Publications by authors named "Natsuko Nozaki-Taguchi"

21 Publications

  • Page 1 of 1

Effects of opioids on respiration assessed by a contact-free unconstraint respiratory monitor with load cells under the bed in advanced cancer patients.

J Appl Physiol (1985) 2021 Apr 22. Epub 2021 Apr 22.

Department of Anesthesiology, Chiba University, Japan.

Nocturnal periodic breathing of chronic opioid users has been predominantly documented by use of polysomnography. No previous studies have assessed the opioid effects of respiratory rhythms throughout the day without use of physical restraint. We recently developed a contact-free unconstraint vital sign monitoring system with four load cells placed under the bed legs which allows continuous measurements of respiratory change at the center of gravity on the bed. We aimed to reveal details of the patient's 24-hour respiratory status under a monitoring system and to test the hypothesis that respiratory rhythm abnormalities are opioid dose-dependent and worsens during the night-time. Continuous 48-hour respiratory measurements were successfully performed in 51 advanced cancer patients (12 opioid-free patients and 39 opioid receiving patients). Medians of respiratory variables with minimal body movement artifacts were calculated for each 8-hour split time period. Compared with opioid-free patients, opioid-receiving patients had slower respiratory rate with higher respiratory rate irregularity without changing tidal centroid shift regardless of the time period. Irregular ataxic breathing was only identified in opioid-receiving patients (33%, p=0.023) while incidence rate of periodic breathing did not differ between the groups. Multivariate regression analyses revealed that opioid dose was an independent risk factor for occurrence of irregular breathing (odds ratio 1.81(95%CI: 1.39-2.36), p<0.001), and ataxic breathing (odds ratio 2.08 (95%CI: 1.60-2.71), p<0.001). Females developed the ataxic breathing at lower opioid dose compared to males. We conclude that respiratory rhythm irregularity is a predominant specific feature of opioid-dose dependent respiratory depression particularly in female advanced cancer patients.
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http://dx.doi.org/10.1152/japplphysiol.00904.2020DOI Listing
April 2021

Propofol midazolam for sedation during radiofrequency ablation in patients with hepatocellular carcinoma.

JGH Open 2021 Feb 22;5(2):273-279. Epub 2020 Dec 22.

Departmetn of Anesthesiology, Graduate School of Medicine Chiba University Chiba Japan.

Background And Aim: Standardization of the sedation protocol during radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC) is needed. This randomized, single-blind, investigator-initiated trial compared clinical outcomes during and after RFA using propofol and midazolam, respectively, in patients with HCC.

Methods: Few- and small-nodule HCC patients (≤3 nodules and ≤3 cm) were randomly assigned to either propofol or midazolam. Patient satisfaction was assessed using a 100-mm visual analog scale (VAS) (1 mm = not at all satisfied, 100 mm = completely satisfied). Sedation recovery rates 1, 2, 3, and 4 h after RFA were evaluated based on Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores; full recovery was defined as a MOAA/S score of 5.

Results: Between July 2013 and September 2017, 143 patients with HCC were enrolled, and 135 patients were randomly assigned to the treatment group. Compared with midazolam, propofol exhibited similar median procedural satisfaction (propofol: 73.1 mm, midazolam: 76.9 mm, = 0.574). Recovery rates 1 and 2 h after RFA were higher in the propofol group than in the midazolam group. Meanwhile, recovery rates observed 3 and 4 h after RFA were similar in the two groups. The safety profiles during and after RFA were almost identical in the two groups.

Conclusion: Patient satisfaction was almost identical in patients receiving propofol and midazolam sedation during RFA. Propofol sedation resulted in reduced recovery time compared with midazolam sedation in patients with HCC. The safety profiles of both propofol and midazolam sedation during and after RFA were acceptable.
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http://dx.doi.org/10.1002/jgh3.12483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857294PMC
February 2021

Qualitative measurement of opioid effects on pain and dyspnea: gender difference in the sensitivity.

JA Clin Rep 2020 Oct 20;6(1):85. Epub 2020 Oct 20.

Department of Anesthesiology, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo, Chiba, 260-8670, Japan.

Background: An increasing number of patients come to the operating room in use of opioid analgesics. They have different levels of tolerance to opioid effects which challenge the anesthesiologists in search of safe and effective opioid dosing perioperatively. The tested hypothesis is that simple measures introduced will allow us to measure tolerance qualitatively. Opioid effects on pain (analgesia) and dyspnea sensations (relieving effect) are tested. Patients were allocated to three groups according to pre-operative analgesics: (1) control, without any opioid analgesics, (2) weak opioid, and (3) strong opioid. Pressure pain threshold (PPT) and no-respiratory sensation period (NRSP) were measured at two points: before and 3 min after intravenous fentanyl administration.

Results: A total of 58 (43 controls, 9 weak opioids, and 6 strong opioids) patients were enrolled. PPT and NRSP, after iv 2 μg/kg ideal body weight (IBW) fentanyl, were significantly elevated in the control patients (PPT: 6.2 ± 2.1 N to 9.2 ± 3.9 N, p < 0.0001, NRSP: 17.8 ± 10.8 s to 22.8 ± 18.7 s, p < 0.005, paired t test). However, preoperative opioid use, though with tendency, did not show a significant decrease of the opioid effect. Due to an insufficient number of participants, no conclusion could be drawn. Further analysis of the data from control patients showed a significant difference between the two sexes in sensitivity to PPT and NRSP, as well as fentanyl effect on PPT.

Conclusions: Current data showed a simple method of measuring the opioid effect on two dimensions: pain and respiration. Though not able to show a qualitative measurement of tolerance formation in opioid-users, data from control patients showed females to be more sensitive to pain and dyspnea but is less sensitive to the opioid effect. Further studies are necessary to show whether these gender differences serve as clinical relevance.

Trial Registration: UMIN, UMIN 000011580. Registered 27 August 2013, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000013352&language=J.
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http://dx.doi.org/10.1186/s40981-020-00391-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575662PMC
October 2020

A report of three cancer patients on opioid analgesia receiving spinal anesthesia: abrupt pain elimination without respiratory depression.

JA Clin Rep 2020 Jul 1;6(1):49. Epub 2020 Jul 1.

Department of Anesthesiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo Chiba, 260-8670, Japan.

Background: Complete removal of pain with regional anesthesia has been reported to cause fatal respiratory depression in opioid-dependent patients, which leads us to choose general anesthesia. We hereby report three cases of chronically opioid-treated cancer patients operated under spinal anesthesia without respiratory event.

Case Presentation: Case 1: a 32-year-old female treated with high-dose morphine for her cancer pain was planned for cesarean section. Case 2: a 65-year-old female on moderate dose of oxycodone was planned for surgery of her femoral bone fracture. Case 3: a 65-year-old male on low-dose oxycodone was planned for intramedullary nailing for metastatic femoral bone tumor. In all three cases, spinal anesthesia was chosen. Continuous respiratory monitoring revealed no apnea or bradypnea.

Conclusion: Spinal anesthesia was safely performed without respiratory depression in chronic opioid users for cancer pain.
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http://dx.doi.org/10.1186/s40981-020-00355-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329962PMC
July 2020

A high concentration of sevoflurane induces gasping breaths in mice.

Respir Physiol Neurobiol 2020 08 11;279:103445. Epub 2020 May 11.

Dept of Anesthesiology, Graduate School of Medicine, Chiba University, Japan.

The purpose of this study is to compare changes in breathing patterns elicited by hypoxic stress and/or anesthetic stress in mice. Spontaneously breathing anesthetized mice whose tracheae were intubated with a tracheal cannula were challenged with hypoxic stress and/or sevoflurane-induced anesthetic stress while ventilation was measured with a pneumotachograph. When anesthesia was maintained at a light level with inhalation of 2.3 % sevoflurane (0.7 MAC), exposure to severe hypoxic gas (5% O in N) triggered a breathing pattern characterized by gasping respiration. Inhalation of a high concentration of sevoflurane (6.5 %: 2.0 MAC) under hyperoxia elicited the same gasping. Also, the combination of mild hypoxia (inhalation of 10 % O in N) and moderate sevoflurane anesthesia (3.25 %: 1.0 MAC) consistently elicited the same gasping, while mild hypoxic and moderate anesthetic stress alone did not elicit any gasping. These findings suggest that both hypoxia-induced gasping and sevoflurane-induced gasping could be generated by the same intrinsic mechanism within the brainstem.
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http://dx.doi.org/10.1016/j.resp.2020.103445DOI Listing
August 2020

Low-dose of olanzapine has ameliorating effects on cancer-related anorexia.

Cancer Manag Res 2019 19;11:2233-2239. Epub 2019 Mar 19.

Palliative Care Center, Chiba University Hospital, Chiba, Japan.

Background: Olanzapine (OLZ) has become well-known for its antiemetic effects on chemotherapy-induced nausea and vomiting. However, it remains unclear whether OLZ also has efficacy for treating cancer-related anorexia. This study, therefore, retrospectively examined whether or not OLZ administration affects the food intake in anorexic cancer patients who exhibit neither nausea nor vomiting.

Methods: Eighty patients prescribed OLZ were extracted from 951 inpatients who consulted with our palliative care team at Chiba University Hospital from April 2008 to March 2016. Their food intake described on a nursing record was compared before and after OLZ administration. The observation period was 3 days before and after the start of OLZ treatment, because most inpatients whose food intake increased were discharged in 3 days.

Results: In those 80 patients, the average dose of OLZ for 3 days was 2.28±0.87 (mean±SD) mg/day. First, the food intake in 80 patients was significantly higher after than before starting OLZ, and the relative change in food intake was 149% on average (<0.0001, Student's paired -test). Second, OLZ increased the food intake even in 40 out of 80 patients without nausea or vomiting, and the relative change in food intake was 143% on average (<0.001, Student's paired -test). Third, the average food intake increased in 13 out of 40 patients who were prescribed 1.5 mg/day of OLZ, and the relative change in food intake was 124% on average (<0.01, Student's paired -test). There was no significant difference in food intake between a dose of 1.5 mg/day and a dose of >1.5 mg/day of OLZ (=0.18, Welch's unpaired -test).

Conclusion: We have herein reported OLZ's ameliorating efficacy in cancer-related anorexia at the low dose of 1.5 mg/day. Although our study has many limitations, low-dose OLZ can be a promising treatment for cancer-related anorexia.
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http://dx.doi.org/10.2147/CMAR.S191330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433113PMC
March 2019

Contact-free unconstraint respiratory measurements with load cells under the bed in awake healthy volunteers: breath-by-breath comparison with pneumotachography.

J Appl Physiol (1985) 2019 05 14;126(5):1432-1441. Epub 2019 Feb 14.

Department of Preventive Medicine and Public Health, Keio University School of Medicine , Tokyo , Japan.

Rate of respiration is a fundamental vital sign. Accuracy and precision of respiratory rate measurements with contact-free load cell sensors under the bed legs were assessed by breath-by-breath comparison with the pneumotachography technique during two different dynamic breathing tasks in 16 awake human adults resting on the bed. The subject voluntarily increased and decreased the respiratory rate between 4 and 16 breaths/min ( = 8) and 10 and 40 breaths/min ( = 8) at every 2 breaths in 6 different lying postures such as supine, left lateral, right lateral, and 30, 45, and 60° sitting postures. Reciprocal phase changes of the upper and lower load cell signals accorded with the respiratory phases indicating respiratory-related shifts of the centroid along the long axis of the bed. Bland-Altman analyses revealed 0.66 and 1.59 breaths/min standard deviation differences between the techniques (limits of agreement: -1.22 to 1.36 and -2.96 to 3.30) and 0.07 and 0.17 breaths/min fixed bias differences (accuracy) (confidence interval: 0.04 to 0.10 and 0.12 to 0.22) for the mean respiratory rates of 10.5 ± 3.7 and 24.6 ± 8.9 breaths/min, respectively, regardless of the body postures on the bed. Proportional underestimation by this technique was evident for respiratory rates >40 breaths/min. Sample breath increase up to 10 breaths improved the precision from 1.59 to 0.26 breaths/min. Abnormally faster and slower respirations were accurately detected. We conclude that contact-free unconstraint respiratory rate measurements with load cells under the bed legs are accurate and may serve as a new clinical and investigational tool. Four load cells placed under the bed legs successfully captured a centroid shift during respiration in human subjects lying on a bed. Breath-by-breath comparison of the breaths covering a wide respiratory rate range by pneumotachography confirmed reliability of the contact-free unconstraint respiratory rate measurements by small standard deviations and biases regardless of body postures. Abnormally faster and slower respirations were accurately detected. This technique should be an asset as a new clinical and investigational tool.
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http://dx.doi.org/10.1152/japplphysiol.00730.2018DOI Listing
May 2019

Differences of Recovery from Rocuronium-induced Deep Paralysis in Response to Small Doses of Sugammadex between Elderly and Nonelderly Patients.

Anesthesiology 2018 11;129(5):901-911

From the Department of Anesthesiology, Chiba University Hospital, Chiba, Japan (T.M., N.N.-T., Y.K.) the Department of Anesthesiology (S.I., T.I., J.O.) Department of Global Clinical Research (Y.S.), Graduate School of Medicine, Chiba University, Chiba, Japan the Department of Anesthesiology, Kimitsu Chuo Hospital, Kisarazu, Japan (N.M.).

What We Already Know About This Topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Complete recovery from rocuronium-induced muscle paralysis with sugammadex is reported to be delayed in elderly patients. The authors tested a hypothesis that recovery from deep neuromuscular block with low-dose sugammadex is slower (primary hypothesis) and incidence of recurarization is higher (secondary hypothesis) in elderly patients than in nonelderly patients.

Methods: In anesthetized elderly (n = 20; 76.9 ± 5.0 yr of age) and nonelderly patients (n = 20; 53.7 ± 12.8 yr of age) under deep paralysis with rocuronium, change of train-of-four ratio per minute (primary outcome variable) was measured with an acceleromyograph neuromuscular monitor during spontaneous recovery from rocuronium-induced muscle paralysis (0.6 mg/kg) and after infusion of low-dose sugammadex (50 µg · kg · min). Recurarization was defined as the negative change of train-of-four ratio.

Results: Spontaneous train-of-four ratio recovery rate was significantly slower in the elderly group (median [25th percentile, 75th percentile]: 1.89 [1.22, 2.90] %/min) than in the nonelderly group (3.45 [1.96, 4.25] %/min, P = 0.024). Train-of-four ratio change rate in response to low-dose sugammadex was significantly slower in elderly (0.55 [-0.29, 1.54] %/min) than in the nonelderly group (1.68 [0.73, 3.13] %/min, P = 0.024). Incidence of recurarization was significantly higher in the elderly group than in the nonelderly group (35% vs. 5%, P = 0.044). Multiple linear regression analyses indicate that slower spontaneous train-of-four ratio recovery rate and impaired renal function are two major contributing factors that decrease train-of-four ratio change rate in response to low-dose sugammadex.

Conclusions: Elderly patients are at greater risk for recurarization and residual muscle paralysis when low-dose sugammadex is administered.
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http://dx.doi.org/10.1097/ALN.0000000000002412DOI Listing
November 2018

New approach to relieving pain and distress during high-dose-rate intracavitary irradiation for cervical cancer.

Brachytherapy 2015 Sep-Oct;14(5):642-7. Epub 2015 May 27.

Department of Radiology and Radiation Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Radiology, Chiba University Hospital, Chiba, Japan.

Background And Purpose: To relieve the pain and distress experienced by women who undergo high-dose-rate intracavitary radiotherapy (HDR-ICRT) for cervical cancer and to improve the current status of gynecologic brachytherapy in Japan, a new intravenous anesthetic protocol involving the administration of a combination of propofol and ketamine was developed. The primary aim of this study is to investigate the efficacy and safety of this new anesthetic protocol during HDR-ICRT for cervical cancer.

Methods And Materials: All the patients who were diagnosed with cervical cancer between December 2008 and February 2011, treated with three-channel brachytherapy and subjected to the new sedation protocol, were evaluated. A visual analog scale (VAS) was used to assess the pain during brachytherapy, and we collected VAS score at the next HDR-ICRT. Toxicities were graded using the Common Toxicity Criteria, version 3.

Results: A total of 178 sessions of HDR-ICRT were delivered to 57 patients. The patients' median VAS pain score was 0 (range, 0-10). The most frequent side effect was Grade 1-2 nausea, which occurred in 33 sessions (34%). However, 13 of 14 patients received concurrent cisplatin chemotherapy. None of the patients experienced Grade 3 or 4 adverse events.

Conclusions: We have demonstrated that our new intravenous anesthetic protocol produces appropriate effects and can be performed by radiation oncologists who were required to finish training in basic life support and the cooperative system of emergency according to in-house guideline.
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http://dx.doi.org/10.1016/j.brachy.2015.04.009DOI Listing
May 2016

Assessment of reasons for referral and activities of hospital palliative care teams using a standard format: a multicenter 1000 case description.

J Pain Symptom Manage 2014 Mar 21;47(3):579-587.e6. Epub 2013 Aug 21.

Department of Palliative and Supportive Care, Palliative Care Team and Seirei Hospice, Seirei Mikatahara General Hospital, Shizuoka, Japan.

Context: The many benefits of hospital palliative care teams (PCTs) are well known. However, their specific activities have not been fully clarified, and no standardized methods for reporting PCT activities are available.

Objectives: The aim of this study was to investigate, through the use of a standard format, the activities performed by hospital PCTs in Japan.

Methods: This was a prospective observational study. A total of 21 hospital PCTs were included in this study, and each recruited approximately 50 consecutively referred patients. Participating PCTs filled in a standard form for reporting activities.

Results: We obtained data from 1055 patients who were referred to PCTs. Of the 1055 patients, 1005 patients (95%) had cancer. The median number of reasons for referral and problems identified by PCTs was two (0-22) and four (0-18), respectively. The two major reasons for referral were pain (63%) and anxiety/depression/grief/emotional burden (22%). The major recommendations were pharmacological treatment (74%), care for the patient's physical symptoms (49%), and support for patient's decision making (38%). The major activities performed by the PCTs were comprehensive assessment (90%), care for the patient's physical symptoms (77%), and pharmacological treatment (74%).

Conclusion: The components of hospital PCT activities were successfully measured using the Standard Format for Reporting Hospital PCT Activity. The results of this study and the format for reporting hospital PCT activity could be effective in improving hospital PCT practice and for the education of new hospital PCT members.
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http://dx.doi.org/10.1016/j.jpainsymman.2013.04.009DOI Listing
March 2014

Lung/chest expansion contributes to generation of pleasantness associated with dyspnoea relief.

Respir Physiol Neurobiol 2012 Oct 22;184(1):27-34. Epub 2012 Jul 22.

Department of Anesthesiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohanacho, Chiba, Japan.

Pleasantness associated with dyspnoea relief or 'respiratory pleasure' is considered as a particular sensory experience. The purpose of this study is to elucidate the mechanism of generation of this particular sensory experience. After taking deep breaths during normal breathing, 35 healthy subjects received three different magnitudes of inspiratory loads (light: 8.4; moderate: 23.4; severe: 70.5 cm H2O/L/s) to induce dyspnoeic sensation. We found that (1) deep breaths during normal breathing rarely induce 'respiratory pleasure', (2) a sudden removal of dyspnoea alone is not sufficient to produce 'respiratory pleasure', and (3) the generation of 'respiratory pleasure' can be observed when a sudden removal of dyspnoea accompanies a large increase in tidal volume (V(T)). In addition, qualitative assessment of 'respiratory pleasure' showed that this sensation is compatible with a strong, positively valenced sensation. These findings indicate that an increase in V(T) after removal of respiratory loading plays a crucial role in generation of 'respiratory pleasure' that is a specific sensory-emotional experience.
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http://dx.doi.org/10.1016/j.resp.2012.07.008DOI Listing
October 2012

Effects of different forms of dyspnoea on pain perception induced by cold-pressor test.

Respir Physiol Neurobiol 2011 Aug 19;177(3):320-6. Epub 2011 May 19.

Department of Anesthesiology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan.

Although dyspnoea has been shown to attenuate pain, whether different forms of dyspnoea exert a similar inhibitory effect on pain has never been tested. We examined the effects of two different forms of dyspnoea, i.e., "air hunger" sensation (AIR HUNGER) and "work/effort" sensation (WORK/EFFORT), on pain induced by a cold-pressor test. Dyspnoea was induced by two different dyspnoea stimuli (i.e., AIR HUNGER and WORK/EFFORT stimuli) and the magnitudes of both sensations were evaluated by using a visual analogue scale (VAS). At equi-dyspneic VAS levels of two different forms of dyspnoea, pain was induced and the unpleasantness of pain was assessed by pain VAS, pain threshold time (PTT) and pain endurance time (PET). Both AIR HUNGER and WORK/EFFORT caused an increase in PTT and an increase in PET or a decrease in maximal pain VAS. Our findings suggest that AIR HUNGER and WORK/EFFORT exert a similar analgesic effect although the WORK/EFFORT-induced analgesia was slightly more effective.
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http://dx.doi.org/10.1016/j.resp.2011.05.013DOI Listing
August 2011

Potential utility of peripherally applied loperamide in oral chronic graft-versus-host disease related pain.

Jpn J Clin Oncol 2008 Dec 24;38(12):857-60. Epub 2008 Oct 24.

Department of Anesthesiology and Palliative Medicine, Chiba University Graduate School of Medicine, Chuo, Chiba, Japan.

Four patients with oral chronic graft-versus-host disease pain were treated with loperamide oral-rinse solution. Two-week continued use of the drug solution improved not only the pain scores but also the pain-causing disabilities associated with eating, drinking and sleeping, with no noticeable side effects. Current results suggest that the mu-opioid agonist, loperamide, has a potential analgesic effect that could be clinically used as a peripheral analgesic agent for stomatitis pain. However, these observations will need to be further confirmed in a randomized-controlled trial.
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http://dx.doi.org/10.1093/jjco/hyn110DOI Listing
December 2008

[Assessment of pain].

Nihon Rinsho 2007 Jan;65(1):22-6

Department Of Anesthesiology, Chiba University Hospital.

Assessment of patient's pain is crucial to effective pain management. It requires not only the knowledge of pain scale, but also a closely listening ear and a sharp eye. It also needs to be constantly re-evaluated by the healthcare team. While taking pain history, encourage the patient to do most of the talking and explain the pain characteristics with his/her own words. This is important when classifying the pain to predominantly nociceptive or neuropathic pain. Since cancer pain is not purely acute pain, assessment of pain needs not only to evaluate pain scores but also to evaluate patients' physical function and the impact of pain on his/her daily activities. Assessing secondary effect of pain, such as anxiety or financial worries, and reducing them may decrease the overall experience of pain.
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January 2007

Spinal opioid receptor like1 receptor agonist, but not N-methyl-D-aspartic acid antagonist, reverses the secondary mechanical allodynia induced by intradermal injection of capsaicin in rats.

Anesth Analg 2005 Apr;100(4):1087-92

Department of Anesthesiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan.

Secondary mechanical allodynia induced by intradermal injection of capsaicin has been widely used to search for the underlying mechanisms of tissue injury induced mechanical allodynia. However, the capsaicin concentration dependency of the development of secondary mechanical allodynia and the underlying mechanisms of development and maintenance of capsaicin-induced mechanical allodynia are not fully understood. In the present study, we clarify the capsaicin concentration dependency for development and maintenance of secondary mechanical allodynia and the role of spinal opioid receptor like1 (ORL1) receptor and N-methyl-D-aspartate receptor in the development and maintenance of secondary mechanical allodynia induced by an intradermal capsaicin injection. Capsaicin 50 microL of 0.03% induced the most intense secondary mechanical allodynia. Intrathecal injection of nociceptin, an ORL1 receptor agonist, attenuated the maintenance of secondary mechanical allodynia but had no effect on the development of secondary mechanical allodynia. An intrathecal injection of MK801, an N-methyl-D-aspartate receptor antagonist, had no effect on the development and maintenance of secondary mechanical allodynia. These findings suggest that spinal ORL1 receptor should be the target of study for the treatment of secondary mechanical allodynia induced by tissue injury.
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http://dx.doi.org/10.1213/01.ANE.0000147509.01309.EBDOI Listing
April 2005

Analgesic effect of intrathecally administered orexin-A in the rat formalin test and in the rat hot plate test.

Br J Pharmacol 2002 Sep;137(2):170-6

Department of Anesthesiology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8677, Japan.

1. Orexin-A and orexin-B (also known as hypocretin-1 and hypocretin-2) are hypothalamic peptides and regulate feeding behaviour, energy metabolism and the sleep-wake cycle. Orexin-A binds equally to both orexin-1 and orexin-2 receptors, while orexin-B has a preferential affinity for orexin-2 receptors. 2. Orexins are also known to be concentrated in superficial laminae of the spinal dorsal horn, and orexin-A and orexin-1 receptors are found in the dorsal root ganglion cells. 3. In the present study, the authors examined the effect of intrathecal injection of either orexin-A or orexin-B in the rat formalin test (a model of inflammatory pain) and in the rat hot plate test. The paw formalin injection induces biphasic flinching (phase 1: 0-6 min; phase 2: 10-60 min) of the injected paw. 4. Intrathecal injection of orexin-A, but not orexin-B, decreased the sum of flinches in phases 1 and 2 in the formalin test and increased the hot plate latency. These effects of orexin-A were completely antagonized by pre-treatment with SB-334867, a selective orexin-1 receptor antagonist. Intrathecal injection of SB-334867 alone had no effect in the formalin test or in the hot plate test. 5. Intrathecal injection of orexin-A suppressed the expression of Fos-like immunoreactivity (Fos-LI), induced by paw formalin injection, in laminae I-II of L4-5 of the spinal cord. 6. These data suggest that the spinal orexin-1 receptor is involved in the nociceptive transmission and that the activation of the spinal orexin-1 receptor produces analgesic effects in the rat formalin test and in the rat hot plate test.
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http://dx.doi.org/10.1038/sj.bjp.0704851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1573477PMC
September 2002

Spinal and peripheral mu opioids and the development of secondary tactile allodynia after thermal injury.

Anesth Analg 2002 Apr;94(4):968-74, table of contents

Department of Anesthesiology, University of California, San Diego, La Jolla 92093-0818, USA.

Unlabelled: Local thermal injury to the paw leads to an increased sensitivity to a noxious stimulus applied to the site (primary thermal hyperalgesia) and an increased sensitivity to tactile stimuli in skin sites adjacent to the primary injury (secondary tactile allodynia; 2 degrees TA). We sought to define the peripheral and spinal actions of mu opioids in regulating 2 degrees TA. First, a mild thermal injury was induced on one heel, producing 2 degrees TA. This 2 degrees TA was blocked by pretreatment, but not posttreatment, with a topical mu-opioid agonist, loperamide (1.7%-5%). Second, 2 degrees TA was blocked by intrathecal morphine (0.1-10 microg) pre- and postinjury. 2 degrees TA reappeared when systemic naloxone was given before, but not after, injury in intrathecal morphine-pretreated rats. Intrathecal remifentanil, a short-lasting mu-opioid agonist, infused periinjury (3 microg/min), did not block subsequent primary thermal hyperalgesia, but it produced a dose-dependent (0.3-3 microg/min) abolition of 2 degrees TA. Local tissue injury leads to 2 degrees TA by the activation of opiate-sensitive afferents and the initiation of a cascade that persists in the absence of that initiating injury-induced stimulus.

Implications: Sensitivity to touch observed in areas adjacent to injury is blocked by opioids applied before, but not after, injury. This suggests that injury-activated opioid-sensitive fibers are responsible for sensitization and reveals a cascade that is diminished by pretreatment but not posttreatment, providing a rationale for adequate analgesia before injury (surgery) has occurred.
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http://dx.doi.org/10.1097/00000539-200204000-00036DOI Listing
April 2002

The role of cyclooxygenase-1 and -2 in the rat formalin test.

Anesth Analg 2002 Apr;94(4):962-7, table of contents

Department of Anesthesiology, Chiba University Hospital, Chiba, Japan.

Unlabelled: Prostaglandins are thought to play an important role in nociceptive transmission at peripheral sites and in the spinal cord. Prostaglandins are produced by cyclooxygenase (COX), which catalyzes the conversion of arachidonic acid. Two forms of COX have been identified: COX-1, which is constitutively expressed, and COX-2, which is an inducible enzyme. To define the role of COX-1 in nociceptive transmission, we examined the effect of oral and intrathecal administration of 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560), a selective COX-1 inhibitor, on the rat formalin test and compared the effect of SC-560 with that of celecoxib, a COX-2 selective inhibitor, and indomethacin, a nonselective COX-1 and COX-2 inhibitor, on the rat formalin test. Oral and intrathecal administration of SC-560 had no effect on the agitation behavior in the rat formalin test. Oral and intrathecal administration of celecoxib and indomethacin depressed agitation behavior during the rat formalin test. These data suggest that prostaglandins synthesized by COX-1 are not involved in nociceptive transmission during the rat formalin test but that COX-2 does play an important role in the rat formalin test.

Implications: Our data suggest that a COX-2 selective inhibitor, but not a COX-1 selective inhibitor, may produce a good analgesic effect on the inflammatory pain state in a clinical situation.
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http://dx.doi.org/10.1097/00000539-200204000-00035DOI Listing
April 2002

Pharmacology of spinal glutamatergic receptors in post-thermal injury-evoked tactile allodynia and thermal hyperalgesia.

Anesthesiology 2002 Mar;96(3):617-26

Department of Anesthesiology, University of California-San Diego, La Jolla, California 92093-0818, USA.

Background: After a focal thermal injury to the heel of a rat, thermal hyperalgesia appears at the injury site (primary thermal hyperalgesia), and tactile allodynia appears at the off-injury site (secondary tactile allodynia). The pharmacology of spinal glutamatergic receptors in the initiation and maintenance of secondary tactile allodynia was examined.

Methods: In rats prepared with chronic intrathecal catheters, the heel of one hind paw was exposed to a 52 degrees C surface for 45 s, resulting in a local erythema without blistering. Intrathecal N-methyl-d-aspartate (NMDA) receptor antagonists (MK-801, AP5) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-kainate (AMPA-KA) receptor antagonists (CNQX, NBQX, NS257, etc.) were administered either before (pretreatment) or after (posttreatment) the induction of the injury. Tactile withdrawal thresholds and thermal paw withdrawal latencies were assessed.

Results: Pretreatment and posttreatment with AMPA-KA antagonists produced a dose-dependent blockade of secondary tactile allodynia. However, NMDA antagonists, in doses that effectively block other models of facilitated states, showed little or no effect. Primary thermal hyperalgesia was blocked only by high-dose AMPA-KA antagonists.

Conclusion: Spinal AMPA-KA receptors play a major role in the initiation of secondary tactile allodynia induced by focal thermal injury. In contrast, spinal NMDA receptors play only a minimal role.
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http://dx.doi.org/10.1097/00000542-200203000-00018DOI Listing
March 2002

Vincristine-induced allodynia in the rat.

Pain 2001 Jul;93(1):69-76

Anesthesiology Research Laboratory, Department of Anesthesiology 0818, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0818, USA.

The aims of this study were two-fold: first, to simplify the method for creating a recently described neuropathic pain model in the rat, and second, to evaluate the effects of a number of drugs with analgesic or antihyperalgesic properties, in this model. Continuous intravenous vincristine infusion (1-100 microg kg(-1) day (-1)) for 14 days resulted in a dose dependent tactile allodynia (as measured by von Frey filaments) by 7 days at doses between 30 - 100 microg kg(-1) day (-1), with a hindlimb motor deficit observed at doses greater than 50 microg kg(-1) day (-1). No thermal hyperalgesia was observed. Systemic morphine, lidocaine, mexiletine and pregabalin (given intraperitoneally) produced significant reduction of the allodynia, while tetrodotoxin was without effect. Continuous intravenous infusion of vincristine in rats thus provides a reliable model of chemotherapy induced neuropathy which may be used in defining the mechanism and pharmacology of this clinically relevant condition.
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http://dx.doi.org/10.1016/S0304-3959(01)00294-9DOI Listing
July 2001

Depression of sighing in the first three postoperative days with epidural morphine analgesia.

J Anesth 1994 Dec;8(4):415-419

Department of Anesthesiology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, 277, Kashiwa, Chiba, Japan.

We have studied the effect of spontaneous sighs on maintaining arterial oxygenation in patients receiving epidural morphine for analgesia after upper abdominal surgery. Sixteen patients scheduled for elective gastrectomy were monitored continuously with pulse oximetry and respiratory inductive plethysmography (RIP) during one night preoperatively and for 60 h postoperatively with repeate arterial blood gas analysis. An average of 3.1±1.2 (±SD) sighs were observed per hour preoperatively during sleep while postoperative sighs were significantly depressed to an average less than one per hour throughout the 60 h of the monitoring period (P<0.05). Although postoperative Pao values were significantly lower than preoperative values, there was no correlation between the decreases in Pao values and number of sighs. Thus, it is unlikely that the long-term absence of spontaneous sighs observed may serve as a contributing factor for the long-lasting hypoxemia in the postoperative period.
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http://dx.doi.org/10.1007/BF02514619DOI Listing
December 1994