Current Status of Adverse Events Related with Opioid Analgesics in Japan: Assessment Based on Japanese Adverse Drug Event Report Database.

Opioid analgesics have greatly contributed to the advancement of pain management. However, although opioids have been appropriately used in Japan, they rarely induce serious adverse events, such as respiratory depression. The present study aimed to investigate the temporal changes in the occurrence of opioid-related adverse events and deaths between 2004 and 2017 in Japan using the Japanese Adverse Drug Event Report (JADER) database. We analyzed the following points using data extracted from JADER website: 1) temporal changes in the number and proportion of opioid-related adverse event reports; 2) temporal changes in the number of morphine-, oxycodone-, and fentanyl-related adverse event reports per annual consumption; and 3) cases in which the reported outcome following opioid-related adverse events was death. Our results showed no dramatic changes in the overall incidence of opioid-related adverse events, despite the temporal changes in the annual consumption and shared component of each opioid during the survey period. However, the number and rate of fentanyl-related adverse events and their outcome "death" increased since 2010, being the highest among all adverse event including those related to morphine and oxycodone. Outcome "death" by fentanyl-related adverse events was caused mainly due to respiratory depression. These findings suggest that, although opioid-related adverse events can be controlled through proper monitoring and management by medical personnel in Japan, extra caution should be continuously paid for the rare but serious fentanyl-induced adverse events.

A cross-sectional survey of methods for controling hand-foot syndrome in patients receiving capecitabine treatment.

Medical personnel actively provide patients taking capecitabine with information on the items to prevent and treat hand-foot syndrome (HFS). However, they are typically unable to ascertain the extent of patient compliance with the recommended items. Thus, the aim of the present study was to ascertain the association between patient compliance with preventative measures for HFS and the development of HFS. Subjects included 90 patients who were treated with a drug regimen that included capecitabine. Patients were treated at one of four facilities between July 2015 and January 2017. The main parameters studied were the extent to which items to prevent and treat HFS were (or were not) followed, and the associaiton between this extent and the development of HFS symptoms. A manual prepared by a pharmaceutical company that manufactures capecitabine describes 15 routine items to follow in order to prevent and treat HFS. The two activities patients most often performed were 'applying a moisturizer' (74.1%) and 'keeping one's skin clean (e.g., washing one's hands and feet)' (64.7%). The two activities patients least often performed were 'using sunscreen on exposed areas' (14.1%) and 'using soft insoles' (11.8%). Patients who performed more items to prevent and treat HFS were significantly less likely to develop symptoms of HFS (P=0.022). Based on these findings, it is recommended that medical personnel provide instructions to the patients regarding the specific items necessary to prevent and treat HFS, and to follow-up with the patients regarding their compliance, with an emphasis on the items they are less likely to take and on the instructions to avoid external irritants. Following these guidelines should lead to qualitative improvement in HFS management.

Effects of mirtazapine on sleep disturbance under neuropathic pain-like state.

Sleep disturbance has been reported to be one of the most frequent symptoms in patients suffered from severe pain. Benzodiazepines are effective and reduce anxiety in the hours after use, but the induced sleep tends to be less than ideal in quality, with increased Stages I-II and reduces Stages III-IV sleep. In the present study, we investigated sleep disturbance under a neuropathic pain-like state in mice using electroencephalogram (EEG)/electromyogram (EMG). 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, 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. Mirtazapine (MTZ) is an antidepressant, which is considered to enhance noradrenergic and serotonergic neurotransmission via antagonistic action at central α2-adrenergic autoreceptors and heteroreceptors. In the present binding study, MTZ showed higher affinity for histamine H1 and serotonin 5-HT(2A/2C) receptors than other receptors, including α2-adrenergic receptor, in the mouse brain tissue. The thermal hyperalgesia and sleep disturbance following nerve ligation were almost completely alleviated by MTZ. These findings suggest that MTZ may improve the quality of sleep as well as control pain in patients with neuropathic pain mainly through histamine H1- and serotonin 5-HT2-receptor antagonistic actions.

Sigma-1 receptor function is critical for both the discriminative stimulus and aversive effects of the kappa-opioid receptor agonist U-50488H.

The present study was undertaken to identify possible similarities between the effects of kappa-opioid receptor agonist, N-methyl-D-aspartate-receptor antagonist, and sigma receptor agonist on the discriminative stimulus effects of U-50488H, and the possible involvement of sigma receptors in the discriminative stimulus and aversive effects of U-50488H. The kappa-opioid receptor agonist U-50488H produced significant place aversion as measured by the conditioned place preference procedure, and this effect was completely abolished by treatment with the putative sigma-1 receptor antagonist NE-100. In addition, phencyclidine (+)-SKF-10047 and (+)-pentazocine, which are sigma receptor agonists, generalized to the discriminative stimulus effects of U-50488H in rats that had been trained to discriminate between U-50488H (3.0 mg/kg) and saline. Furthermore, NE-100 significantly attenuated the discriminative stimulus effects of U-50488H and the U-50488H-like discriminative stimulus effects of phencyclidine. These results suggest that the sigma-1 receptor is responsible for both the discriminative stimulus effects and aversive effects of U-50488H.

Olanzapine suppresses the rewarding and discriminative stimulus effects induced by morphine.

Atypical antipsychotic medications are effective for treating both the positive and negative symptoms of schizophrenia. Olanzapine is an atypical antipsychotic that blocks dopaminergic, serotonergic, adrenergic, histaminergic, and muscarinic receptors. In this study, we used rodents to investigate whether olanzapine could suppress the hyperlocomotion, rewarding effect, and discriminative stimulus effect induced by the prototypic µ-opioid morphine, which are all considered to reflect the abuse potential or psychoactive effects of µ-opioids. Olanzapine at doses that failed to induce motor coordination produced a dose-dependent reduction in hyperlocomotion induced by morphine in mice. Olanzapine at a dose that did not produce motor dysfunction also inhibited the significant place preference induced by morphine in mice. Furthermore, the discriminative stimulus effect induced by morphine in rats was dose-dependently and significantly attenuated by olanzapine at the dose that did not induce the motor dysfunction. These results suggest that treatment with both µ-opioids and olanzapine at a dose lower than that at which it induces motor dysfunction could be very useful for preventing the abuse potential and/or psychoactive effects of µ-opioids.

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.

Enhancement of glutamatergic transmission in the cingulate cortex in response to mild noxious stimuli under a neuropathic pain-like state.

Pain is evoked by noxious body stimulation or through negative emotional events and memories. There are several caveats to the simple proposition that pain and emotion are linked in the cingulate cortex (CG). In this study, we investigated whether mild noxious heat stimuli could affect the neuronal activity in the CG of rats with sciatic nerve ligation. We produced a partial sciatic nerve injury by tying a tight ligature in rats. Seven days after sciatic nerve ligation, rats received mild noxious heat stimuli. Mild noxious heat stimuli produced flinching behaviors in sciatic nerve-ligated rats, but not sham-operated rats. In addition, the mild noxious heat stimuli caused a significant increase in the release of glutamate in the CG of nerve-ligated rats compared with that of sham-operated rats. Furthermore, phosphorylated-NR1-positive cells in this area significantly increased after mild noxious heat stimuli under a neuropathic pain. Under this condition, there were no significant changes in the levels of immediate-early genes such as c-fos, c-jun, JunB, and Fra1 in the CG between nerve-ligated and sham-operated rats. However, mild noxious heat stimuli under a neuropathic pain-like state produced a marked increase in the phosphorylated-c-jun (p-c-jun) immunoreactivity, which is commonly used to map neurons in the brain that can be activated after N-methyl-D-aspartate receptor activation. These findings raise the possibility that mild noxious heat stimuli under a peripheral nerve injury may increase the release of glutamate and promote its related postneuronal activity in the CG.

Hippocampal epigenetic modification at the brain-derived neurotrophic factor gene induced by an enriched environment.

Environmental enrichment is an experimental paradigm that increases brain-derived neurotrophic factor (BDNF) gene expression accompanied by neurogenesis in the hippocampus of rodents. In the present study, we investigated whether an enriched environment could cause epigenetic modification at the BDNF gene in the hippocampus of mice. Exposure to an enriched environment for 3-4 weeks caused a dramatic increase in the mRNA expression of BDNF, but not platelet-derived growth factor A (PDGF-A), PDGF-B, vascular endothelial growth factor (VEGF), nerve growth factor (NGF), epidermal growth factor (EGF), or glial fibrillary acidic protein (GFAP), in the hippocampus of mice. Under these conditions, exposure to an enriched environment induced a significant increase in histone H3 lysine 4 (H3K4) trimethylation at the BDNF P3 and P6 promoters, in contrast to significant decreases in histone H3 lysine 9 (H3K9) trimethylation at the BDNF P4 promoter and histone H3 lysine 27 (H3K27) trimethylation at the BDNF P3 and P4 promoters without any changes in the expression of their associated histone methylases and demethylases in the hippocampus. The expression levels of several microRNAs in the hippocampus were not changed by an enriched environment. These results suggest that an enriched environment increases BDNF mRNA expression via sustained epigenetic modification in the mouse hippocampus.