional significance of the excess cytokines in previously morphine treated animals. Mice treated chronically treated with morphine prior to incision were found to have enhanced skin levels of IL-1beta, IL-6, G-CSF, KC and TNFalpha after incision at one or more time points compared to saline pretreated controls. The time courses of individual cytokines followed different patterns. There was no discernable effect of chronic morphine treatment on wound area neutrophil infiltration. Pentoxifylline reduced cytokine levels and reversed the excess mechanical sensitization caused by chronic morphine administration prior to incision. Morphine treatment initiated at the time of incision did not lead to a generalized enhancement of cytokine production or nociceptive sensitization in excess of the levels observed after incision alone.The enhanced level of nociceptive sensitization seen after incision in animals chronically exposed to morphine is associated with elevated levels of several cytokines previously reported to be relevant to this incisional pain model. The cytokines may be functional in supporting nociceptive sensitization because pentoxifylline reverses both peri-incisional skin cytokine levels and OIH. Opioid administration beginning at the time of incision does not seem to have the same cytokine enhancing effect. Approaches to postoperative pain control involving a reduction of cytokines may be an effective way to control excessive pain in patients chronically using opioids prior to surgical procedures.
View details for DOI 10.1186/1744-8069-4-7
View details for Web of Science ID 000254762200001
View details for PubMedID 18294378
View details for PubMedCentralID PMC2279109
Human in-vivo bioassay for the tissue-specific measurement of nociceptive and inflammatory mediators.
Journal of visualized experiments : JoVE
This in-vivo human bioassay can be used to study human volunteers and patients. Samples are collected from pertinent tissue sites such as the skin via aseptically inserted microdialysis catheters (Dermal Dialysis, Erlangen, Germany). Illustrated in this example is the collection of interstitial fluid from experimentally inflamed skin in human volunteers. Sample collection can be combined with other experimental tests. For example, the simultaneous assessment of locally released biochemicals and subjective sensitivity to painful stimuli in experimentally inflamed skin provides the critical biochemical-behavioral link to identify biomarkers of pain and inflammation. Presented assay in the living human organism allows for mechanistic insight into tissue-specific processes underlying pain and/or inflammation. The method is also well suited to examine the effectiveness of existing or novel interventions--such as new drug candidates - targeting the treatment of painful and/or inflammatory conditions. This article will provide a detailed description on the use of microdialysis techniques for collecting interstitial fluid from experimentally inflamed skin lesion of human study subjects. Interstitial fluid samples are typically processed with aid of multiplex bead array immunoassays allowing assaying up to 100 analytes in samples as small in volume as 50 microliters.
View details for DOI 10.3791/1074
View details for PubMedID 19229167
Collecting and measuring nociceptive and inflammatory mediators in surgical wounds.
Journal of visualized experiments : JoVE
We describe a methodology by which we are able to collect and measure inflammatory and nociceptive biochemical mediators at the surgical wound site. Collecting site-specific biochemical markers allows us to evaluate the relationship between surgical wound and serum levels;determine any associations between mediator release, pain and analgesic consumption; and evaluate the effect of systemic and peripheral drug administration on surgical wound biochemistry.This methodology has been applied to healthy women undergoing elective cesarean delivery with spinal anesthesia. Wound exudate and serum mediators, in conjunction with pain scores and analgesics consumption were measured at 1, 6, 24, and 48 hours post-cesarean delivery.Biochemical mediators that were detected included IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, TNFα, INFγ, G-CSF, GM-CSF,MCP-1 and MIP-1β, nerve growth factor (NGF), prostaglandin E2 (PG-E2) and substance P. We found no correlations between wound and serum cytokines concentrations or time-release profiles (J Pain. 2008 Jul 9(7):650-7). This article describes and demonstrates the feasibility of collecting and assaying nociceptive and inflammatory mediators in surgical wounds at specific time points. The lack of significant correlations between serum and wound levels shows the importance of determining site-specific release if surgical wounds and localized pathologies are to be studied [corrected].
View details for DOI 10.3791/962
View details for PubMedID 19078937
Morphine reduces local cytokine expression and neutrophil infiltration after incision
Inflammation and nociceptive sensitization are hallmarks of tissue surrounding surgical incisions. Recent studies demonstrate that several cytokines may participate in the enhancement of nociception near these wounds. Since opioids like morphine interact with neutrophils and other immunocytes, it is possible that morphine exerts some of its antinociceptive action after surgical incision by altering the vigor of the inflammatory response. On the other hand, keratinocytes also express opioid receptors and have the capacity to produce cytokines after injury. Our studies were directed towards determining if opioids alter cytokine production near incisions and to identify cell populations responsible for producing these cytokines.A murine incisional model was used to measure the effects of acute morphine administration (0.1-10 mg/kg) on nociceptive thresholds, neutrophil infiltration and cytokine production in hind paw skin 30 minutes and 2 hours after incision. Incised hind paws displayed profound allodynia which was reduced by morphine (0.1-10 mg/kg) in the 2 hours following incision. Skin samples harvested from these mice showed enhanced levels of 5 cytokines: IL-1 beta, IL-6, tumor necrosis factor alpha (TNFalpha), granulocyte colony stimulating factor (G-CSF) and keratinocyte-derived cytokine (KC). Morphine reduced these incision-stimulated levels. Separate analyses measuring myeloperoxidase (MPO) and using immunohistochemistry demonstrated that morphine dose-dependently reduced the infiltration of neutrophils into the peri-incisional tissue. The dose of morphine required for reduction of cytokine accumulation, however, was below that required for inhibition of peri-incisional neutrophil infiltration. Additional immunohistochemical studies revealed wound edge keratinocytes as being an important source of cytokines in the acute phase after incision.Acute morphine administration of doses as low as 0.1 mg/kg reduces peri-incisional cytokine expression. A reduction in neutrophil infiltration does not provide a complete explanation for this effect, and keratinocytes may be responsible for some incision area cytokine production. These studies suggest that morphine may alter the inflammatory milieu of incisional wounds, but these alterations do not likely contribute significantly to analgesia in the acute setting.
View details for DOI 10.1186/1744-8069-3-28
View details for Web of Science ID 000251452200001
View details for PubMedID 17908329
View details for PubMedCentralID PMC2096620
- When Opioids cause pain JOURNAL OF CLINICAL ONCOLOGY 2007; 25 (28): 4497-4498
- Comment on Koltzenburg et al.: Differential sensitivity of three experimental pain models in detecting the analgesic effects of transdermal fentanyl and buprenorphine. Pain 2006;126 : 165-74 PAIN 2007; 128 (3): 292-294
Experimental heat pain for detecting pregnancy-induced analgesia in humans
ANESTHESIA AND ANALGESIA
2006; 103 (5): 1283-1287
Animal studies suggest that increased circulating estrogen and progesterone, and activation of the endorphin system cause prenancy-induced antinociceptive effects. Human studies have provided inconsistent results and have often lacked a nonpregnant control group. In this study, we compared sensitivity to experimental heat and cold pain in pregnant and nonpregnant women. Nineteen healthy nonpregnant female volunteers and 20 pregnant women at term were enrolled. Pain threshold and tolerance were examined using experimental heat-induced pain and cold pressor pain models. Subjects were evaluated pre- and 1-2 days post-delivery (pregnant), or on consecutive days (nonpregnant). Heat pain tolerance was significantly increased in the pregnant women during pre and postdelivery when compared with nonpregnant controls (50.0 +/- 1.0 vs 49.0 +/- 1.2 and 50.1 +/- 0.7 vs 49.2 +/- 1.2 degrees C; mean +/- sd). However, pain induced by the cold pressor test was endured for a similar amount of time by both study groups. Pregnancy-induced analgesic effects at term can be detected in a model of experimental heat pain. These effects persist during the first 24-48 h after delivery. Experimental heat pain is a suitable modality for further characterizing the phenomenon of pregnancy-induced analgesia in humans.
View details for DOI 10.1213/01.ane.0000239224.48719.28
View details for Web of Science ID 000241570600038
View details for PubMedID 17056970
Blockade of the complement C5a receptor reduces incisional allodynia, edema, and cytokine expression
2006; 104 (6): 1274-1282
Activation of the complement system is one component of the inflammatory response. Various components of the complement system participate in killing foreign organisms, recruiting immune cells, enhancing edema, and stimulating cytokine formation. Complement-mediated enhancement of the inflammation surrounding surgical incisions may increase pain.In these studies, the authors used a murine hind paw incisional model to study the role of the complement C5a receptor in supporting incisional inflammation. At baseline and at various time points after incision, they measured the effects of a highly selective C5a receptor antagonist on nociceptive thresholds, edema formation, and cytokine production in the skin surrounding the incision. They also measured changes in C5a receptor expression near the incisions.The once-daily injection of the C5a receptor antagonist AcF-[OPdChaWR] reduced mechanical allodynia and edema in the incised hind paw. A multiplexed cytokine assay revealed that 8 of the 18 cytokines examined showed significant increases in skin tissue abundance after incision. Distinct time courses for the patterns of elevation were seen, though some degree of resolution occurred for all cytokines within 96 h. For 7 of these 8 cytokines, the C5a receptor antagonist reduced the enhancement of expression. In addition, the authors found that the C5a receptor messenger RNA level increased 15-fold in the skin surrounding the incisions within 24 h and then slowly declined.The tissue directly surrounding incisions in mouse hind paws undergoes large changes in the content of specific cytokines in addition to demonstrating edema and nociceptive sensitization. By blocking the receptor for one component of the complement system, C5a, all of these changes can be reduced. Complement receptor inhibitors may constitute a novel group of compounds useful in reducing the pain and swelling of surgical incisions.
View details for Web of Science ID 000237869500023
View details for PubMedID 16732100
Opioid-induced hyperalgesia - A qualitative systematic review
2006; 104 (3): 570-587
Opioids are the cornerstone therapy for the treatment of moderate to severe pain. Although common concerns regarding the use of opioids include the potential for detrimental side effects, physical dependence, and addiction, accumulating evidence suggests that opioids may yet cause another problem, often referred to as opioid-induced hyperalgesia. Somewhat paradoxically, opioid therapy aiming at alleviating pain may render patients more sensitive to pain and potentially may aggravate their preexisting pain. This review provides a comprehensive summary of basic and clinical research concerning opioid-induced hyperalgesia, suggests a framework for organizing pertinent information, delineates the status quo of our knowledge, identifies potential clinical implications, and discusses future research directions.
View details for Web of Science ID 000235766400024
View details for PubMedID 16508405
Pharmacology of drugs formulated with DepoFoaM (TM) - A sustained release drug delivery system for parenteral administration using multivesicular liposome technology
2006; 45 (12): 1153-1176
Lamellar liposome technology has been used for several decades to produce sustained-release drug formulations for parenteral administration. Multivesicular liposomes are structurally distinct from lamellar liposomes and consist of an aggregation of hundreds of water-filled polyhedral compartments separated by bi-layered lipid septa. The unique architecture of multivesicular liposomes allows encapsulating drug with greater efficiency, provides robust structural stability and ensures reliable, steady and prolonged drug release. The favourable characteristics of multivesicular liposomes have resulted in many drug formulations exploiting this technology, which is proprietary and referred to as DepoFoam. Currently, two formulations using multivesicular liposome technology are approved by the US FDA for clinical use, and many more formulations are at an experimental developmental stage. The first clinically available formulation contains the antineoplastic agent cytarabine (DepoCyt) for its intrathecal injection in the treatment of malignant lymphomatous meningitis. Intrathecal injection of DepoCyt reliably results in the sustained release of cytarabine and produces cytotoxic concentrations in cerebrospinal fluid (CSF) that are maintained for at least 2 weeks. Early efficacy data suggest that DepoCyt is fairly well tolerated, and its use allows reduced dosing frequency from twice a week to once every other week and may improve the outcome compared with frequent intrathecal injections of unencapsulated cytarabine. The second available formulation contains morphine (DepoDur) for its single epidural injection in the treatment of postoperative pain. While animal studies confirm that epidural injection of DepoDur results in the sustained release of morphine into CSF, the CSF pharmacokinetics have not been determined in humans. Clinical studies suggest that the use of DepoDur decreases the amount of systemically administered analgesics needed for adequate postoperative pain control. It may also provide superior pain control during the first 1-2 postoperative days compared with epidural administration of unencapsulated morphine or intravenous administration of an opioid. However, at this timepoint the overall clinical utility of DepoDur has yet to be defined and some safety concerns remain because of the unknown CSF pharmacokinetics of DepoDur in humans. The versatility of multivesicular liposome technology is reflected by the many agents including small inorganic and organic molecules and macromolecules including proteins that have successfully been encapsulated. Data concerning many experimental formulations containing antineoplastic, antibacterial and antiviral agents underscore the sustained, steady and reliable release of these compounds from multivesicular liposomes after injection by the intrathecal, subcutaneous, intramuscular, intraperitoneal and intraocular routes. Contingent on the specific formulation and manufacturing process, agents were released over a period of hours to weeks as reflected by a 2- to 400-fold increase in elimination half life. Published data further suggest that the encapsulation process preserves bioactivity of agents as delicate as proteins and supports the view that examined multivesicular liposomes were non-toxic at studied doses. The task ahead will be to examine whether the beneficial structural and pharmacokinetic properties of multivesicular liposome formulations will translate into improved clinical outcomes, either because of decreased drug toxicity or increased drug efficacy.
View details for Web of Science ID 000242842400001
View details for PubMedID 17112293
Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: A preliminary prospective study
JOURNAL OF PAIN
2006; 7 (1): 43-48
There is accumulating evidence that opioid therapy might not only be associated with the development of tolerance but also with an increased sensitivity to pain, a condition referred to as opioid-induced hyperalgesia (OIH). However, there are no prospective studies documenting the development of opioid tolerance or OIH in patients with chronic pain. This preliminary study in 6 patients with chronic low back pain prospectively evaluated the development of tolerance and OIH. Patients were assessed before and 1 month after initiating oral morphine therapy. The cold pressor test and experimental heat pain were used to measure pain sensitivity before and during a target-controlled infusion with the short-acting mu opioid agonist remifentanil. In the cold pressor test, all patients became hyperalgesic as well as tolerant after 1 month of oral morphine therapy. In a model of heat pain, patients exhibited no hyperalgesia, although tolerance could not be evaluated. These results provide the first prospective evidence for the development of analgesic tolerance and OIH by using experimental pain in patients with chronic back pain. This study also validated methodology for prospectively studying these phenomena in larger populations of pain patients.Experimental evidence suggests that opioid tolerance and opioid-induced hyperalgesia might limit the clinical utility of opioids in controlling chronic pain. This study validates a pharmacologic approach to study these phenomena prospectively in chronic pain patients and suggests that both conditions do occur within 1 month of initiating opioid therapy.
View details for DOI 10.1016/j.jpain.2005.08.001
View details for Web of Science ID 000235142300008
View details for PubMedID 16414554
Activation of naloxone-sensitive and -insensitive inhibitory systems in a human pain model
JOURNAL OF PAIN
2005; 6 (11): 757-764
We investigated naloxone effects in a model of electrically induced pain and hyperalgesia. In a double-blind, placebo-controlled, cross-over study, 15 volunteers underwent four 150-minute sessions of high-current-density electrical stimulation of their forearms. After 60 minutes, naloxone or placebo was given intravenously (increasing plasma concentrations of 0.1, 1, and 10 ng/mL; 30 minutes each) in 3 of the 4 sessions. Pain ratings and areas of mechanical hyperalgesia were assessed at regular intervals during all sessions. The low doses of naloxone did not cause any significant change of pain rating of areas of hyperalgesia. In terms of intrasession effects, pain ratings and areas of hyperalgesia significantly decreased during the sessions to 62% (pain rating), 70% (area of punctuate hyperalgesia), and 82% (area of allodynia) of the initial values. Naloxone (10 ng/ml) reversed these decreases. In terms of between-session effects, the time course of pain ratings remained constant from session to session. In contrast, the areas of punctate hyperalgesia successively decreased to 60% of initial value at the fourth repetition. The session effect was not reversed by naloxone. High-current-density electrical stimulation provokes central sensitization, but in addition inhibitory systems are activated that are only partly naloxone-sensitive.Endogenous inhibitory systems are of major importance for clinical pain conditions, but are not reflected in traditional human pain models. Here we show activation of a naloxone-sensitive short-term and a naloxone-insensitive long-term inhibitory system in a new model of electrically induced pain and hyperalgesia.
View details for DOI 10.1016/j.jpain.2005.07.002
View details for Web of Science ID 000233497900006
View details for PubMedID 16275600
Mild intraoperative hypothermia during surgery for intracranial aneurysm
NEW ENGLAND JOURNAL OF MEDICINE
2005; 352 (2): 135-145
Surgery for intracranial aneurysm often results in postoperative neurologic deficits. We conducted a randomized trial at 30 centers to determine whether intraoperative cooling during open craniotomy would improve the outcome among patients with acute aneurysmal subarachnoid hemorrhage.A total of 1001 patients with a preoperative World Federation of Neurological Surgeons score of I, II, or III ("good-grade patients"), who had had a subarachnoid hemorrhage no more than 14 days before planned surgical aneurysm clipping, were randomly assigned to intraoperative hypothermia (target temperature, 33 degrees C, with the use of surface cooling techniques) or normothermia (target temperature, 36.5 degrees C). Patients were followed closely postoperatively and examined approximately 90 days after surgery, at which time a Glasgow Outcome Score was assigned.There were no significant differences between the group assigned to intraoperative hypothermia and the group assigned to normothermia in the duration of stay in the intensive care unit, the total length of hospitalization, the rates of death at follow-up (6 percent in both groups), or the destination at discharge (home or another hospital, among surviving patients). At the final follow-up, 329 of 499 patients in the hypothermia group had a Glasgow Outcome Score of 1 (good outcome), as compared with 314 of 501 patients in the normothermia group (66 percent vs. 63 percent; odds ratio, 1.14; 95 percent confidence interval, 0.88 to 1.48; P=0.32). Postoperative bacteremia was more common in the hypothermia group than in the normothermia group (5 percent vs. 3 percent, P=0.05).Intraoperative hypothermia did not improve the neurologic outcome after craniotomy among good-grade patients with aneurysmal subarachnoid hemorrhage.
View details for Web of Science ID 000226251700006
View details for PubMedID 15647576
- Dexmedetomidine and opioid interactions: Defining the role of dexmedetomidine for intensive care unit sedation ANESTHESIOLOGY 2004; 101 (5): 1059-1061
Management of perioperative pain in patients chronically consuming opioids
REGIONAL ANESTHESIA AND PAIN MEDICINE
2004; 29 (6): 576-591
The prevalence of licit and illicit opioid use is growing, and a greater percentage of chronically opioid-consuming patients are presenting for surgery. These patients can be expected to experience increased postoperative pain, greater postoperative opioid consumption, and prolonged use of healthcare resources for managing their pain.Achieving adequate pain control in these patients can be challenging because commonly used strategies for alleviating postoperative pain may have diminished effectiveness. We explore the prevalence and characteristics of opioid use in the United States and discuss its impact on the perioperative management of pain. We examine mechanistically why adequate perioperative pain control in chronically opioid-consuming patients may be difficult.We present strategies for providing adequate analgesia to these patients that include the optimal use of opioids, adjuvant medications, and regional anesthetic techniques.
View details for DOI 10.1016/j.rapm.2004.06.009
View details for Web of Science ID 000226144300011
View details for PubMedID 15635517
Comparative analgesic and mental effects of increasing plasma concentrations of dexmedetomidine and alfentanil in humans
2004; 101 (3): 744-752
In animals, systemic and intrathecal administration of the alpha2 -adrenergic receptor agonist dexmedetomidine results in robust antinociceptive effects in models of heat pain. In humans, systemically administered dexmedetomidine is approved for sedating patients in the intensive care unit. However, whether systemic administration of dexmedetomidine in humans produces significant analgesia at doses causing sedation but not unconsciousness remains controversial.This study in human volunteers used a placebo-controlled, double-blind, and randomized design to examine whether dexmedetomidine at doses causing mild to severe sedation produces analgesia in experimental models of heat and electrical pain. Results were compared to the effects of the mu-opioid receptor agonist alfentanil. A computer-controlled infusion provided four median step-up plasma concentrations of dexmedetomidine (0.09, 0.24, 0.54, and 1.23 ng/ml) and alfentanil (13.4, 33.8, 67.8, and 126.1 ng/ml).Sedative and cognitive effects of dexmedetomidine were dose-dependent, resulting in a median sedation score of 95 of 100 and slowing of cognitive speed (reaction time, trail-making test) by a factor of about two at the highest plasma concentration. Dexmedetomidine did not attenuate heat or electrical pain. Alfentanil caused severe sedation (median sedation score 88 of 100) and slowed cognitive speed by a factor of approximately 1.4 at the highest plasma concentration. Alfentanil attenuated heat and electrical pain dose dependently.This study documents that systemic dexmedetomidine lacks analgesic efficacy for heat and electrical pain at doses causing mild to severe sedation. These results provide further evidence suggesting that systemic administration of dexmedetomidine lacks broad analgesic activity in models of acute pain at doses not rendering humans unconscious.
View details for Web of Science ID 000223605100022
View details for PubMedID 15329600
The site of action of epidural fentanyl infusions in the presence of local anesthetics: A minimum local analgesic concentration infusion study in nulliparous labor
Annual Meeting of the Society-of-Obstetric-Anesthesiology-and-Perinatology
LIPPINCOTT WILLIAMS & WILKINS. 2003: 1439–45
We have previously demonstrated that continuous epidural infusions of fentanyl without local anesthetics elicit analgesia by a systemic mechanism. In this study, we examined the hypothesis that, in the presence of epidural bupivacaine, continuous infusions of epidural fentanyl elicit analgesia by a spinal mechanism. Forty-eight nulliparous women in active labor participated in this prospective, randomized, double-blinded study. Women received lumbar epidural analgesia with 20-30 mL bupivacaine 0.125% until pain free. Subjects were then randomized to either IV or epidural (EPI) fentanyl infusion groups. Each infusion delivered fentanyl 30 microg/h. All women received an epidural infusion of bupivacaine at a rate of 20 mL/h, the concentration of which was determined by the response of the previous woman in the same group to the analgesic regimen used. Unlike previous studies that assessed the minimum local analgesic concentration (MLAC) for bolus administration at the initiation of analgesia, this study assessed MLAC(infusion) for the maintenance of analgesia throughout the first stage of labor. MLAC(infusion) was determined using the up-down sequential analysis described by Dixon and Massey. The MLAC(infusion) of epidural bupivacaine was 0.063% (95% confidence interval, 0.058-0.068) and 0.019% (95% confidence interval, 0.000-0.038) in the IV and EPI groups respectively. A continuous infusion of fentanyl was more than three times as potent when administered by the epidural than by the IV route. This marked increase in potency for the epidural route is highly suggestive for a predominantly spinal mechanism of action for infused epidural fentanyl under the conditions of this study.This study determined the median effective concentration for epidural infusions of bupivacaine during labor analgesia. Coadministered epidural fentanyl infusions were more than three times more potent than IV fentanyl infusions, suggesting a predominantly spinal mechanism of opioid action under these study conditions.
View details for DOI 10.1213/01.ANE.0000081792.84877.A2
View details for Web of Science ID 000186143600038
View details for PubMedID 14570662
Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal
2003; 106 (1-2): 49-57
Numerous animal studies suggest that acute and chronic exposure to opioids can be associated with the development of hyperalgesia, i.e. an increased sensitivity to noxious stimuli. Hyperalgesia has been documented during withdrawal and on occasion while animals were still exposed to opioids. A pivotal role in the genesis of opioid-associated hyperalgesia has been attributed to a pain facilitating system involving the N-methyl-D-aspartate (NMDA)-receptor. In humans little direct evidence documents opioid-associated hyperalgesia, albeit observational data suggest that such hyperalgesia may be relevant in a clinical context. This study used a double blind, randomized, crossover and placebo-controlled design to test in opioid-naïve, healthy human volunteers whether hyperalgesia would develop within 30 min of stopping a 90-min infusion with the mu-opioid agonist remifentanil, and whether co-administration of the NMDA-receptor antagonist S-ketamine would prevent such hyperalgesia. We found that a skin area with pre-existing mechanical hyperalgesia was significantly enlarged after stopping the remifentanil infusion. However, the pain response to heat assessed in regular skin was not different before and after the infusion of remifentanil. Co-administration of the NMDA-receptor antagonist S-ketamine abolished observed enlargement of the hyperalgesic skin area. This study provides direct evidence in humans that short-term administration of an opioid can enhance hyperalgesia as observed during withdrawal and points to a potential role of the NMDA-receptor system in mediating such a hyperalgesic response. This study also points to a differential susceptibility of different pain modalities for the expression of hyperalgesia associated with opioid administration.
View details for DOI 10.1016/S0304-3959(03)00276-8
View details for Web of Science ID 000186693400008
View details for PubMedID 14581110
Naloxone provokes similar pain facilitation as observed after short-term infusion of remifentanil in humans
2003; 106 (1-2): 91-99
In contrast to an expected preventive analgesic effect, clinical observations suggest that intraoperatively applied opioids can induce postoperative hyperalgesia. We tested the development of post-infusion hyperalgesia in a newly developed experimental model of electrically induced pain and secondary mechanical hyperalgesia. In a double-blind, placebo controlled, cross-over study, 13 subjects received either saline placebo, remifentanil (0.05 or 0.1 microg/kg/min) or naloxone (0.01 mg/kg). Remifentanil dose-dependently reduced pain and mechanical hyperalgesia during the infusion, but upon withdrawal, pain and hyperalgesia increased significantly above control level (p<0.01 and p<0.05, respectively). Naloxone infusion similarly resulted in increased pain (anti-analgesia) (p<0.001) and mechanical hyperalgesia (p<0.01). Increased pain ratings following withdrawal of remifentanil significantly correlated to anti-analgesia evoked by the mu-opioid antagonist naloxone (p<0.01) and was of similar magnitude, suggesting inhibition of endogenous opioids as an underlying mechanism. In contrast, hyperalgesia after remifentanil was more pronounced than hyperalgesia after naloxone administration and did not correlate to the observed anti-analgesic effects, suggesting the involvement of additional receptors systems other than the endorphin system.
View details for DOI 10.1016/S0304-3959(03)00294-X
View details for Web of Science ID 000186693400013
View details for PubMedID 14581115
The site of action of epidural fentanyl in humans: The difference between infusion and bolus administration
Annual Meeting of the Society-of-Obstetric-Anesthesiology-and-Perinatology
LIPPINCOTT WILLIAMS & WILKINS. 2003: 1428–38
Most published studies suggesting that epidural fentanyl acts predominantly at spinal sites administered the drug as a bolus injection, whereas most studies suggesting that it acts predominantly at supraspinal sites administered the drug as an infusion. In this study we tested the hypothesis that the mode of administration (bolus versus infusion) of epidural fentanyl determines its site of action. Ten healthy volunteers were enrolled in this randomized, double-blinded, cross-over study. On separate study days fentanyl was administered into the epidural space as a bolus (0.03 mg followed by 0.1 mg 210 min later) and as an infusion (0.03 mg/h followed by 0.1 mg/hr 210 min later for 200 min). Using a thermal and electrical experimental pain model, the heat ( degrees C) and electrical current (mA) causing maximum tolerable pain were assessed repetitively over a period of 420 min. The analgesic efficacy measures were obtained at a lumbar and a cranial dermatome. Plasma fentanyl concentrations were determined throughout the study. Epidural bolus administration of fentanyl resulted in segmental analgesia (leg > head), whereas the epidural infusion of fentanyl produced nonsegmental analgesia (leg = head). There was a significant linear relationship between the analgesic effect and the plasma concentration of fentanyl for the epidural infusion but not for the epidural bolus administration of fentanyl. These findings support our hypothesis and might explain the apparent conflict in the literature regarding the site of action of epidural fentanyl.In an experimental pain study in volunteers, epidural fentanyl caused segmental analgesia when administered as a bolus and nonsegmental systemic analgesia when administered as a continuous infusion. This finding may help resolve the long-standing controversy surrounding the site of action of epidural fentanyl.
View details for DOI 10.1213/01.ANE.0000081793.60059.10
View details for Web of Science ID 000186143600037
View details for PubMedID 14570661
Seizure duration with remifentanil/methohexital vs. methohexital alone in middle-aged patients undergoing electroconvulsive therapy
ACTA ANAESTHESIOLOGICA SCANDINAVICA
2003; 47 (9): 1064-1066
The object of this study was to test whether substituting part of the methohexital dose with the short-acting opioid remifentanil would prolong seizure duration in middle-aged patients while providing a similar depth of anesthesia as with methohexital alone. This has been reported for the combined use of methohexital and remifentanil in elderly patients, but has not been investigated in middle-aged patients likely to require a higher total dose of methohexital for inducing anesthesia.Seven patients (42+/-10 years; mean +/-SD) receiving electroconvulsive therapy (ECT) were anesthetized with methohexital (1.25 mg kg-1) or with methohexital (0.625 mg kg-1) plus remifentanil (1 micro g kg-1) in this randomized, double blind, crossover study. Additional methohexital was given as needed until loss of eyelash reflex was observed. Suxamethonium (1 mg kg-1) was used for muscular paralysis.Motor and EEG seizure durations were significantly longer after induction with methohexital plus remifentanil (45+/-14 and 58+/-15 s) than with methohexital alone (31+/-11 and 42+/-18 s). A methohexital dose of 1.2+/-0.3 and 1.9+/-0.3 mg was necessary to achieve loss of eyelash reflex if methohexital was used with and without remifentanil. Peak heart rate after ECT was significantly higher if remifentanil was coadministered with methohexital (148+/-12 vs. 126+/-24 b.p.m).Substituting part of the methohexital dose with remifentanil is a useful anesthetic technique to prolong seizure duration in middle-aged patients requiring a 1.5-fold higher induction dose of methohexital than elderly patients, the only population studied to date for the combined use of methohexital and remifentanil in ECT.
View details for Web of Science ID 000185251000003
View details for PubMedID 12969096
The mu-opioid agonist remifentanil attenuates hyperalgesia evoked by blunt and punctuated stimuli with different potency: a pharmacological evaluation of the freeze lesion in humans
International CPT Congress
ELSEVIER SCIENCE BV. 2003: 151–61
Experimental pain models inducing hyperalgesia, i.e. an increased sensitivity to noxious stimuli often present in clinical pain, are important tools for studying antinociceptive drug profiles. The correct interpretation of results obtained in these models necessitates their mechanistic understanding. This study evaluated the freeze lesion, an experimental model of hyperalgesia, in humans. Twelve healthy subjects were tested with mechanical (brush, punctuated and blunt) and electrical (5, 250, and 2000 Hz sine wave current) stimuli before and after freezing the skin, and during a computer-controlled infusion of the mu-opioid agonist remifentanil targeting five different plasma concentrations between 0 and 6 ng/ml in a two-staged, single occasion, randomized, and double blind study design. Pharmacodynamic modeling techniques were used to describe the effect of freezing and drug administration on the mechanical and electrical pain thresholds. Freezing the skin resulted in hyperalgesia to blunt and punctuated stimuli and lowered the respective pain threshold by 29 and 73%. Hyperalgesia to brushing or electrical stimuli was not detected. Remifentanil attenuated hyperalgesia to blunt stimuli about twice as potently as hyperalgesia to punctuated stimuli, as indicated by a significantly steeper linear relationship between the remifentanil plasma concentration and the increase of the pain threshold to blunt stimuli. Remifentanil attenuated electrical pain with greater potency for low frequency stimulation. The potency difference of remifentanil suggests that different neuronal mechanisms mediate hyperalgesia to blunt and punctuated stimulation. Absence of brush-evoked and electrical hyperalgesia is compatible with the view that mechanical hyperalgesia to blunt and punctuated stimulation of the freeze lesion is predominantly caused by a peripheral mechanism.
View details for DOI 10.1016/S0304-3959(02)00349-4
View details for Web of Science ID 000181712100016
View details for PubMedID 12620606
Input characteristics and bioavailability after administration of immediate and a new extended-release formulation of hydromorphone in healthy volunteers
Annual Meeting of the American-Society-of-Anesthesiologists
LIPPINCOTT WILLIAMS & WILKINS. 2002: 827–36
To compare the pharmacokinetics of intravenous, oral immediate-release (IR), and oral extended-release (OROS ) formulations of hydromorphone.In this randomized, six-session, crossover-design study, 12 subjects received hydromorphone 8-mg intravenous, 8-mg IR oral, and 8-, 16-, and 32-mg OROS formulations or placebo orally followed by plasma sampling for hydromorphone determination. Pharmacokinetic analysis was performed using NONMEM. Using the disposition of hydromorphone from the intravenous administration, deconvolution was used to estimate the input rate function (release rate from the gut to the blood) for the IR and OROS formulations. A linear spline was used to describe the drug input rate function.The deconvolution using linear splines described the release characteristics of both the IR and OROS formulations. The mean absolute bioavailability for the 8-mg OROS formulation was significantly larger ( = 0.025) than for the 8-mg IR formulation: 0.24 (SD 0.059) versus 0.19 (SD 0.054), respectively. The bioavailability was the same for the three doses of the OROS formulation. Predicted degree of fluctuation of plasma concentrations would be expected to be 130% and 39% for the IR and OROS 8-mg doses, respectively.The OROS formulation of hydromorphone produced continued release of medication over 24 h, which should allow for once-daily oral dosing. The extended release of hydromorphone will produce less fluctuation of plasma concentrations compared with IR formulations, which should provide for more constant pain control. The in vivo release of hydromorphone from both IR and OROS formulations were adequately described using a linear spline deconvolution approach. The increased bioavailability from the OROS formulation may be related to decreased metabolism by a first-pass effect or enterohepatic recycling of hydromorphone.
View details for Web of Science ID 000178409800012
View details for PubMedID 12357147
Opioid-induced hyperalgesia and incisional pain
ANESTHESIA AND ANALGESIA
2001; 93 (1): 204-209
Opioids occupy a position of unsurpassed clinical utility in the treatment of pain of many etiologies. However, recent reports in laboratory animals and humans have documented the occurrence of hyperalgesia when the administration of opioids is abruptly tapered or discontinued, a condition known as opioid-induced hyperalgesia (OIH). In these studies we documented that rats administered morphine (40 mg. kg(-1). day(-1) for 6 days) via subcutaneous osmotic minipumps demonstrated thermal hyperalgesia and mechanical allodynia for several days after the cessation of morphine administration. Additional experiments using a rat model of incisional pain showed that that attributable to OIH were additive with the hyperalgesia and allodynia that resulted from incision. In our final experiments we observed that if naloxone is administered chronically before incision then discontinued (20 mg. kg(-1). day(-1) for 6 days), the hyperalgesia and allodynia that result from hind paw incision was markedly reduced. In contrast, naloxone 1 mg/kg administered acutely after hind paw incision increased hyperalgesia and allodynia. We conclude that the chronic administration of exogenous opioid receptor agonists and antagonists before incision can alter the hyperalgesia and allodynia observed in this pain model, perhaps by altering intrinsic opioidergic systems involved in setting thermal and mechanical nociceptive thresholds. Implications: The chronic administration of opioids followed by abrupt cessation can lead to a state of hyperalgesia. In these studies we demonstrate that the hyperalgesia from opioid cessation and from hind paw incision are additive in rats. We suggest that failure to take into consideration preoperative opioid use can lead to excessive postoperative pain.
View details for Web of Science ID 000169645900040
View details for PubMedID 11429366
The relationship between tracheal width and left bronchial width: Implications for left-sided double-lumen tube selection
JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA
2001; 15 (2): 216-217
To determine if there is a relationship between tracheal width (TW) and left bronchial width (LBW).Three-dimensional chest computed tomography (CT) scans were used to reconstruct major airways for measurement of TW and LBW.Stanford University Medical Center, Stanford, California.Thirty-one adult patients undergoing chest CT scans.Cursors were used to directly measure internal diameter from coronal images of the trachea at midclavicular level and the left main bronchus at a level 1 cm below the carina.TW and LBW, but not the LBW-to-TW ratio, were significantly larger in men than in women. The LBW-to-TW ratio was consistent for men (0.75 +/- 0.09) and women (0.77 +/- 0.10).LBW is proportional to TW. If LBW cannot be measured directly but TW can, the ratio of LBW to TW can be used to predict LBW. An appropriate-sized left double-lumen tube can then be selected for the patient.
View details for Web of Science ID 000168082600014
View details for PubMedID 11312482
A murine model of opioid-induced hyperalgesia
MOLECULAR BRAIN RESEARCH
2001; 86 (1-2): 56-62
Controversies surround the possible long-term physiological and psychological consequences of opioid use. Analgesic tolerance and addiction are commonly at the center of these controversies, but other concerns exist as well. A growing body of evidence suggests that hyperalgesia caused by the chronic administration of opioids can occur in laboratory animals and in humans. In these studies we describe a murine model of opioid-induced hyperalgesia (OIH). After the treatment of mice for 6 days with implanted morphine pellets followed by their removal, both thermal hyperalgesia and mechanical allodynia were documented. Additional experiments demonstrated that prior morphine treatment also increased formalin-induced licking behavior. These effects were intensified by intermittent abstinence accomplished through administration of naloxone during morphine treatment. Experiments designed to determine if the mu-opioid receptor mediated OLH in our model revealed that the relatively-selective mu-opioid receptor agonist fentanyl induced the thermal hyperalgesia and mechanical allodynia characteristic of OIH when administered in intermittent boluses over 6 days. In complimentary experiments we found that CXBK mice which have reduced mu-opioid receptor binding displayed no significant OIH after morphine treatment. Finally, we explored the pharmacological sensitivities of OIH. We found that the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) and the heme oxygenase (HO) inhibitor tin protoporphyrin (Sn-P) dose-dependently reduced OIH in this model while the NSAID indomethacin had no effect. Thus we have characterized a murine model of OIH which will be useful in the pursuit of the molecular mechanisms underlying this phenomenon.
View details for Web of Science ID 000166721100008
View details for PubMedID 11165371
Pharmacodynamics of orally administered sustained-release hydromorphone in humans
2001; 94 (1): 63-73
The disposition kinetics of hydromorphone generally necessitates oral administration every 4 h of the conventional immediate-release tablet to provide sustained pain relief. This trial examined time course and magnitude of analgesia to experimental pain after administration of sustained-release hydromorphone as compared with that after immediate-release hydromorphone or placebo.Using a 4 x 4 Latin square double-blind design, 12 subjects were randomized to receive a single dose of 8, 16, and 32 mg sustained-release hydromorphone and placebo. The same subjects had received 8 mg immediate-release hydromorphone before this study. Using an electrical experimental pain paradigm, analgesic effects were assessed for up to 30 h after administration, and venous hydromorphone plasma concentrations were measured at corresponding times.The hydromorphone plasma concentration peaked significantly later (12.0 h [12.0--18.0] vs. 0.8 h [0.8--1.0]; median and interquartile range) but was maintained significantly longer at greater than 50% of peak concentration (22.7 +/- 8.2 h vs. 1.1 +/- 0.7 h; mean +/- SD) after sustained-release than after immediate-release hydromorphone. Similarly, sustained-release hydromorphone produced analgesic effects that peaked significantly later (9.0 h [9.0--12.0] vs. 1.5 h [1.0--2.0]) but were maintained significantly longer at greater than 50% of peak analgesic effect (13.3 +/- 6.3 h vs. 3.6 +/- 1.7 h). A statistically significant linear relation between the hydromorphone plasma concentration and the analgesic effect on painful stimuli existed.A single oral dose of a new sustained-release formulation of hydromorphone provided analgesia to experimental pain beyond 24 h of its administration.
View details for Web of Science ID 000166262300010
View details for PubMedID 11135723
- Painless Electrodiagnostic Current Perception Threshold and Pain Tolerance Threshold Values in CRPS Subjects and Healthy Controls: A Multi-Center Study Pain Practice 2001; 1: 53-60
Antinociceptive effects of morphine-6-glucuronide in homozygous MDR1a P-glycoprotin knockout and in wildtype mice in the hotplate test
2000; 66 (24): 2393-2403
Morphine-6-glucuronide (M6G), a major metabolite of morphine with agonist opioid-receptor activity, was reported to be a substrate of P-glycoprotein (P-gp). Inhibition of P-gp may thus result in higher brain uptake of M6G. The goal of this observer-blinded, placebo controlled study, was to compare the antinociceptive effects of M6G in homozygous P-gp knockout (mdr1a(-/-)) and wildtype (mdr1a(+/+)) mice. M6G was injected intraperitoneally as a single dose of 0, 0.5, 1, 2.5, 5, and 10 mg/kg. Eight P-gp knockout and eight wildtype mice were studied per dose. A hot plate test was performed before and 5, 15, 30, 60, 90, 120, and 150 min after M6G administration. Plasma-concentrations of M6G, morphine, and morphine-3-glucuronide (M3G) were measured after intraperitoneal injection of 5 mg/kg M6G in another 14 P-gp knockout and 14 wildtype mice. No difference neither in the dose response relationship, nor in the time course of response latency times were observed between P-gp knockout and wildtype mice. However, latency times increased with higher doses of M6G, with antinociception significantly different from placebo at a M6G dose of 5 and 10 mg/kg. P-gp knockout mice tended to have higher plasma concentrations than the wildtype. However, plasma concentrations widely overlapped between groups and therefore no statistical significant group difference could be detected. We conclude that despite reported doubling of M6G brain uptake, absence of mdr1a coded P-gp does not enhance antinociceptive effects of M6G in the hotplate test after acute single-dose administration in mdr1a(-/-) knockout mice.
View details for Web of Science ID 000086827900008
View details for PubMedID 10864101
- Insidious intoxication after morphine treatment in renal failure: Delayed onset of morphine-6-glucuronide action ANESTHESIOLOGY 2000; 92 (5): 1473-1476
Orthotopic liver transplantation for carcinoid tumour metastatic to the liver: anesthetic management
CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE
2000; 47 (4): 334-337
To report the anesthetic management of a patient with carcinoid tumour metastatic to the liver who presented for orthotopic liver transplantation. Anesthetic implications of metastatic carcinoid tumour on liver transplantation and the use of octreotide are discussed.A 51-yr-old woman with intestinal carcinoid tumour metastatic to the liver presented for orthotopic liver transplantation, a recent treatment option for patients with extensive hepatic carcinoid metastases and disabling symptoms unresponsive to conventional therapy. Despite continuous administration of the somatostatin analogue octreotide via a hepatic artery infusate pump, the patient suffered from daily break through symptoms, which included flushing, palpitations, paroxysmal hypertension, and dyspnea. The patient presented to the operating room with sinus tachycardia and severe arterial hypertension. Octreotide and phentolamine were used to prevent further mediator release and to control the paroxysmal hypertension. Midazolam, fentanyl, thiopental, succinylcholine, vecuronium, and isoflurane were used to induce and maintain anesthesia safely. An intravenous octreotide infusion was initiated after induction and continued throughout the case. Infrequent and non-threatening peaks in arterial blood pressure were readily treated with small intravenous doses of vasoactive drugs and octreotide. No other manifestations of the carcinoid syndrome occurred. The patient had an uneventful recovery and was discharged on postoperative day #6.The patient safely underwent orthotopic liver transplantation for treatment of symptomatic carcinoid tumour metastatic to the liver. The anesthetic management followed recent recommendations favouring the use of octreotide to prevent patients from becoming symptomatic. Outlined dosing regimen for octreotide provided satisfactory hemodynamic stability.
View details for Web of Science ID 000089776300009
View details for PubMedID 10764178
Lumbar epidural morphine in humans and supraspinal analgesia to experimental heat pain
2000; 92 (2): 312-324
Epidural administration of morphine is a common analgesic technique to manage pain. Morphine spreads from the epidural space to the cerebrospinal fluid and then rostrally, causing side effects mediated by the brain stem. However, data on the rostral spread of morphine-mediated analgesia are sparse. This study examined the rostral spread of analgesic effects on heat and electrical pain after epidural administration of morphine.In a randomized, double-blinded, placebo-controlled, crossover study, 5 mg morphine or saline placebo were injected into the lumbar epidural space in nine healthy volunteers. Correct needle placement was confirmed with fluoroscopy. Analgesia to experimental nociceptive heat and electrical stimuli was measured at lumbar (L4), thoracic (T10), cervical (C2), and trigeminal (V2) levels before and 2, 5, 10, and 24 h after epidural injection. Plasma samples for assaying morphine concentrations were drawn before and after each analgesic evaluation.Epidural morphine significantly attenuated experimental heat pain at all dermatomes tested compared with saline placebo. Analgesic effects were significant at L4 after 2, 5, and 10 h, at T10 after 5, 10, and 24 h, and at V2 after 10 h. Electrical pain was attenuated at the lumbar and thoracic but not at the cervical dermatome. Analgesic effects were significant at L4 after 2, 5, and 10 h and at T10 after 5 and 10 h. Morphine plasma concentrations were below the detection limit (1 ng/ml) in eight of the nine subjects 10 h after epidural injection.Lumbar epidural injection of morphine attenuated cutaneous heat pain up to the trigeminal dermatome during a 24-h observation period. In a clinical context, this implies that some types of pain may be attenuated up to the supraspinal level after lumbar epidural administration of morphine.
View details for Web of Science ID 000085078600007
View details for PubMedID 10691216
The relationship between the visual analog pain intensity and pain relief scale changes during analgesic drug studies in chronic pain patients
1999; 91 (1): 34-41
Most analgesic drug studies in humans quantify drug action based on verbal reports of pain intensity and pain relief. Although measures of pain intensity and pain relief show a good overall correlation, it is not known if they relate to each other consistently over time Such consistency is necessary if both measures are used to depict analgesic drug action versus time. This study examined in chronic pain patients if the relationship between visual analog pain intensity and pain relief scores was consistent during two analgesic drug studies.Data from two independently performed analgesic drug studies were analyzed using linear regression. Data were split into pain intensity and pain relief scores recorded before and after patients' experience of maximum analgesia (>90% of maximum pain relief). The slopes of the linear regression line depicting pain intensity versus pain relief scores before and after maximum analgesia were statistically compared.The slope of the linear regression line before and after maximum analgesia was significantly different in both drug studies (nonoverlapping 95% confidence intervals), -2.16+/-0.57 versus -1.05+/-0.10 and -1.47+/-0.26 versus -1.09+/-0.07, respectively. These results are compatible with the observation that patients indicating the same pain intensity before and after maximum analgesia reported a different magnitude of pain relief.The relationship between visual analog pain intensity and pain relief scores changed systematically during both analgesic drug studies. The authors hypothesize that patients' interpretation of the pain relief scale had changed during the studies and therefore suggest using the pain intensity scale to quantify analgesic drug action over time.
View details for Web of Science ID 000081188400008
View details for PubMedID 10422926
Factors affecting the pharmacokinetic characteristics of rapacuronium
1999; 90 (4): 993-1000
Rapacuronium is a new nondepolarizing muscle relaxant with rapid onset and offset. As part of a study to determine its neuromuscular effects, the authors sampled plasma sparsely to determine the influence of age, gender, and other covariates on its pharmacokinetic characteristics.Of 181 patients receiving a single bolus dose of 0.5-2.5 mg/kg rapacuronium, 43 (aged 24-83 yr) had plasma sampled 3 or 4 times to determine plasma concentrations of rapacuronium and its metabolite, ORG9488. Pharmacokinetic analysis was performed using a population approach (mixed-effects modeling) to determine the influence of demographic characteristics and preoperative laboratory values on the pharmacokinetic parameters.Rapacuronium's weight-normalized plasma clearance was 7.03 x (1 - 0.0507 x (HgB - 13)) ml x kg(-1) x min(-1), where HgB is the patient's preoperative value for hemoglobin (g/100 ml); however, rapacuronium's blood clearance (11.4+/-1.4 ml x kg(-1) x min(-1), mean +/- SD) did not vary with hemoglobin. Rapacuronium's weight-normalized pharmacokinetic parameters were not influenced by age, gender, or other covariates examined. Plasma concentrations of ORG9488 were typically less than 14% those of rapacuronium during the initial 30 min after rapacuronium administration.In this patient population, neither age nor gender influence elimination of rapacuronium. This finding contrasts to an age-related decrease in plasma clearance observed in a study of 10 healthy volunteers and in a pooled analysis of the pharmacokinetic data from 206 adults in multiple clinical studies. Even if ORG9488 has a potency similar to that of rapacuronium, its plasma concentrations after a single bolus dose of rapacuronium are sufficiently small to contribute minimally to neuromuscular blockade.
View details for Web of Science ID 000079457600010
View details for PubMedID 10201669
Pharmacokinetics, cortisol release, and hemodynamics after intravenous and subcutaneous injection of human corticotropin-releasing factor in humans
CLINICAL PHARMACOLOGY & THERAPEUTICS
1998; 64 (5): 499-510
Two clinical trials investigated the pharmacokinetics of human corticotropin-releasing factor (hCRF), resulting cortisol release, and associated hemodynamic changes.In a 3 x 3 Latin square design, subjects were randomized to receive a single dose of 5 microg x kg(-1) hCRF as a 10-minute intravenous infusion, a 180-minute infusion, and a subcutaneous injection in separate study sessions 7 days apart. Twelve additional subjects obtained a subcutaneous dose of either 300, 600, or 1200 microg hCRF on 3 consecutive days. Noncompartmental and compartmental pharmacokinetic analysis was performed. Hemodynamic response was characterized with use of pharmacodynamic models.The volume of distribution at steady state was 9.81 +/- 3.0 and 15.61 +/- 2.9, and the clearance was 256 +/- 40 mL x min(-1) and 345 +/- 90 mL x min(-1) for the 10-minute and 180-minute intravenous infusion, respectively (P < .05). Corresponding elimination half-life was 45 +/- 7 minutes and 37 +/- 10 minutes. Two-compartment and 1-compartment models adequately described the 10-minute and 180-minute infusions, respectively. The bioavailability of hCRF after subcutaneous administration was 67% +/- 17%. Apparent clearance remained unchanged for different subcutaneous doses. Peak plasma cortisol concentrations were similar after subcutaneous and intravenous administration of hCRF. Repetitive administration of hCRF did not result in accumulation but produced a reduced plasma cortisol response. A sigmoidal model related plasma hCRF concentrations to increase in heart rate (maximum, 39 beats x min(-1)). The relationship between the modest decrease in diastolic blood pressure and plasma hCRF concentrations was linear.The pharmacokinetics of intravenously administered hCRF were nonlinear, but apparent clearance was constant for various subcutaneous doses. An excellent bioavailability and preserved bioactivity make the subcutaneous route an attractive choice. Repetitive administration of hCRF probably caused tolerance of the cortisol response.
View details for Web of Science ID 000077167800005
View details for PubMedID 9834042
- Dose-response function of epidural fentanyl versus sufentanil ANESTHESIA AND ANALGESIA 1998; 86 (4): 918-919
Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapid-onset, short-duration muscle relaxant
ANESTHESIA AND ANALGESIA
1997; 84 (5): 1011-1018
The purpose of this multicenter, randomized, assessorblind placebo-controlled study was to determine which of five doses of the new, rapid-onset neuromuscular relaxant, ORG 9487, provided both good to excellent tracheal intubating conditions 60 s after administration and a clinical duration of action < 20 min in 120 younger (aged 18-64 yr) and 61 elderly (aged 65-85 yr) adult patients. Anesthesia was induced with fentanyl (2-5 micrograms/kg) and thiopental (3-6 mg/kg) and maintained with N2O/O2 and a propofol infusion (50-300 micrograms.kg-1.min-1). Neuromuscular train-of-four (TOF) monitoring by electromyography (Datex Relaxograph) commenced immediately after anesthetic induction and was followed, within 30 s, by one of five doses of ORG 9487 (0.5, 1.0, 1.5, 2.0, 2.5 mg/kg) or a placebo. Tracheal intubation was attempted at 60 s and again, in the case of failure, at 90 s. Conditions were assessed with a 4-point scale. Maximum block, clinical duration (time to 25% T1 recovery), and recovery (TOF > or = 0.7) were measured. Dose-dependent changes were observed in tracheal intubating conditions and neuromuscular block. Good to excellent intubating conditions at 60 s were present in most younger adult (52 of 60) and elderly (26 of 31) patients administered doses > or = 1.5 mg/kg. Mean clinical durations < 20 min were observed in adult patients at doses up to 2.0 mg/kg and in geriatric patients up to 1.5 mg/kg. Thus, doses of 1.5-2.0 mg/kg ORG 9487 enabled both rapid tracheal intubation and a short clinical duration of action in adult and elderly patients.
View details for Web of Science ID A1997WW54700012
View details for PubMedID 9141923
- A New Double-Lumen IV Infusion Set Reduces Pain on Injection of Propofol. J Clin Anesth 1997
CORTICOSTEROID-INDUCED STIMULATION OF ATRIAL NATRIURETIC PEPTIDE IN MAN
1988; 118 (2): 179-186
Previously, we reported elevated plasma immunoreactive ANP (irANP) levels from the 2nd to the 9th day of administering either prednisone, 50 mg/day, or 9 alpha-fludrocortisone acetate (9 alpha F), 0.6 mg/day, to normal humans. To investigate the course of plasma irANP levels during the first 48 h of corticosteroid administration, 9 healthy men (mean age +/- SEM, 24 +/- 1 years) received in randomised sequence A) a 4-h iv infusion of prednisolone sodium tetrahydrophthalate followed by oral administration of prednisone for 2 days; or B) a 4-h infusion of aldosterone followed by oral administration of 9 alpha F for 2 days. Basal supine plasma irANP levels averaged 32 +/- 5 ng/l in study A and 30 +/- 6 ng/l in study B; they were unchanged or even deceased up to 24 h of glucocorticoid or mineralocorticoid administration, but rose (P less than 0.01) to 56 +/- 9 and 62 +/- 12 ng/l at 48 h, respectively, of the two interventions. During glucocorticoid treatment, blood pressure (BP) and indices of the sodium-fluid volume state were unchanged after 48 h. During 9 alpha F administration, body weight increased (1.1 +/- 0.3%, P less than 0.001), whereas urinary sodium excretion (63 +/- 7%, P less than 0.001), hematocrit (4.1 +/- 1.1%, P less than 0.001), and plasma renin activity (38 +/- 4%, P less than 0.001) decreased. Conclusions: The increase in circulating irANP at 48 h of administration of either a glucocorticoid or a mineralocorticoid demonstrates a distinct but slow response of the ANP system to these corticosteroids in normal humans.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1988N635200004
View details for PubMedID 2968749