High prevalence of severe pain is associated with low opioid availability in patients with advanced cancer: Combined database study and nationwide questionnaire survey in Japan.

OBJECTIVES: Opioid availability for the palliative care of patients with advanced cancer is increasing globally. However, opioid availability remains extremely low in Japan. We investigated whether pain is appropriately controlled by low-dose opioid prescriptions in patients with advanced cancer in Japan. METHODS: A web-based nationwide survey for caregivers from 2000 community comprehensive support care centers was performed in Japan to assess details about pain in the 30 days before patients died of end-stage cancer. Separately, the data for opioid prescription doses and medical services in the 90 days before the death of patients with cancer were extracted from a health insurance claim database. RESULTS: Responses from 1034 responders were retrieved and 665 patients were included. In total, 254 patients (38.2%) complained of severe-to-intolerable cancer-related pain. The median cumulative prescription dose of opioids in the 90 days before patient death was 311.0 mg by oral morphine equivalent doses. Multiple regression analyses across prefectures revealed that the proportion of patients with severe-to-intolerable cancer-related pain was negatively associated with the cumulative opioid consumption expressed as morphine-equivalent doses within 90 days before death. CONCLUSIONS: The very low availability of opioids for patients with end-stage cancer could result in high rate of severe-to-intolerable cancer-related pain patients. There were several limitations in this study, and the interpretations of the findings should be carefully. However, the increase in the absolute dose of opioids could improve the palliative care framework to the pain control levels of the global standard.

Secondary trigeminal neuralgia caused by lung adenocarcinoma metastasis on trigeminal nerve roots successfully relieved by opioids: A case report.

Secondary trigeminal neuralgia (TN) is caused by identifiable diseases or lesions of the trigeminal nerve root, Gasserian ganglion and/or pons. TN is a neuropathic pain disorder characterized by electric shock-like or stabbing pain in the facial region, which can lead to impaired health-related quality of life. The present case report describes a rare case of secondary TN caused by trigeminal nerve metastases from lung adenocarcinoma, in which opioids provided symptomatic relief. The patient was a 46-year-old man with stage IV lung adenocarcinoma. They were admitted to hospital for the introduction of fifth-line chemotherapy because of previous chemotherapy-refractory disease progression. Electric shock-like or stabbing pain in the left facial area and bilateral auditory disturbances coincided with intracranial peri-brainstem metastases. Facial pain was triggered by mastication, making it difficult for the patient to eat. A fentanyl transdermal patch (25 mcg/h) was initiated following a diagnosis of TN secondary to lung adenocarcinoma metastases on the trigeminal nerves by magnetic resonance imaging. Subsequently, the facial pain improved rapidly. In conclusion, unlike classic and idiopathic TN, which is usually treated with carbamazepine as a first-line drug, oncologic secondary TN can be treated with opioids.

Immune checkpoint inhibitor-associated colitis in unresectable hepatocellular carcinoma: two cases of early onset after treatment with durvalumab plus tremelimumab.

The HIMALAYA trial is the first chemotherapeutic trial to demonstrate the efficacy of combined immune checkpoint inhibitors (ICIs) for unresectable hepatocellular carcinoma (u-HCC). The STRIDE regimen used in this trial consists of a cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor and programmed cell death ligand 1 (PD-L1) inhibitor. Herein, we report two cases of ICI-colitis that occurred immediately after the initiation of the STRIDE regimen for u-HCC. A 73-year-old man and 75-year-old man with u-HCC were treated with the STRIDE regimen. Both patients developed grade 3 diarrhea (Common Terminology Criteria for Adverse Events, ver. 5.0) within 10 days of treatment initiation. Colonoscopy revealed aphthous erosions and erythema extending from the terminal ileum to the rectum in one case, while the other showed aphthous ulcers in the terminal ileum and shallow ulcers in the colorectum. Histopathological examination of a biopsy specimen revealed epithelial cell apoptosis and neutrophil infiltration bodies, consistent with ICI-colitis. Prednisolone (0.5 mg/kg) was effective in both patients. Our experience suggests the need for both careful monitoring and early endoscopic examination of ICI colitis in patients with unresectable HCC treated with the STRIDE regimen.

Development of a Japanese Version of the Quality of Life at the End of Life-Cancer Scale.

CONTEXT: The Quality of Life at the End of Life-Cancer Scale (QUAL-EC) is a self-reported instrument to assesses the quality of life of patients with cancer near the end of life. OBJECTIVE: To test the reliability and validity of the QUAL-EC-J, a Japanese translated version of the QUAL-EC. METHODS: A total of 179 Japanese patients with advanced cancer completed the QUAL-EC-J, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Rosenberg Self-Esteem Scale, Multidimensional Scale of Perceived Social Support, Functional Assessment of Cancer Therapy-General Scale, and Functional Assessment of Chronic Illness Therapy-Spiritual questionnaires. We performed confirmatory factor analysis of the four structures of the QUAL-EC and exploratory factor analysis of the QUAL-EC-J. Internal consistency was assessed using Cronbach's α coefficient and validity was examined by calculating correlations with relevant scales. RESULTS: Confirmatory factor analysis showed an inadequate fit to the original QUAL-EC structure. Exploratory factor analysis revealed a three-factor structure of the QUAL-EC-J, with Cronbach's α values of 0.68-0.88. All subscales were negatively correlated with depression and anxiety. Each subscale was correlated with related measures: "symptom control" with "physical well-being"; "acceptance of disease and life" with "social and family well-being" and "meaning/peace"; and "preparation for end of life" with "emotional well-being" and "meaning/peace." CONCLUSIONS: The QUAL-EC-J has a three-factor structure with acceptable reliability and sufficient validity. Differences in the factor structure between the QUAL-EC-J and the QUAL-EC may be due to cultural factors. Study findings suggest that utilization of the QUAL-EC-J could help to improve research and clinical care in advanced cancer in Japan.

Efficacy of treatments for pain and numbness in cancer survivors: a systematic review and meta-analysis.

BACKGROUND: Pain and numbness in cancer survivors frequently have negative impacts on quality of life (QoL). This meta-analysis aimed to identify the current treatment options for pain and numbness in cancer survivors and to evaluate their effects. METHODS: Cancer survivors were defined as patients diagnosed with cancer who had completed active cancer treatment, whose conditions were stable, and who had no evidence of recurrent or progressive disease. A systematic search through the PubMed, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, PsycInfo, and CINAHL databases was conducted, which targeted randomized controlled trials (RCTs) published until April 2022 that evaluated any type of treatment for pain or numbness in cancer survivors. A meta-analysis was conducted using the random-effects model to obtain the effect sizes of 7 types of treatments: opioid therapy, nonopioid pharmacotherapy, interventional therapy, acupuncture, education/cognitive behavioral therapy (CBT), physical exercise, and alternative medicine. RESULTS: A total of 36 studies involving 2,870 cancer survivors were included. Among them, 35 (n=2,813) were included in the meta-analysis for pain. The analysis suggested that physical exercise [n=761; 13 studies; standardized mean difference (SMD) -0.84; 95% confidence interval (CI): -1.14 to -0.55], acupuncture (n=409; 3 studies; SMD -0.80; 95% CI: -1.04 to -0.56), and alternative medicine (n=206; 6 studies; SMD -0.44; 95% CI: -0.71 to -0.16) could significantly reduce pain. Nonopioid pharmacotherapy and education/CBT did not demonstrate significant effects. No studies were identified that investigated the effects of opioid therapy or interventional therapy on pain. Regarding numbness, 5 studies (n=566) were included in the meta-analysis. Acupuncture (n=99; 2 studies) did not demonstrate significant effects on numbness, and the effects of nonopioid pharmacotherapy, education/CBT, and physical exercise could not be determined due to the small number of included studies. No studies were identified that investigated the effects of opioid therapy, interventional therapy, or alternative medicine on numbness. CONCLUSIONS: This meta-analysis suggested that physical exercise, acupuncture, and alternative medicine may reduce pain in cancer survivors, with a very small to moderate amount of evidence. The effect of treatments for numbness could not be determined due to the limited number of included studies. Further studies are needed, particularly on widely used pharmacotherapy.

Genetic polymorphism of pleiotrophin is associated with pain experience in Japanese adults: Case-control study.

Genetic factors play a role in individual differences in pain experience. Here, we performed a genome-wide association study (GWAS) to identify novel loci regulating pain processing. We conducted a 2-stage GWAS and the candidate single-nucleotide polymorphisms (SNPs) association study on pain experience using an exploratory cohort of patients with cancer pain. The confirmatory cohort comprised of participants from the general population with and without habitual use of analgesic medication. In the exploratory cohort, we evaluated pain intensity using a numerical rating scale, recorded daily opioid dosages, and calculated pain reduction rate. In the confirmatory cohort, pain experience was defined as habitual nonsteroidal anti-inflammatory drug usage. Using linear regression models, we identified candidate SNP in the exploratory samples, and tested the association between phenotype and experienced pain in the confirmatory samples. We found 1 novel SNP (rs11764598)-located on the gene encoding for pleiotrophin on chromosome 7-that passed the genome-wide suggestive significance at 20% false discovery rate (FDR) correction in the exploratory samples of patients with cancer pain (P = 1.31 × 10-7, FDR = 0.101). We confirmed its significant association with daily analgesic usage in the confirmatory cohort (P = .028), although the minor allele affected pain experience in an opposite manner. We identified a novel genetic variant associated with pain experience. Further studies are required to validate the role of pleiotrophin in pain processing.

Excess fructose enhances oleatic cytotoxicity via reactive oxygen species production and causes necroptosis in hepatocytes.

Non-alcoholic fatty liver disease (NAFLD), the hepatic phenotype of metabolic syndrome, has been identified as a major health concern as the number of cirrhosis and deaths associated with NAFLD is expected to increase. Although fructose intake has been considered to be a progressive factor in the pathophysiology of NAFLD, it remains unclear how fructose contributes to hepatocellular damage during lipotoxicity. In the present study, we aimed to analyze the hepatotoxicity of fructose in steatosis. Fructose effects on lipotoxicity were evaluated in HepG2 cells, primary mouse hepatocytes, and in mice fed a high-fat diet with or without sucrose (HFDS/HFD). Oleate induced caspase 3-independent cell death in HepG2 cells and primary mouse hepatocytes cultured in fructose-supplemented medium, and induced cleavage of caspase-1 in primary mouse hepatocytes. In addition, the number of cells stained positive for reactive oxygen species (ROS) was significantly increased, and N-acetyl cysteine was found to inhibit ROS production and cell death. Cell death was confirmed to be through necrotic cell death, and phosphorylation of mixed lineage kinase domain-like (MLKL) protein was observed. Taken together, hepatocyte cytotoxicity was due to excess fructose with oleate-induced ROS-mediated necroptosis. HFDS mice showed progressive hepatic fibrosis and inflammation and a higher NAS score than HFD mice or mice fed a control diet. The expression of hemoxygenase-1, phosphorylation of MLKL, cleavage of caspase1, and apoptosis were significantly increased in the livers of mice fed a HFDS. Overall, excess fructose intake induces necroptosis through the production of ROS and enhances the toxicity of oleatic cytotoxicity.

Gabapentinoid Use Is Associated With Reduced Occurrence of Hyperactive Delirium in Older Cancer Patients Undergoing Chemotherapy: A Nationwide Retrospective Cohort Study in Japan.

BACKGROUND: It is unclear whether gabapentinoids affect the development of delirium. We aimed to determine the association between gabapentinoid use and hyperactive delirium in older cancer patients undergoing chemotherapy. METHODS: We conducted propensity score-matched analyses using data from a nationwide inpatient database in Japan. We included cancer patients with pain ≥70 years of age undergoing chemotherapy between April 2016 and March 2018. Patients receiving gabapentinoids were matched with control patients using propensity scores. The primary outcome was occurrence of hyperactive delirium during hospitalization, and the secondary outcomes were length of hospital stay, in-hospital fractures, and in-hospital mortality. Hyperactive delirium was identified by antipsychotic use or discharge diagnoses from the International Classification of Diseases, 10th Revision. RESULTS: Among 143,132 identified patients (59% men; mean age, 76.3 years), 14,174 (9.9%) received gabapentinoids and 128,958 (90.1%) did not (control group). After one-to-one propensity score matching, 14,173 patients were included in each group. The occurrence of hyperactive delirium was significantly lower (5.2% vs 8.5%; difference in percent, -3.2% [95% confidence interval, -3.8 to -2.6]; odds ratio, 0.60 [0.54-0.66]; P < .001), the median length of hospital stay was significantly shorter (6 days [interquartile range, 3-15] vs 9 days [4-17]; subdistribution hazard ratio, 1.22 [1.19-1.25]; P < .001), and the occurrence of in-hospital mortality was significantly lower in the gabapentinoid group than in the control group (1.3% vs 1.8%; difference in percent, -0.6% [-0.9 to -0.3]; odds ratio, 0.69 [0.57-0.83]; P < .001). Gabapentinoid use was not significantly associated with the occurrence of in-hospital fractures (0.2% vs 0.2%; difference in percent, 0.0% [-0.1 to 0.1]; odds ratio, 1.07 [0.65-1.76]; P = .799). The results of sensitivity analyses using stabilized inverse probability of treatment weighting were consistent with the results of the propensity score-matched analyses. CONCLUSIONS: Our findings suggest that gabapentinoid use is associated with reduced hyperactive delirium in older cancer patients undergoing chemotherapy, with no evidence of an increase in the fracture rate, length of hospital stay, or in-hospital death.

Effect of Antimicrobial Prophylaxis Duration on Health Care-Associated Infections After Clean Orthopedic Surgery: A Cluster Randomized Trial.

Importance: Postoperative health care-associated infections are associated with a greater deterioration in patients' general health status and social and economic burden, with at least 1 occurring in approximately 4% of acute care hospital patients. Antimicrobial prophylaxis prevents surgical site infections in various orthopedic procedures; however, its relationship with health care-associated infections remains unknown. Objective: To examine whether a shorter antimicrobial prophylaxis duration of less than 24 hours after surgery is not inferior to a longer duration in preventing health care-associated infections after clean orthopedic surgery. Design, Setting, and Participants: This open-label, multicenter, cluster randomized, noninferiority clinical trial was conducted in 5 tertiary referral hospitals in greater Tokyo metropolitan area, Japan, from May to December 2018. Adult patients undergoing clean orthopedic surgery were recruited until the planned number of participants was achieved (500 participants per group). Statistical analysis was conducted from July to December 2019. Interventions: Antimicrobial prophylaxis was discontinued within 24 hours after surgery in group 24 and 24 to 48 hours after surgery in group 48. Group allocation was switched every 2 or 4 months according to the facility-based cluster rule. Study-group assignments were masked from participants. Main Outcomes and Measures: The primary outcome was the incidence of health care-associated infections requiring antibiotic therapies within 30 days after surgery. The noninferiority margin was 4%. Results: Of the 1211 participants who underwent cluster allocation, 633 participants were in group 24 (median [IQR] age, 73 [61-80] years; 250 men [39.5%] and 383 women [60.5%]), 578 participants were in group 48 (median [IQR] age, 74 [62-81] years; 204 men [35.3%] and 374 women [64.7%]), and all were eligible for the intention-to-treat analyses. Health care-associated infections occurred in 29 patients (4.6%) in group 24 and 38 patients (6.6%) in group 48. Intention-to-treat analyses showed a risk difference of -1.99 percentage points (95% CI, -5.05 to 1.06 percentage points; P < .001 for noninferiority) between groups, indicating noninferiority. Results of adjusted intention-to-treat, per-protocol, and per designated procedure population analyses supported this result, without a risk of antibiotic resistance and prolonged hospitalization. Conclusions and Relevance: This cluster randomized trial found noninferiority of a shorter antimicrobial prophylaxis duration in preventing health care-associated infections without an increase in antibiotic resistance risk. These findings lend support to the global movement against antimicrobial resistance and provide additional information on adequate antimicrobial prophylaxis for clean orthopedic surgery. Trial Registration: Identifier: UMIN000030929.

Imaging features inferring symptom onset due to spinal metastasis progression: a preliminary study.

BACKGROUND: Spinal metastases can cause intractable pain and neurological deficits, which can markedly worsen both patients' activities of daily living (ADL) and their health-related quality of life (QOL). Early intervention is essential to prevent irreversible neurological deficits and pain associated with spinal metastases. We investigated the imaging features of spinal metastases that led to neurological deficits. METHODS: We analyzed axial cross-sectional computed tomography (CT) images of cervical and thoracic spinal metastases in patients with and without lower limb motor paralysis, neuropathic pain, and local nociceptive pain. We distinguished regions of the spine associated with these respective symptoms, and explored their inferable performance using images obtained before symptom onset. In addition, we analyzed the imaging features and type of bone metastasis (osteolytic and osteoblastic). RESULTS: Spinal lesions occupied the area in and around the spinal canal and around the pedicle in patients with motor paralysis. Lesions around the pedicle and in the most posterior vertebral body part before symptom onset were inferable. In patients with neuropathic pain, spinal metastases spread along the pedicle before symptom onset, and had surrounded the spinal canal circumferentially at symptom onset. Local nociceptive pain was more common near the center of the vertebral body either at or before symptom onset. There was no difference in the imaging features according to the type of bone metastasis. CONCLUSIONS: Lesions in certain regions in the asymptomatic metastatic spine can indicate the onset of spinal metastasis-related symptoms in the next few months. Early therapeutic intervention might be applied to prevent neurological disorder.

Use of naldemedine is associated with reduced incidence of hyperactive delirium in cancer patients with opioid-induced constipation: A nationwide retrospective cohort study in Japan.

BACKGROUND: Medical benefits of peripherally acting mu-opioid receptor antagonists other than improving opioid-induced constipation remain unclear. Our aim was to evaluate the association between the use of naldemedine and incidence of hyperactive delirium in cancer patients receiving chemotherapy and opioid therapy. METHODS: We conducted a propensity score-matched analysis using a nationwide inpatient database in Japan. Cancer patients receiving both inpatient chemotherapy and opioid therapy from June 1, 2017, to March 31, 2018, were included. Patients receiving naldemedine were matched to control patients by propensity score. Our primary outcome was the incidence of hyperactive delirium during hospitalization, and secondary outcomes were the length of hospital stay, hospital costs, in-hospital mortality, and incidence of ileus. RESULTS: Of 34,031 patients receiving inpatient chemotherapy and opioid therapy, 1905 (5.6%) were included in the naldemedine group. After one-to-four propensity score matching, 1904 patients were included in the naldemedine group and 7616 in the control group. Naldemedine users had significantly reduced incidence of hyperactive delirium compared with the control patients (19.4% vs 23.3%; risk difference, -3.9 [95% confidence interval, -5.9 to -1.9]; risk ratio, 0.83 [0.75-0.92]; p<0.001; subdistribution hazard ratio, 0.85 [0.75-0.97]; p = 0.015). The median length of hospital stay was significantly shorter in the naldemedine group compared with the control group (12 days [interquartile range, 6-23] vs 14 days [6-26]; p = 0.001). The median hospital costs were also significantly lower in the naldemedine group compared with the control group (US $6179 [3351-10,026] vs US $6576 [3436-11,107]; p < 0.001). No significant differences were found for in-hospital mortality or incidence of ileus between the groups. CONCLUSIONS: Our findings suggest that the use of naldemedine may have benefits in preventing hyperactive delirium, shortening hospital stay, and decreasing hospital costs in cancer patients receiving chemotherapy and opioid therapy.

Impact of Alternate Gait Training Using Knee-Ankle-Foot Orthoses with Oil Damper Ankle Hinge in Patients with Subacute Severe Hemiplegia.

Patients with severe hemiplegia along with knee instability require knee-ankle-foot orthoses (KAFOs) for gait training. However, in these patients, it is unclear which type of walking training is more effective to improve gait function. Providing alternate gait training (AGT) improves walking function in patients with spinal cord injury, but it is still unclear whether this is effective in hemiplegic stroke patients. In this study, we defined "unified AGT" as AGT performed with the same therapeutic concept by physiotherapists. We then investigated whether AGT improved gait function quicker than our traditional gait training in hemiplegic stroke patients. We enrolled 15 subjects with severe hemiplegia and knee instability who had undergone unified AGT using KAFOs with hinged oil dampers at the ankles, and 30 historical control (HC) subjects who had undergone traditional gait training. We used multiple comparison and survival analyses to analyze the differences in the functional independence measure (FIM) gait score changes between the two groups. The multiple comparison revealed a significant increase (p < 0.05) in the FIM gait score compared with its initial score in the subjects with unified AGT. However, this improvement was not seen in the HC subjects. Additionally, the survival analysis of time taken to recover revealed a significant difference between the subjects with unified AGT and HC subjects (p < 0.05). These findings suggest that unified AGT using a KAFO facilitates gait improvement in patients with severe hemiplegia and knee instability.

Capecitabine-induced hand-foot syndrome does not emerge in the complex regional pain syndrome-affected limb: A case report.

Hand-foot syndrome (HFS) is a frequent adverse effect of various anti-tumour drugs, such as capecitabine, that affects their dose-limiting toxicity. The mechanism of HFS remains unknown and there are currently no effective strategies to treat HFS, except for cessation. The current study presented a female case where one hand, affected by brachial plexus infiltration due to the subclavian lymph node metastasis of breast cancer, exhibited not only pain and partial motor paralysis but also anhidrosis, oedema and skin colour changes. The patient met the diagnostic criteria for complex regional pain syndrome (CRPS). After treatment with capecitabine, their anhidrosis hand completely prevented HFS. The other hand and both feet demonstrated typical symptoms of HFS, which improved consequent to capecitabine cessation. The CRPS-affected hand remained normal. Considering the limited presentation of HFS concomitant with anhidrosis, the exocrine release of condensed capecitabine through sweat glands might be a promising mechanism of HFS induction.

Serum alpha-fetoprotein increases prior to fibrosis resolution in a patient with acute liver failure.

A 78-year-old woman who was diagnosed with acute liver failure due to an undetermined cause presented with liver atrophy. Coagulopathy was normalized at 35 days of hospitalization, although atrophy in the liver persisted. During the observation period, alpha-fetoprotein (AFP) bi-modally increased at 36 and 377 days. Around the second peak of AFP, the liver volume was regained within the normal range. Fucosylated AFP was found at the first peak but not at the second peak. Cytokines/chemokines were simultaneously evaluated, and the results were evaluated using PANTHER ( http://www.pantherdb.org/ ). Although transaminase and prothrombin time were within the normal range, cytokines/chemokines associated with angiogenesis and inflammation increased prior to the second peak of AFP. Our study suggests that the first peak of AFP occurs in response to acute insult, while the second peak may be associated with the resolution of liver fibrosis. The present case provides new insights into the mechanism of AFP elevation.

The Impact of Cefazolin Shortage on Surgical Site Infection Following Spine Surgery in Japan.

STUDY DESIGN: Retrospective study using prospectively collected data. OBJECTIVE: This study aimed to investigate the effect of alternative antimicrobial prophylaxis agents on surgical site infections (SSIs) after spine surgery. SUMMARY OF BACKGROUND DATA: Although the use of alternative antimicrobial prophylaxis agents might have a negative effect on SSI prevention, their association with SSI risk in spine surgery remains unclear. METHODS: We used the registry data of consecutive patients undergoing spine surgery from April 2017 to January 2020 in four institutions participating in the University of Tokyo Spine Group. Before March 2019, all institutions used cefazolin for antimicrobial prophylaxis. After March 2019, the institutions used broad-spectrum beta-lactam agents as an alternative due to a cefazolin shortage in Japan. RESULTS: Among the 3841 enrolled patients (2289 males), 2024 received cefazolin and 1117 received alternative agents. The risk of reoperation for deep SSI within 30 days of spine surgery was significantly higher in the alternative antimicrobial prophylaxis agent group (adjusted odds ratio [aOR] 1.96; 95% confidence interval [CI], 1.15-3.35; P = 0.014). In subgroup analyses, the SSI risk was significantly higher in the thoracolumbar surgery group (aOR 1.98; 95% CI, 1.06-3.73; P = 0.03). A nonsignificant consistent trend was found in all other subgroups: posterior decompression (aOR 1.91; 95% CI, 0.86-4.21; P = 0.11); posterior fixation (aOR 2.05; 95% CI, 0.99-4.24; P = 0.05); and cervical spine surgery (aOR 2.30; 95% CI, 0.82-6.46; P = 0.11). CONCLUSION: Alternative antimicrobial prophylaxis agents increased the risk of reoperation for SSI after spine surgery compared with cefazolin. Our study supports the current practice of using first-generation cephalosporins as first-line antimicrobial prophylaxis agents in spine surgery as recommended in multiple guidelines.Level of Evidence: 3.

Prefectural Adequacy of Opioid Availability for Cancer Pain and Its Determinants in Japan: A Preliminary Study.

INTRODUCTION: Opioid analgesics are the mainstay of cancer pain management. The annual opioid consumption globally indicates adequate opioid availability and the quality of palliative care. We investigated the current situation regarding the adequacy of opioid availability in individual prefectures in Japan and explored the determinants of adequacy. METHODS: We analyzed nationwide databases open to public inspection depicting the current Japanese healthcare situation. Opioid consumption for cancer pain was estimated from oxycodone and morphine data in the nationwide database. On the basis of the World Health Organization recommendations, we calculated adequacy based on the annual cancer deaths in each prefecture in 2013 and 2015. We investigated the associations between adequacy and either outpatient medical expenditure for hypertension and diabetes as a proxy of primary care practice or ratios of these risk holders in community. Outpatient medical expenditures for musculoskeletal disorders and neoplasms were also investigated. RESULTS: The nationwide adequacy of opioid availability was approximately 75%. The largest gaps in adequacy between prefectures were more than 65%. The adequacy correlated with expenditure but not local volumes of hypertension and diabetes in both years. The other two expenditures did not relate to opioid availability. CONCLUSIONS: Although precise data are required, our preliminary findings indicate that primary care practice is the key regulator of adequate opioid availability. Opioid adequacy in Japan is thus delayed in matching the global standard, and gaps in opioid adequacy among prefectures should be bridged rapidly to expand universal access to effective palliative care and cancer pain relief.

Clopidogrel, an ADP-P2Y12 Receptor Antagonist, Can Prevent Severe Postoperative Pain: A Retrospective Chart Review.

The purinergic P2Y12 receptor regulates microglial activation, resulting in persistence and aggravation of pain in neuropathic and nociceptive pain models. We conducted a retrospective chart review to explore the analgesic potency of the P2Y12 receptor-specific antagonist, clopidogrel, for clinical management of postoperative pain in patients who underwent abdominal surgery. Twenty-seven patients with cardiovascular comorbidities, who underwent laparoscopic abdominal surgery and had ceased aspirin (ASP, n = 17) or clopidogrel (CLP, n = 10) for 14 days pre-operatively, were enrolled retrospectively. In both groups, the number of opioids and non-steroidal anti-inflammatory drugs (NSAIDs) consumed for managing postoperative pain was compared using the chi-square test and Mann-Whitney test. Our results showed that from postoperative day (POD) 0 to POD 3, the average numerical rating reflecting the postoperative pain was comparable between the two groups (CLP: 4.0 ± 1.4 vs. ASP: 3.7 ± 0.8, P-value = 0.56). However, at POD 7, opioid consumption in the CLP-treated group (fentanyl-equivalent dose: 0.49 ± 0.56 mg) was significantly lower than that in the ASP-treated group (1.48 ± 1.35 mg, P-value = 0.037). After reaching a stable state by repeated systemic administration, clopidogrel sustained the analgesic efficacy for a certain period. In conclusion, microglial P2Y12 receptors may mediate signal transduction of postoperative nociceptive pain and enhance clinical opioid analgesia.

Adiponectin receptor 1 gene is potentially associated with severity of postoperative pain but not cancer pain.

Adiponectin is an adipose tissue-derived cytokine that exerts its antiinflammatory effects by binding to 2 adiponectin receptors, adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2). However, the role of these adiponectin receptors on inflammatory pain remains unclear. We investigated the association between single nucleotide polymorphisms (SNPs) of these genes and inflammatory pain, such as postoperative pain and cancer pain.We analyzed 17 SNPs of the ADIPOR1 gene and 27 SNPs of the ADIPOR2 gene in 56 adult patients with postlaparotomy pain. We compared these genotypes with pain intensity and opioid consumption, adjusting for multiple testing. We analyzed the genotypes of 88 patients with cancer pain and examined the association of the relevant SNP(s) with pain intensity and opioid consumption.One variant of the ADIPOR1 gene (rs12045862) showed significant association with postoperative pain intensity; patients with minor allele homozygote (n = 7) demonstrated significantly worse pain intensity than that of combined patient group exhibiting major allele homozygote or the heterozygote (n = 49; Mann-Whitney test, P < .00002), although their opioid consumptions were comparable. Cancer pain intensity between minor allele homozygote patients (n = 7) and other 2 genotype patients (n = 81) were comparable.The rs12045862 SNP of the ADIPOR1 gene was associated with postoperative pain but not cancer pain. This might result from functional alteration of the ADIPOR1 signalling pathways, which influence the inflammatory process. ADIPOR1 may be a novel potential target for developing analgesics of postoperative pain.

A sliding scale to predict postoperative complications undergoing posterior spine surgery.

BACKGROUND: There is a lack of consensus of operative time (OT) and estimated blood loss (EBL) for elderly patients based on the predicted risk of complications after posterior spine surgery. The purpose of this study was to evaluate the effect of age, OT, and EBL on the postoperative complication risk and to develop a simple sliding scale. METHODS: We explored prospectively collected data of consecutive patients who underwent posterior spine surgery in seven tertiary referral hospitals from November 2013 to May 2016. Age (<70, 70-74, 75-79, 80-84, ≥85 years), OT (<2, 2-<3, 3-<4, 4-<5, ≥5 h), and EBL (<500, 500-<1000, 1000-<1500, 1500-<2000, ≥2000 ml) were categorized ranging from 1 (lowest) to 5 (highest). The association between the crude cumulative categories' number and the incidence of complications was analyzed. We further evaluated the association by re-categorizing the cumulative number into three groups (3-4, 5-10, ≥11). RESULTS: Total of 2416 patients (median age: 70 years old) were enrolled and major complications were observed in 75 (3.1%) patients. Age, OT, and EBL showed similar odds ratio (1.18-1.19) as each category increased. The cumulative categories' number fitted the estimate complication risk (Hosmer-Lemeshow P = 0.87), and statistically significant trend was observed between predicted and actual complication rates (Cochran-Armitage test, P < 0.001). When cumulative categories' numbers were stratified into three groups, significant increasing trend of risk were observed (Mantel-Haenszel P < 0.001). Based on the categorical numbers, we proposed a simple sliding scale. CONCLUSION: Our data indicated that the risk of postoperative complication was associated with cumulative score based on increased age, OT, and EBL. A simple sliding scale was developed based on these factors, which may be useful to predict complication risk after posterior spine surgery.