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Nayef E Saade - One of the best experts on this subject based on the ideXlab platform.
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involvement of the α7 nicotinic acetylcholine receptors in the anti inflammatory action of the thymulin related peptide pat
Neuroscience, 2013Co-Authors: B Safiehgarabedian, Murat Oz, Farah Shamaa, A Ashoor, Omar M A Elagnaf, Nayef E SaadeAbstract:Abstract Background and Purpose Peptide analog of thymulin (PAT) has been shown to have anti-hyperalgesic and anti-inflammatory properties in animal models of inflammation. Recent reports suggest that the peripheral cholinergic system has an anti-inflammatory role mediated by α7-nicotinic acetylcholine receptor (α7-nAChR). Our aim is to investigate whether the action of PAT is mediated, via the cholinergic pathway. Experimental Approach The anti-hyperalgesic and anti-inflammatory action of PAT was assessed in rat models of inflammatory nociceptive hyperactivity (carrageenan and endotoxin) and in a mice air-pouch model for localized inflammation, respectively; the possible attenuation of PAT’s effects by pretreatment with the α7-nAchR specific antagonist methyllycaconitine citrate (MLA) was also investigated. In another series of experiments, using two electrode recordings, the effect of PAT on the α7-nAChRs, expressed in Xenopus Oocytes, was also determined. Key Results Administration of PAT reversed inflammatory nociceptive hyperactivity and cold and tactile hyperactivity in rats. This effect was partially or totally prevented by MLA, as assessed by different behavioral Pain Tests. Treatment with PAT also reduced the alteration of cytokines and NGF levels by carrageenan injection in the mouse air pouch model; this effect was partially antagonized by MLA. Electrophysiological recording demonstrated that PAT significantly potentiated the α7-nAchR expressed in Xenopus Oocytes. These effects were not observed when a control peptide, with a reverse sequence (rPAT), was utilized. Conclusions and Implications The behavioral and electrophysiological observations described in this report demonstrate that PAT mediates, at least partially, its anti-inflammatory action by potentiating the α7-nAChR. These results indicate that PAT has a potential for new therapeutic applications as anti-inflammatory and analgesic agent.
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thymulin reverses inflammatory hyperalgesia and modulates the increased concentration of proinflammatory cytokines induced by i c v endotoxin injection
Neuroscience, 2003Co-Authors: Bared Safiehgarabedian, Samir Atweh, Suhayl J. Jabbur, C I Ochoachaar, Stephen Poole, C A Massaad, Nayef E SaadeAbstract:The immunomodulatory thymic hormone thymulin has been shown previously to possess anti-inflammatory actions in the periphery. In this study, we have examined the effect of i.c.v. injections of either endotoxin (ET) or thymulin, in separate groups of conscious rats, on Pain-related behavior and cytokine levels in different areas of the brain. Furthermore, we investigated the effect of pretreatment with either i.c.v. or i.p. injections of thymulin on endotoxin-induced hyperalgesia and the effect of pretreatment with i.c.v. thymulin on endotoxin-induced up-regulation of cytokine levels. Our results demonstrate that i.c.v. injection of endotoxin (1 μg in 5 μl saline) resulted in a significant decrease in the nociceptive thresholds as assessed by different Pain Tests, with peak hyperalgesia at 3h. However, thymulin at different doses, when injected (i.c.v.), had no significant effect on Pain related behavior. Pretreatment (i.c.v.) with thymulin (0.1, 0.5 and 1 μg in 5 μl saline) 20 min before endotoxin (i.c.v.) injection (1 μg in 5 μl saline) reduced, in a dose dependent manner, the endotoxin-induced hyperalgesia and exerted differential effects on the up-regulated levels of cytokines in different areas of the brain. The results provide behavioral and immunochemical characterization of a rat model for intracerebral inflammation and indicates a neuroprotective role for thymulin in the CNS.
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the role of cytokines and prostaglandin e2 in thymulin induced hyperalgesia
Neuropharmacology, 2000Co-Authors: Bared Safiehgarabedian, Salim A Kanaan, Samir Atweh, Mireille Dardenne, Suhayl J. Jabbur, Nayef E SaadeAbstract:We have recently reported that intraperitoneal (i.p.) injection of thymulin at low doses (50 ng) resulted in thermal and mechanical hyperalgesia and upregulation of the level of interleukin-1β in the liver. In this study, we demonstrate that such injections of thymulin result in a significant elevation in the levels of TNF-α (P<0.01), NGF (P<0.01) and PGE2 (P<0.01) in the liver of the treated rats, in addition to the increase in the levels of IL-1β. Pretreatment with specific antagonists to each of these factors (polyclonal anti-TNF-α, anti-NGF antiserum and IL-1 receptor antagonist) did not result in the abolition of the hyperalgesia as assessed by the paw pressure, hot plate, paw immersion and tail flick Tests. However, pretreatment with a combination of the above antagonist and antisera almost completely prevented thymulin-induced hyperalgesia. The cyclooxygenase inhibitor, meloxicam, reversed in a dose dependent manner (0.2, 0.4 and 2 mg/kg) thymulin effects as assessed by the different Pain Tests. It also abolished the thymulin-induced increase in the level of cytokines and NGF in the liver. Our results indicate that PGE2 could be the key mediator of the hyperalgesic action of thymulin and the observed upregulation of proinflammatory cytokines and NGF.
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involvement of interleukin 1β nerve growth factor and prostaglandin e2in the hyperalgesia induced by intraplantar injections of low doses of thymulin
Brain Behavior and Immunity, 1997Co-Authors: Bared Safiehgarabedian, Salim A Kanaan, Raffy H Jalakhian, Suhayl J. Jabbur, Nayef E SaadeAbstract:Abstract The effect of various doses of intraplantar thymulin injection, on nociceptive thresholds, in the hind paw of rats was assessed using different Pain Tests. As little as 0.5 ng thymulin resulted in localized mechanical hyperalgesia as assessed by the paw pressure test and thermal hyperalgesia as assessed by the paw immersion, hot plate, and tail flick Tests. The highest dose of thymulin (10 ng) reduced both paw pressure and paw immersion latencies in the noninjected paw also. Thymulin (5 ng) also resulted in significant elevation in the levels of interleukin-1β (IL-1β) and nerve growth factor (NGF) levels in the injected paw. Both dexamethasone and indomethacin reversed thymulin-induced hyperalgesia. Also interleukin-1 receptor antagonist (IL-1ra) and a polyclonal anti-NGF antiserum significantly reduced thymulin-induced hyperalgesia. On the other hand, the tripeptide lys-D-pro-val (known to antagonize IL-1β and PGE 2 induced hyperalgesia) reversed the hyperalgesia due to thymulin. In conclusion, thymulin induces localized hyperalgesia which is mediated by PGE 2 -dependent mechanisms and this pathway could be either partially dependent on or totally independent of IL-1β mechanisms.
Bared Safiehgarabedian - One of the best experts on this subject based on the ideXlab platform.
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thymulin reverses inflammatory hyperalgesia and modulates the increased concentration of proinflammatory cytokines induced by i c v endotoxin injection
Neuroscience, 2003Co-Authors: Bared Safiehgarabedian, Samir Atweh, Suhayl J. Jabbur, C I Ochoachaar, Stephen Poole, C A Massaad, Nayef E SaadeAbstract:The immunomodulatory thymic hormone thymulin has been shown previously to possess anti-inflammatory actions in the periphery. In this study, we have examined the effect of i.c.v. injections of either endotoxin (ET) or thymulin, in separate groups of conscious rats, on Pain-related behavior and cytokine levels in different areas of the brain. Furthermore, we investigated the effect of pretreatment with either i.c.v. or i.p. injections of thymulin on endotoxin-induced hyperalgesia and the effect of pretreatment with i.c.v. thymulin on endotoxin-induced up-regulation of cytokine levels. Our results demonstrate that i.c.v. injection of endotoxin (1 μg in 5 μl saline) resulted in a significant decrease in the nociceptive thresholds as assessed by different Pain Tests, with peak hyperalgesia at 3h. However, thymulin at different doses, when injected (i.c.v.), had no significant effect on Pain related behavior. Pretreatment (i.c.v.) with thymulin (0.1, 0.5 and 1 μg in 5 μl saline) 20 min before endotoxin (i.c.v.) injection (1 μg in 5 μl saline) reduced, in a dose dependent manner, the endotoxin-induced hyperalgesia and exerted differential effects on the up-regulated levels of cytokines in different areas of the brain. The results provide behavioral and immunochemical characterization of a rat model for intracerebral inflammation and indicates a neuroprotective role for thymulin in the CNS.
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the role of cytokines and prostaglandin e2 in thymulin induced hyperalgesia
Neuropharmacology, 2000Co-Authors: Bared Safiehgarabedian, Salim A Kanaan, Samir Atweh, Mireille Dardenne, Suhayl J. Jabbur, Nayef E SaadeAbstract:We have recently reported that intraperitoneal (i.p.) injection of thymulin at low doses (50 ng) resulted in thermal and mechanical hyperalgesia and upregulation of the level of interleukin-1β in the liver. In this study, we demonstrate that such injections of thymulin result in a significant elevation in the levels of TNF-α (P<0.01), NGF (P<0.01) and PGE2 (P<0.01) in the liver of the treated rats, in addition to the increase in the levels of IL-1β. Pretreatment with specific antagonists to each of these factors (polyclonal anti-TNF-α, anti-NGF antiserum and IL-1 receptor antagonist) did not result in the abolition of the hyperalgesia as assessed by the paw pressure, hot plate, paw immersion and tail flick Tests. However, pretreatment with a combination of the above antagonist and antisera almost completely prevented thymulin-induced hyperalgesia. The cyclooxygenase inhibitor, meloxicam, reversed in a dose dependent manner (0.2, 0.4 and 2 mg/kg) thymulin effects as assessed by the different Pain Tests. It also abolished the thymulin-induced increase in the level of cytokines and NGF in the liver. Our results indicate that PGE2 could be the key mediator of the hyperalgesic action of thymulin and the observed upregulation of proinflammatory cytokines and NGF.
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involvement of interleukin 1β nerve growth factor and prostaglandin e2in the hyperalgesia induced by intraplantar injections of low doses of thymulin
Brain Behavior and Immunity, 1997Co-Authors: Bared Safiehgarabedian, Salim A Kanaan, Raffy H Jalakhian, Suhayl J. Jabbur, Nayef E SaadeAbstract:Abstract The effect of various doses of intraplantar thymulin injection, on nociceptive thresholds, in the hind paw of rats was assessed using different Pain Tests. As little as 0.5 ng thymulin resulted in localized mechanical hyperalgesia as assessed by the paw pressure test and thermal hyperalgesia as assessed by the paw immersion, hot plate, and tail flick Tests. The highest dose of thymulin (10 ng) reduced both paw pressure and paw immersion latencies in the noninjected paw also. Thymulin (5 ng) also resulted in significant elevation in the levels of interleukin-1β (IL-1β) and nerve growth factor (NGF) levels in the injected paw. Both dexamethasone and indomethacin reversed thymulin-induced hyperalgesia. Also interleukin-1 receptor antagonist (IL-1ra) and a polyclonal anti-NGF antiserum significantly reduced thymulin-induced hyperalgesia. On the other hand, the tripeptide lys-D-pro-val (known to antagonize IL-1β and PGE 2 induced hyperalgesia) reversed the hyperalgesia due to thymulin. In conclusion, thymulin induces localized hyperalgesia which is mediated by PGE 2 -dependent mechanisms and this pathway could be either partially dependent on or totally independent of IL-1β mechanisms.
Lars Arendt-nielsen - One of the best experts on this subject based on the ideXlab platform.
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Association Between a Composite Score of Pain Sensitivity and Clinical Parameters in Low-Back Pain
The Clinical journal of pain, 2014Co-Authors: Søren O'neill, Claus Manniche, Thomas Graven-nielsen, Lars Arendt-nielsenAbstract:Background and Aims:A limited number of quantitative sensory Pain Tests (QST) were selected on the basis of ease of application and interpretation in a clinical setting. QST results were summarized as a composite score on a scale of 0 to 4 that was deemed to facilitate clinical interpretation. The Q
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Effect of transdermal opioids in experimentally induced superficial, deep and hyperalgesic Pain.
British journal of pharmacology, 2011Co-Authors: Trine Andresen, Lars Arendt-nielsen, Camilla Staahl, A Oksche, Heikki Mansikka, Asbjørn Mohr DrewesAbstract:BACKGROUND AND PURPOSE Chronic Pain and hyperalgesia can be difficult to treat with classical opioids acting predominately at the µ-opioid receptor. Buprenorphine and its active metabolite are believed to act through µ-, κ- and δ-receptors and may therefore possess different analgesic and anti-hyperalgesic effects compared with pure µ-receptor agonists, for example, fentanyl. Here, we have compared the analgesic and anti-hyperalgesic effects of buprenorphine and fentanyl. EXPERIMENTAL APPROACH Twenty-two healthy volunteers were randomized to treatment with transdermal buprenorphine (20 µg·h−1, 144 h), fentanyl (25 µg·h−1, 72 h) or placebo patches in a double-blind, cross-over experimental Pain study. The experimental Pain Tests (phasic Pain, sensitization) involved pressure at the tibial bone, cutaneous electrical and thermal stimulation, intramuscular nerve growth factor, UVB light burn injury model and intradermal capsaicin-induced hyperalgesia. Pain testing was carried out at baseline, 24, 48, 72 and 144 h after application of the drugs. KEY RESULTS Compared with placebo, buprenorphine, but not fentanyl, significantly attenuated pressure at the tibial bone as well as pressure Pain in the primary hyperalgesic area induced by UVB light The two drugs were equipotent and better than placebo against cutaneous thermal Pain stimulation), but failed to show significant analgesic effect to cutaneous electrical stimulation, nerve growth factor-induced muscle soreness and to capsaicin-induced hyperalgesia. CONCLUSIONS AND IMPLICATIONS Buprenorphine, but not fentanyl, showed analgesic effects against experimentally induced, bone-associated Pain and primary hyperalgesia compared with placebo. These tissue- and modality-differentiated properties may reflect the variable effects of opioid drugs observed in individual patients.
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Reference values of mechanical and thermal Pain Tests in a Pain-free population.
European journal of pain (London England), 2010Co-Authors: Alban Y. Neziri, Lars Arendt-nielsen, Pasquale Scaramozzino, Ole Kæseler Andersen, Anthony H. Dickenson, Michele CuratoloAbstract:Quantitative sensory Tests are widely used in human research to evaluate the effect of analgesics and explore altered Pain mechanisms, such as central sensitization. In order to apply these Tests in clinical practice, knowledge of reference values is essential. The aim of this study was to determine the reference values of Pain thresholds for mechanical and thermal stimuli, as well as withdrawal time for the cold pressor test in 300 Pain-free subjects. Pain detection and Pain tolerance thresholds to pressure, heat and cold were determined at three body sites: (1) lower back, (2) suprascapular region and (3) second toe (for pressure) or the lateral aspect of the leg (for heat and cold). The influences of gender, age, height, weight, body-mass index (BMI), body side of testing, depression, anxiety, catastrophizing and parameters of Short-Form 36 (SF-36) were analyzed by multiple regressions. Quantile regressions were performed to define the 5th, 10th and 25th percentiles as reference values for Pain hypersensitivity and the 75th, 90th and 95th percentiles as reference values for Pain hyposensitivity. Gender, age and/or the interaction of age with gender were the only variables that consistently affected the Pain measures. Women were more Pain sensitive than men. However, the influence of gender decreased with increasing age. In conclusion, normative values of parameters related to pressure, heat and cold Pain stimuli were determined. Reference values have to be stratified by body region, gender and age. The determination of these reference values will now allow the clinical application of the Tests for detecting abnormal Pain reactions in individual patients.
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Comparison of five experimental Pain Tests to measure analgesic effects of alfentanil.
Anesthesiology, 2001Co-Authors: Martin Luginbühl, Lars Arendt-nielsen, Thomas W. Schnider, Steen Petersen-felix, Alex M. ZbindenAbstract:Background Several experimental Pain models have been used to measure opioid effects in humans. The aim of the current study was to compare the qualities of five frequently used experimental Pain Tests to measure opioid effects. Methods The increase of electrical, heat, and pressure Pain tolerance and the decrease of ice-water and ischemic Pain perception was determined at baseline and at four different plasma concentrations of alfentanil (n = 7) administered as target controlled infusion or placebo (n = 7). A linear mixed-effects modeling (NONMEM) was performed to detect drug, placebo, and time effect as well as interindividual and intraindividual variation of effect. Results Only the electrical, ice-water, and pressure Pain Tests are sensitive to assess a concentration–response curve of alfentanil. At a plasma alfentanil concentration of 100 ng/ml, the increase in Pain tolerance compared with baseline was 42.0% for electrical Pain, 22.2% for pressure Pain, and 21.7% for ice-water Pain. The slope of the linear concentration–response curve had an interindividual coefficient of variation of 58.3% in electrical Pain, 35.6% in pressure Pain, and 60.0% in ice-water Pain. The residual error including intraindividual variation at an alfentanil concentration of 100 ng/ml was 19.4% for electrical Pain, 6.1% for pressure Pain, and 13.0% for ice-water Pain. Electrical Pain was affected by a significant placebo effect, and pressure Pain was affected by a significant time effect. Conclusion Electrical, pressure, and ice-water Pain, but not ischemic and heat Pain, provide significant concentration–response curves in the clinically relevant range of 200 ng/ml alfentanil or lower. The power to detect a clinically relevant shift of the curve is similar in the three Tests. The appropriate test(s) for pharmacodynamic studies should be chosen according to the investigated drug(s) and the study design.
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Comparison of the analgesic potency of xenon and nitrous oxide in humans evaluated by experimental Pain.
British journal of anaesthesia, 1998Co-Authors: Steen Petersen-felix, Lars Arendt-nielsen, Martin Luginbühl, Michele Curatolo, T. W. Schnider, Alex M. ZbindenAbstract:We have compared the analgesic potency of MAC-equivalent concentrations of xenon (10, 20, 30 and 40%) and nitrous oxide (15, 30, 45 and 60%) in humans using a multimodal experimental Pain testing and assessment technique. We tested 12 healthy volunteers in a randomized, single-blind, crossover study. The following experimental Pain Tests were used: nociceptive reflex to repeated stimuli; Pain tolerance to maximal effort tourniquet ischaemia; electrical stimulation; mechanical pressure; and cold. Reaction time was also measured. Xenon and nitrous oxide produced analgesia to ischaemic, electrical and mechanical stimulation, but not to cold Pain. There was no difference in MAC-equivalent concentrations of xenon and nitrous oxide. Both increased reaction time in a similar manner. Xenon and nitrous oxide evoked nausea and vomiting in a large number of volunteers.
Ronald Melzack - One of the best experts on this subject based on the ideXlab platform.
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Dissociable effects of lidocaine injection into medial versus lateral thalamus in tail-flick and formalin Pain Tests
Pathophysiology, 1994Co-Authors: John E. Mckenna, Ronald MelzackAbstract:Abstract Lidocaine was injected into the centromedial (CM) or ventroposterolateral (VPL) thalamic nuclei of alert, unrestrained rats prior to investigation in the formalin and tail-flick Tests. Regional anesthesia of CM resulted in a reduction of formalin-induced Pain behaviors, while injection into VPL had no significant effect. In the tail-flick test, however, lidocaine injection into VPL caused a significant decrease in withdrawal latencies, indicating increased sensitivity to noxious stimulation. Lidocaine injection into CM was ineffective in the tail-flick test. These results provide evidence of the relatively greater importance of the ‘non-specific' thalamic nuclei in the expression of tonic Pain, and of the VPL in the mediation of withdrawal reflexes to phasic Pain.
Michele Curatolo - One of the best experts on this subject based on the ideXlab platform.
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415 effect of the benzodiazepine clobazam in chronic low back Pain and experimental Pain modalities a randomized placebo controlled crossover study
The Journal of Pain, 2016Co-Authors: Jurg Schliessbach, Lars Arendtnielsen, Pascal Henri Vuilleumier, Andreas Siegenthaler, Lukas Butikofer, Andreas Limacher, Peter Juni, H Zeilhofer, Michele CuratoloAbstract:GABAergic compounds enhance endogenous inhibitory control within the central nervous system and are therefore potentially useful in human Pain conditions. Clobazam is an agonist at the benzodiazepine-binding site of GABA-A receptors. We investigated its effect on low back Pain and experimental Pain modalities in chronic low back Pain. Forty-nine patients with chronic low back Pain received a single oral dose of clobazam 20 mg and the active placebo tolterodine 1 mg in a double-blinded cross-over fashion. Pain intensity (0-10) (primary endpoint) was measured in the supine and sitting position. Nine experimental Pain modalities of pressure, electrical and thermal Pain, including conditioned Pain modulation, were applied at body sites distant to the low back. All assessments were made during 2 hours after drug intake. Pain intensity in the supine position was significantly lower after clobazam compared to placebo (60 minutes: 2.9 vs. 3.5, p=0.008; 90 minutes: 2.7 vs. 3.3, p=0.024; 120 minutes: 2.4 vs. 3.1, p=0.005). Pain intensity in the sitting position was not significantly different between the groups. No effect on experimental Pain Tests was observed. The results are suggestive for an analgesic effect of clobazam in low back Pain. The lack of effect in the sitting position suggests that GABAergic modulation may be less effective during mechanical strain of injured structures that may occur in the sitting position; the effect in the supine position suggests that GABAergic modulation is more effective at rest, when central sensitization processes may predominate over peripheral nociception. The lack of effect on experimental Pain modalities suggests that GABAergic compounds may not be effective on non-sensitized neural pathways that are not functionally connected to the site of injury. The finding of the present study encourages pharmacologic research on GABAergic compounds that are devoid of tolerance and sedation. Funded by the Swiss National Science Foundation.
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evaluation of anti hyperalgesic and analgesic effects of two benzodiazepines in human experimental Pain a randomized placebo controlled study
PLOS ONE, 2013Co-Authors: Pascal Henri Vuilleumier, Lars Arendtnielsen, Marie Besson, Jules Alexandre Desmeules, Michele CuratoloAbstract:Background and Aims Compounds that act on GABA-receptors produce anti-hyperalgesia in animal models, but little is known on their effects in humans. The aim of this study was to explore the potential usefulness of GABA-agonism for the control of Pain in humans. Two agonists at the benzodiazepine-binding site of GABAA-receptors (clobazam and clonazepam) were studied using multiple experimental Pain Tests. Positive results would support further investigation of GABA agonism for the control of clinical Pain.
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Reference values of mechanical and thermal Pain Tests in a Pain-free population.
European journal of pain (London England), 2010Co-Authors: Alban Y. Neziri, Lars Arendt-nielsen, Pasquale Scaramozzino, Ole Kæseler Andersen, Anthony H. Dickenson, Michele CuratoloAbstract:Quantitative sensory Tests are widely used in human research to evaluate the effect of analgesics and explore altered Pain mechanisms, such as central sensitization. In order to apply these Tests in clinical practice, knowledge of reference values is essential. The aim of this study was to determine the reference values of Pain thresholds for mechanical and thermal stimuli, as well as withdrawal time for the cold pressor test in 300 Pain-free subjects. Pain detection and Pain tolerance thresholds to pressure, heat and cold were determined at three body sites: (1) lower back, (2) suprascapular region and (3) second toe (for pressure) or the lateral aspect of the leg (for heat and cold). The influences of gender, age, height, weight, body-mass index (BMI), body side of testing, depression, anxiety, catastrophizing and parameters of Short-Form 36 (SF-36) were analyzed by multiple regressions. Quantile regressions were performed to define the 5th, 10th and 25th percentiles as reference values for Pain hypersensitivity and the 75th, 90th and 95th percentiles as reference values for Pain hyposensitivity. Gender, age and/or the interaction of age with gender were the only variables that consistently affected the Pain measures. Women were more Pain sensitive than men. However, the influence of gender decreased with increasing age. In conclusion, normative values of parameters related to pressure, heat and cold Pain stimuli were determined. Reference values have to be stratified by body region, gender and age. The determination of these reference values will now allow the clinical application of the Tests for detecting abnormal Pain reactions in individual patients.
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Comparison of the analgesic potency of xenon and nitrous oxide in humans evaluated by experimental Pain.
British journal of anaesthesia, 1998Co-Authors: Steen Petersen-felix, Lars Arendt-nielsen, Martin Luginbühl, Michele Curatolo, T. W. Schnider, Alex M. ZbindenAbstract:We have compared the analgesic potency of MAC-equivalent concentrations of xenon (10, 20, 30 and 40%) and nitrous oxide (15, 30, 45 and 60%) in humans using a multimodal experimental Pain testing and assessment technique. We tested 12 healthy volunteers in a randomized, single-blind, crossover study. The following experimental Pain Tests were used: nociceptive reflex to repeated stimuli; Pain tolerance to maximal effort tourniquet ischaemia; electrical stimulation; mechanical pressure; and cold. Reaction time was also measured. Xenon and nitrous oxide produced analgesia to ischaemic, electrical and mechanical stimulation, but not to cold Pain. There was no difference in MAC-equivalent concentrations of xenon and nitrous oxide. Both increased reaction time in a similar manner. Xenon and nitrous oxide evoked nausea and vomiting in a large number of volunteers.
