Effectiveness of Gabapentinoids for Cancer-related Rectal and Vesical Tenesmus: Report of Four Cases.

Gabapentinoids could be assumed to relieve cancer-related rectal/vesical tenesmus based on their pharmacological mechanism. Four patients were refractory for cancer-related rectal/vesical tenesmus although their opioid doses were titrated up. Symptom intensity difference (SID) between initiation and follow-up after 24, 48, and 72 h and daily changes in the frequency of urination, defecation, opioid rescue doses, presence of sleep disruption, and dose of regular opioid medication were evaluated. The median reductions in daily discomfort measured as SID between baseline and follow-up after 24, 48, and 72 h were 87.5%, 70.0%, and 80.0%, respectively, while those in daily pain intensity were 75%, 66.7%, and 66.7%, respectively. The initiation dose of gabapentin was 200 or 400 mg/day and that of pregabalin was 75 mg/day in one patient. Gabapentinoids were effective at low doses administered over a short duration to patients with refractory cancer-related rectal/vesical tenesmus.

Efficacy and Safety of Oxycodone Injection for Relieving Cancer Pain: A Study in Japan Consisting of Two Open Trials for Intravenous and Subcutaneous Administration.

Pure oxycodone injection became increasingly necessary after oral oxycodone was launched in Japan in 2003. However, trials clarifying the efficacy and safety of injection are rare. Therefore, a multicenter open study on injection was designed and carried out in 2010, resulting in the launch of injection therapy in 2012. As published domestic case reports on efficacy already show widespread prescription, this study aimed to provide useful information for cancer pain relief in Japan and other countries. Our oxycodone injection study consisted of two trials, one of intravenous (S#9131) and the other of subcutaneous (S#9132) administration. The minimum required number of enrolled patients suffering cancer pain was determined to be 70 in S#9131 and 20 in S#9132. These studies had the same dose-titration protocol as the main endpoint, i.e., pain relief rate (PRR) defined as the rate of achieving adequate pain control (APC), as in prior oral oxycodone trials in Japan. In S#9131, PRR was 81.4% (95% confidence interval: 70.3-89.7%), therefore, the null hypothesis of PRR<70% was rejected using the binominal one-sided test (p=0.0217). In S#9132, PRR was 73.7% also surpassing 70%. Safety was also assessed in the same way as in prior trials. The majority of adverse effects were moderate or mild and recovered with no sequelae. As shown above, the injection was considered to be effective and safe in cancer pain treatment. The details of these trials, particularly the dose-titration protocol for achieving APC and route switching information, are expected to enhance injection convenience for prescribers.

Negative pain management index scores do not necessarily indicate inadequate pain management: a cross-sectional study.

BACKGROUND: The Pain Management Index (PMI) is widely used in the assessment of pain management, and negative scores are traditionally considered to indicate inadequate pain management. However, it is not known whether negative PMI scores are always problematic. METHODS: In this prospective observational study, we examined the data of 1156 patients with cancer and pain who were hospitalized in a cancer care hospital in Japan from July 2012 to January 2015 and compared the proportion of patients with PI across various PMI scores in this cohort. We further evaluated the predictive validity of PMI scores for PI using different cutoffs. This study aimed to examine the association between PMI scores and the proportion of patients whose pain interferes with their daily lives (i.e., pain interference [PI]). RESULTS: We found that lower PMI scores were generally associated with a higher percentage of patients with PI. A smaller proportion of patients with PMI scores of - 1 (567/1550, 36.6%) reported PI compared with those with PMI scores of 0 (788/1505, 52.4%). The sensitivities of PMI scores < - 1 and < 0 for predicting PI were 0.16 and 0.37 and the corresponding specificities were 0.95 and 0.71, respectively. CONCLUSIONS: These findings suggest that PMI scores are inversely associated with the proportion of patients with PI. However, PMI scores of - 1 do not always indicate inadequate pain management; pain management should therefore be evaluated from multiple perspectives.

Tris-hydroxymethyl-aminomethane enhances capsaicin-induced intracellular Ca(2+) influx through transient receptor potential V1 (TRPV1) channels.

Non-selective transient receptor potential vanilloid (TRPV) cation channels are activated by various insults, including exposure to heat, acidity, and the compound capsaicin, resulting in sensations of pain in the skin, visceral organs, and oral cavity. Recently, TRPV1 activation was also demonstrated in response to basic pH elicited by ammonia and intracellular alkalization. Tris-hydroxymethyl aminomethane (THAM) is widely used as an alkalizing agent; however, the effects of THAM on TRPV1 channels have not been defined. In this study, we characterized the effects of THAM-induced TRPV1 channel activation in baby hamster kidney cells expressing human TRPV1 (hTRPV1) and the Ca(2+)-sensitive fluorescent sensor GCaMP2 by real-time confocal microscopy. Notably, both capsaicin (1 µM) and pH 6.5 buffer elicited steep increases in the intracellular Ca(2+) concentration ([Ca(2+)]i), while treatment with THAM (pH 8.5) alone had no effect. However, treatment with THAM (pH 8.5) following capsaicin application elicited a profound, long-lasting increase in [Ca(2+)]i that was completely inhibited by the TRPV1 antagonist capsazepine. Taken together, these results suggest that hTRPV1 pre-activation is required to provoke enhanced, THAM-induced [Ca(2+)]i increases, which could be a mechanism underlying pain induced by basic pH.

[Screening for Pain in Cancer Patients].

The newly revised 2014 Set of Standards for"Designated Cancer Care Hospitals"mandated the screening of all cancer patients6 for their physical and psychological suffering systematically in both outpatient and inpatient settings as well as rapid response to the suffering detected. It is a step forward as a cancer control policy, but because the pain associated with cancer changes by time depending on factors such as disease progression and treatment, it must be evaluated repeatedly. Simply complying with the standard by measuring once, say on admission or at the initial visit, will not help patients. It is necessary to continuously monitor how the pain was treated and improved or worsened, and whether any new pain develops after admission. In the United States, campaigns to regard pain as the"fifth vital sign"have been are in action since 2001. They made the patient pain intensity be recorded on a numeric scale along with the body temperature on the same daily vital sign charts. However, the US experiences indicated that the simple screening for pain is not enough. One study reported that physicians took action to pain of moderate or greater intensity in only one-sixth of the time. Numerical evaluation of pain intensity captures only one aspect of pain. What matters more to patients with pain, thus is more important to their clinicians, is the degree of impairment of patients in their daily lives due to pain. Our study group set as the goal of pain treatment the elimination of"things one is unable to do or has trouble doing because of pain". We systematically presented the attending physicians the degree of impairment of patient lifestyle due to pain rather than numbers, and physicians became more engaged in the prescribing or increasing the dose of opioids.

Accuracy of using Diagnosis Procedure Combination administrative claims data for estimating the amount of opioid consumption among cancer patients in Japan.

OBJECTIVE: The state of opioid consumption among cancer patients has never been comprehensively investigated in Japan. The Diagnosis Procedure Combination claims data may be used to measure and monitor opioid consumption among cancer patients, but the accuracy of using the Diagnosis Procedure Combination data for this purpose has never been tested. METHODS: We aimed to ascertain the accuracy of using the Diagnosis Procedure Combination claims data for estimating total opioid analgesic consumption by cancer patients compared with electronic medical records at Aomori Prefectural Central Hospital. We calculated percent differences between estimates obtained from electronic medical records and Diagnosis Procedure Combination claims data by month and drug type (morphine, oxycodone, fentanyl, buprenorphine, codeine and tramadol) between 1 October 2012 and 30 September 2013, and further examined the causes of discrepancy by reviewing medical and administrative charts between April and July 2013. RESULTS: Percent differences varied by month for drug types with small prescription volumes, but less so for drugs with larger prescription volumes. Differences also tended to diminish when consumption was compared for a year instead of a month. Total percent difference between electronic medical records and Diagnosis Procedure Combination data during the study period was -0.1% (4721 mg per year per hospital), as electronic medical records as baseline. Half of the discrepancy was caused by errors in data entry. CONCLUSION: Our study showed that Diagnosis Procedure Combination claims data can be used to accurately estimate opioid consumption among a population of cancer patients, although the same conclusion cannot be made for individual estimates or when making estimates for a group of patients over a short period of time.

Breakthrough pain management using fentanyl buccal tablet (FBT) in combination with around-the-clock (ATC) opioids based on the efficacy and safety of FBT, and its relationship with ATC opioids: results from an open-label, multi-center study in Japanese cancer patients with detailed evaluation.

OBJECTIVE: Rapid analgesic onset opioids, particularly fentanyl buccal tablet, is preferable for managing breakthrough pain. The efficacy and safety of fentanyl buccal tablet and its association with around-the-clock opioids needs to be explored with an option of dose adjustments, more closely reflecting administration in clinical practice. The aim of the study was to assess the safety and efficacy of fentanyl buccal tablet in breakthrough pain management in combination with around-the-clock opioids with the dose adjustment option, and explore the dose adjustment's influence on breakthrough pain management using detailed evaluation. METHODS: The 12-week open-label, multi-center study was conducted throughout Japan. Cancer patients aged 20 years or older, experiencing persistent pain controlled with around-the-clock opioids and breakthrough pain with supplemental medications were enrolled. Fentanyl buccal tablet and around-the-clock opioid doses could be adjusted under protocol-specified conditions. Efficacy variables were assessed at each fentanyl buccal tablet administration. Safety was assessed mainly by adverse events. RESULTS: All efficacy variables showed sustained analgesic effect. Nearly half the patients stayed on the same dose; most fentanyl buccal tablet administrations did not require additional supplemental medications. Dose increase of fentanyl buccal tablet and around-the-clock opioids seemed to improve breakthrough pain intensity and frequency, respectively. Fentanyl buccal tablet and around-the-clock opioid doses were not strongly associated. Treatment-related adverse events were all common with opioid treatment and did not increase over time. CONCLUSIONS: Fentanyl buccal tablet can stably and safely manage breakthrough pain in cancer patients with independent dose adjustment based on detailed evaluation of each patient's condition. Breakthrough pain management using fentanyl buccal tablet with around-the-clock opioids at optimal doses may be an important factor in palliative care for cancer patients with breakthrough pain.

Tramadol and its metabolite m1 selectively suppress transient receptor potential ankyrin 1 activity, but not transient receptor potential vanilloid 1 activity.

BACKGROUND: The transient receptor potential vanilloid 1 (TRPV1) and the transient receptor potential ankyrin 1 (TRPA1), which are expressed in sensory neurons, are polymodal nonselective cation channels that sense noxious stimuli. Recent reports showed that these channels play important roles in inflammatory, neuropathic, or cancer pain, suggesting that they may serve as attractive analgesic pharmacological targets. Tramadol is an effective analgesic that is widely used in clinical practice. Reportedly, tramadol and its metabolite (M1) bind to µ-opioid receptors and/or inhibit reuptake of monoamines in the central nervous system, resulting in the activation of the descending inhibitory system. However, the fundamental mechanisms of tramadol in pain control remain unclear. TRPV1 and TRPA1 may be targets of tramadol; however, they have not been studied extensively. METHODS: We examined whether and how tramadol and M1 act on human embryonic kidney 293 (HEK293) cells expressing human TRPV1 (hTRPV1) or hTRPA1 by using a Ca imaging assay and whole-cell patch-clamp recording. RESULTS: Tramadol and M1 (0.01-10 µM) alone did not increase in intracellular Ca concentration ([Ca]i) in HEK293 cells expressing hTRPV1 or hTRPA1 compared with capsaicin (a TRPV1 agonist) or the allyl isothiocyanate (AITC, a TRPA1 agonist), respectively. Furthermore, in HEK293 cells expressing hTRPV1, pretreatment with tramadol or M1 for 5 minutes did not change the increase in [Ca]i induced by capsaicin. Conversely, pretreatment with tramadol (0.1-10 µM) and M1 (1-10 µM) significantly suppressed the AITC-induced [Ca]i increases in HEK293 cells expressing hTRPA1. In addition, the patch-clamp study showed that pretreatment with tramadol and M1 (10 µM) decreased the inward currents induced by AITC. CONCLUSIONS: These data indicate that tramadol and M1 selectively inhibit the function of hTRPA1, but not that of hTRPV1, and that hTRPA1 may play a role in the analgesic effects of these compounds.

Mechanisms of cisplatin-induced muscle atrophy.

Fatigue is the most common side effect of chemotherapy. However, the mechanisms of "muscle fatigue" induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue.

Neutrophil recruitment is critical for 5-fluorouracil-induced diarrhea and the decrease in aquaporins in the colon.

Diarrhea is a common side effect experienced by cancer patients undergoing clinical chemotherapy, such as with 5-fluorouracil (5-FU). However, the precise mechanisms underlying 5-FU-induced diarrhea remain unclear. In the present study, we examined the role of neutrophil in 5-FU-induced diarrhea. Mice were given 5-FU (50mg/kg, i.p.) daily for 4 days. Sivelestat sodium (100 or 300 mg/kg, i.p., neutorophil elastase inhibitor) or SB225002 (3 or 9 mg/kg, i.p., CXCR2 antagonist) was administered before the administration of 5-FU. Gene expression levels of aquaporin (AQP) 4 and 8, CXCL1, CXCL2, CXCL3, neutrophil elastase (Elane) and myeloperoxidase (MPO) in the colon were examined by real-time RT-PCR. The neutrophil (Ly-6G positive cell) number in the mucosa of colon was measured by flow-cytometric analysis. Administration of 5-FU induced diarrhea and decreased the expression levels of AQP 4 and 8 in the colon. Under the present conditions, the expression levels of CXCL1, CXCL2, CXCL3, the neutrophil markers Elane and MPO, as well as Ly-6G-positive neutrophils, in the colon were significantly increased by 5-FU. Neutrophil recruitment with decreased levels of AQP 4 and 8 were dramatically inhibited by either sivelestat sodium or SB225002. Furthermore, these reagents reduced the 5-FU-induced body weight loss and diarrhea. These findings provide evidence that neutrophil recruitment and neutrophil elastase may decrease the levels of AQP 4 and 8 in the colon of mice treated with 5-FU and contribute to the pathophysiology of 5-FU-induced body weight loss and diarrhea.

Novel method of determination of D9-tetrahydrocannabinol(THC) in human serum by high-performance liquid chromatography with electrochemical detection.

In Europe and the United States, D9-tetrahydrocannabinol(THC, dronabinol), one of the psychoactive constituents of cannabis, has been used for both its anti-emetic and orexigenic effects in cancer patient receiving chemotherapy.However, dronabinol has not yet been launched in the market in Japan.In the future, it is necessary to ascertain the pharmacokinetics of dronabinol in cancer paitient.Therefore, we developed an HPLC procedure using electrochemical detection(ECD)for quan- titation of the concentrations of dronabinol in blood.An eluent of 50mM KH2PO4/CH3CN(9:16)was used as the mobile phase.The column was used the XTerra®RP18, and the voltage of the electrochemical detector in dronabinol was set at 400 mV.As a result, the calibration curve was linear in the range of 10 ng/mL to 100 ng/mL(y=964.85x -3,419, r=0.997).The lower limit of quantification was 0.5 ng/mL(S/N=3).The relative within-runs and between-runs standard deviations for the assay dronabinol were less than 4.7%. The method reported here is superior to previously reported methods in cancer patient.

Clinical guideline for pharmacological management of cancer pain: the Japanese Society of Palliative Medicine recommendations.

Pain is the most frequent and distressing symptom in cancer patients. As part of a worldwide effort to improve the quality of pain control, several clinical guidelines for the management of cancer pain have been published and revised in the last decade. The Japanese Society of Palliative Medicine first published a Japanese clinical guideline for the management of cancer pain in 2000. Since then, many clinical studies concerning cancer pain management have been conducted, new drugs have become available in Japan and the methodology of developing a guideline has been refined. Therefore, we decided to develop a novel clinical guideline. This review paper summarizes the recommendations and the rationales of this new clinical guideline for the pharmacological management of cancer pain. In addition, a short summary of the clinical guideline development process is provided. This new Japanese Society of Palliative Medicine guideline highlights the importance of conducting well-designed studies to identify the best practices in cancer pain management.

Mandatory palliative care education for surgical residents: initial focus on teaching pain management.

BACKGROUND: Knowledge concerning palliative care and the associated skills, including effective pain control, is essential for surgeons who treat cancer patients in daily practice. This study focuses on a palliative care training course that has been mandatorily conducted for all surgical residents of our hospital since 2009. METHODS: We evaluated the effectiveness of our mandatory palliative care training course by conducting a retrospective study of the patients' medical records and participants' questionnaire results and discussed the importance of palliative care education for surgical residents. RESULTS: All 12 surgical residents who participated in the course in 2009 had graduated 4-9 years back. They were assigned to look after a total of 92 cases (average, 7.66 cases per resident) during the course. The purpose of care in most cases (92.3%) was to mitigate pain. Introducing analgesic adjuvants such as gabapentin or amitriptyline accounted for the largest part of initial interventions (23.9%) aimed at controlling cancer pain, followed by changes in route of administration or doses of prior opioid analgesics (21.7%). Interventions with opioid analgesics were conducted most frequently (47.7%). The overall pain improvement rate was 89.1%. We used a questionnaire after the course to evaluate its effectiveness. CONCLUSIONS: The surgical residents stated that it was a meaningful course through which they gained practical knowledge on palliative care and that the experience would change their approach to home care.

Usefulness of olanzapine as an adjunct to opioid treatment and for the treatment of neuropathic pain.

BACKGROUND: The use of opioids for pain management is often associated with nausea and vomiting. Although conventional antipsychotics are often used to counter emesis, they can be associated with extrapyramidal symptoms. However, chronic pain can induce sleep disturbance. The authors investigated the effects of the atypical antipsychotic olanzapine on morphine-induced emesis and the sleep dysregulation associated with chronic pain. METHODS: A receptor binding assay was performed using mouse whole brain tissue. The emetic response in ferrets was evaluated by counting retching and vomiting behaviors. Catalepsy in mice was evaluated by placing both of their forepaws over a horizontal bar. Released dopamine was measured by an in vivo microdialysis study. Sleep disturbance in mice in a neuropathic pain-like state was assayed by electroencephalogram and electromyogram recordings. RESULTS: Olanzapine showed high affinity for muscarinic M1 receptor in brain tissue. Olanzapine decreased morphine-induced nausea and vomiting in a dose-dependent manner. However, olanzapine at a dose that had an antiemetic effect (0.03 mg/kg) did not induce catalepsy or hyperglycemia. In addition, olanzapine at this dose had no effect on the morphine-induced release of dopamine or inhibition of gastrointestinal transit. Finally, olanzapine inhibited thermal hyperalgesia and completely alleviated the sleep disturbance induced by sciatic nerve ligation. CONCLUSION: These findings suggest that olanzapine may be useful for the treatment of morphine-induced emesis and as an adjunct for the treatment of neuropathic pain associated with sleep disturbance.

Sensation of abdominal pain induced by peritoneal carcinomatosis is accompanied by changes in the expression of substance P and µ-opioid receptors in the spinal cord of mice.

BACKGROUND: Patients with peritoneal carcinomatosis often report abdominal pain, which is relatively refractory to morphine. It has been considered that a new animal model is required to investigate the mechanism of abdominal pain for the development of optimal treatments for this type of pain. METHODS: To prepare a peritoneal carcinomatosis model, highly peritoneal-seeding gastric cancer cells, 60As6, were implanted into the abdominal cavity. The nociceptive modality for pain-related behavior was assessed in terms of withdrawal behavior in response to mechanical stimuli and hunching behavior. Tissue samples from mouse dorsal root ganglia and spinal cord were subject to immunohistochemistry and real-time reverse transcription polymerase chain reaction. RESULTS: Mice with peritoneal dissemination showed significant hypersensitivity of the abdomen to mechanical stimulation and spontaneous visceral pain-related behavior. There was a significant increase in c-Fos-positive cells in the spinal cord in tumor-bearing mice. Those mice exhibited a remarkable increase in substance P-positive neurons in the dorsal root ganglia (control vs. tumor, 15.4 ± 1.1 vs. 24.2 ± 3.6, P < 0.05, n = 3). A significant decreases in µ-opioid receptor expression mainly in substance P-positive neurons was observed in tumor-bearing mice (69.3 ± 4.9 vs. 38.7 ± 0.9, P < 0.05, n = 3), and a relatively higher dose of morphine was required to significantly reverse the abdominal hypersensitivity. CONCLUSION: Both the up-regulation of substance P and down-regulation of µ-opioid receptor seen in the dorsal root ganglia may be, at least in part, responsible for the abdominal pain-like state associated with peritoneal carcinomatosis.

Recent developments in the management of cancer pain in Japan: education, clinical guidelines and basic research.

The Cancer Control Act of Japan came into effect in 2007. Most physicians, however, have not yet had sufficient opportunity to learn about pain management and other clinical palliative care practices. In an attempt to rectify this situation, the Japanese Society for Palliative Medicine has initiated the Palliative care Emphasis program on symptom management and Assessment for Continuous medical Education project. The two major roles of this project are to establish a faculty development program in palliative care, and to provide support for conducting workshops about basic palliative care throughout Japan. Another important movement is the development of a clinical guideline for the management of cancer pain. The Japanese Society for Palliative Medicine developed a clinical guideline for the pharmacological management of cancer pain in 2010. On the other hand, although clinical experience has demonstrated that psychological dependence is not a major concern when morphine is used to control pain in cancer patients, undue anxiety about psychological dependence on morphine in cancer patients has led physicians and patients to use inadequate doses of opioids. In an attempt to remedy this situation, therefore, Japanese basic researchers are cooperatively involved in conducting high-quality basic research to answer clinical questions in palliative care. They have demonstrated to the world, for the first time, that (i) chronic pain dramatically attenuates the reward effects of opioids and that (ii) atypical antipsychotics, such as olanzapine, can suppress morphine-induced emesis and alleviate the sleep dysregulation associated with neuropathic pain in animals. Thus, we are working in close collaboration to establish new strategies for palliative care in Japan.

Knowledge, beliefs, and concerns about opioids, palliative care, and homecare of advanced cancer patients: a nationwide survey in Japan.

PURPOSE: Patients' knowledge, beliefs, or concerns about opioids, palliative care, and homecare can be potential barriers to providing quality palliative care. The primary aim of this study was to clarify knowledge about opioids, beliefs about palliative care, and concerns about homecare in advanced cancer patients. METHODS: An anonymous questionnaire was sent to 1,619 outpatients with advanced cancer at 25 hospitals in four different regions of Japan. The respondents were asked to report their knowledge about opioids, beliefs about palliative care, and concerns about homecare, in addition to the levels of their sense of security regarding receiving cancer care in the region. RESULTS: A total of 925 responses were received. In total, 28% believed that opioids are addictive and/or shorten life; 52% believed that palliative care is only for terminally ill patients; 75% agreed that being taken care of at home puts a heavy burden on the family; and 61% agreed that home-visit services cannot respond to sudden changes in a patient's condition. Levels of patients' sense of security were significantly higher in those who agreed that "opioids can relieve most pain caused by cancer" "palliative care relieves pain and distress", "palliative care is provided along with chemotherapy and/or radiation therapy", and "pain can be alleviated as effectively through home-visit services as it can at the hospital", and those who disagreed with the statements that "home-visit services cannot respond to sudden changes in a patient's condition" and "being taken care of at home puts a burden on the family". CONCLUSIONS: Advanced cancer patients frequently had incorrect knowledge about opioids, a belief that palliative care is only for terminally ill patients, and concerns about homecare, especially the family burden and responses to sudden changes. Providing appropriate information about the safety of opioids, the availability of palliative care during the entire course of the disease, and realistic information about homecare is of marked importance to promote patients' sense of security.

A region-based palliative care intervention trial using the mixed-method approach: Japan OPTIM study.

BACKGROUND: Disseminating palliative care is a critical task throughout the world. Several outcome studies explored the effects of regional palliative care programs on a variety of end-points, and some qualitative studies investigated the process of developing community palliative care networks. These studies provide important insights into the potential benefits of regional palliative care programs, but the clinical implications are still limited, because: 1) many interventions included fundamental changes in the structure of the health care system, and, thus, the results would not be applicable for many regions where structural changes are difficult or unfeasible; 2) patient-oriented outcomes were not measured or explored only in a small number of populations, and interpretation of the results from a patient's view is difficult; and 3) no studies adopted a mixed-method approach using both quantitative and qualitative methodologies to interpret the complex phenomenon from multidimensional perspectives. METHODS/DESIGNS: This is a mixed-method regional intervention trial, consisting of a pre-post outcome study and qualitative process studies. The primary aim of the pre-post outcome study is to evaluate the change in the number of home deaths, use of specialized palliative care services, patient-reported quality of palliative care, and family-reported quality of palliative care after regional palliative care intervention. The secondary aim is to explore the changes in a variety of outcomes, including patients' quality of life, pain intensity, family care burden, and physicians' and nurses' knowledge, difficulties, and self-perceived practice. Outcome measurements used in this study include the Care Evaluation Scale, Good Death Inventory, Brief pain Inventory, Caregiving Consequence Inventory, Sense of Security Scale, Palliative Care Knowledge test, Palliative Care Difficulties Scale, and Palliative Care Self-reported Practice Scale. Study populations are a nearly representative sample of advanced cancer patients, bereaved family members, physicians, and nurses in the region.Qualitative process studies consist of 3 studies with each aim: 1) to describe the process in developing regional palliative care in each local context, 2) to understand how and why the regional palliative care program led to changes in the region and to propose a model for shaping regional palliative care, and 3) to systemically collect the barriers of palliative care at a regional level and potential resolutions. The study methodology is a case descriptive study, a grounded theory approach based on interviews, and a content analysis based on systemically collected data, respectively. DISCUSSION: This study is, to our knowledge, one of the most comprehensive evaluations of a region-based palliative care intervention program. This study has 3 unique aspects: 1) it measures a wide range of outcomes, including quality of care and quality of life measures specifically designed for palliative care populations, whether patients died where they actually preferred, the changes in physicians and nurses at a regional level; 2) adopts qualitative studies along with quantitative evaluations; and 3) the intervention is without a fundamental change in health care systems. A comprehensive understanding of the findings in this study will contribute to a deeper insight into how to develop community palliative care. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR), Japan, UMIN000001274.

[Retrospective study on intravenous compound injection of cancer pain patients with oxycodone and hydrocotarnine preparation in comparison with subcutaneous administration].

In Japan, although oral oxycodone is widely used for cancer pain treatment, there is no injection preparation of oxycodone used as a single ingredient. Only the compound injection of oxycodone and hydrocotarnine has received approval. Subcutaneous administration of the drug is approved, but there are few efficacy and safety reports about its intravenous administration. We compared 245 patients(187 intravenous administration patients and, 58 subcutaneous administration patients)to whom the compound injection of oxycodone and hydrocotarnine was administered from April, 2008 to September, 2011, in order to investigate the drug's efficacy and safety. The reasons for injection were the impossibility of oral administration in 105 patients, a need for dose adjustment in 56 patients, and that other drugs were not as effective in 37 patients, and side effect reduction in 33 patients. The average change in the numeric rating scale(0-10)was 3. 7→1. 8 in intravenous administration, and 3. 4→1. 2 in subcutaneous administration. The incidence of main adverse events(intravenous administration/subcutaneous administration)were constipation(37%/28%), vomiting(31%/34%), and somnolence(52%/50%). There was no significant difference in efficacy and safety. The conversion ratio differed in a case due to a change, and about 20 to 40% of addition was needed within four days after the start. It is considered that compound injection of oxycodone and hydrocotarnine is effective for cancer pain treatment.

Effects of gabapentin on brain hyperactivity related to pain and sleep disturbance under a neuropathic pain-like state using fMRI and brain wave analysis.

Neuropathic pain is the most difficult pain to manage in the pain clinic, and sleep problems are common among patients with chronic pain including neuropathic pain. In the present study, we tried to visualize the intensity of pain by assessing neuronal activity and investigated sleep disturbance under a neuropathic pain-like state in mice using functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG)/electromyogram (EMG), respectively. Furthermore, we investigated the effect of gabapentin (GBP) on these phenomena. In a model of neuropathic pain, sciatic nerve ligation caused a marked decrease in the latency of paw withdrawal in response to a thermal stimulus only on the ipsilateral side. Under this condition, fMRI showed that sciatic nerve ligation produced a significant increase in the blood oxygenation level-dependent (BOLD) signal intensity in the pain matrix, which was significantly decreased 2 h after the i.p. injection of GBP. Based on the results of an EEG/EMG analysis, sciatic nerve-ligated animals showed a statistically significant increase in wakefulness and a decrease in non-rapid eye movement (NREM) sleep during the light phase, and the sleep disturbance was almost completely alleviated by a higher dose of GBP in nerve-ligated mice. These findings suggest that neuropathic pain associated with sleep disturbance can be objectively assessed by fMRI and EEG/EMG analysis in animal models. Furthermore, GBP may improve the quality of sleep as well as control pain in patients with neuropathic pain.