A Retrospective Cohort Study of Multiple Immune-Related Adverse Events and Clinical Outcomes Among Patients With Cancer Receiving Immune Checkpoint Inhibitors.

BACKGROUND AND OBJECTIVES: Immune checkpoint inhibitors (ICIs) are effective in various types of cancer and cause immune-related adverse events (irAEs). The occurrence of irAEs is associated with improved survival outcome. We investigated the association between the occurrence of irAEs and overall survival (OS) and progression free survival (PFS), and the risk factors for the development of irAEs, in patients with non-small-cell lung cancer (NSCLC), gastric cancer (GC) and melanoma (MM) treated with ICIs. METHODS: This was a retrospective observational cohort study, and the data were taken from inpatients in a hospital. OS and PFS were compared among patients with different numbers of irAEs. Log-rank test and Cox regression and logistic regression analysis were applied, and details of irAEs characteristics were summarized. RESULTS: We obtained data from 200 patients. The major tumor types were NSCLC, GC, and MM. Median OS and PFS in all patients were 9.3 and 3.5 months, respectively. Patients without irAEs tended to have shorter OS or PFS compared with those with a single irAE or multi-system irAEs. Covariate analysis suggested that age (≥75 years), albumin (≥3.5 g/dL) and smoking history were significant for increased occurrence of irAEs. Pneumonitis and thyroiditis tended to occur frequently in patients with NSCLC and MM. The irAE grade was ≤2 in 67.3% of all irAEs, and days of irAEs onset varied. CONCLUSION: We observed patients with irAEs tended to have better OS or PFS in patients with various types of cancers treated with ICIs. We suggest that ICIs should be used appropriately by continuously monitoring the irAEs.

Factors Associated With Efficacy and Nivolumab-Related Interstitial Pneumonia in Non-Small Cell Lung Cancer: A Retrospective Survey.

BACKGROUND AND OBJECTIVES: Immune-checitors have been established as a novel standard treatment for non-small cell lung cancer (NSCLC). The aim of this study was to identify factors associated with efficacy and nivolumab-related interstitial pneumonia in NSCLC by evaluating clinical data at the initiation of and during treatment. METHODS: We retrospectively reviewed the medical records of patients who underwent treatment with nivolumab between October 2015 and December 2017. Using pretreatment patient data, we investigated factors associated with overall survival (OS) and the onset of nivolumab-related pneumonitis. We investigated serum biochemistry during treatment to identify the determinants associated with progressive disease (PD) and the onset of nivolumab-related pneumonitis. RESULTS: A total of 94 patients were included. Eleven patients continued treatment, and 54 patients were diagnosed with progressive disease. Nivolumab-related pneumonitis occurred in 15 patients. A pretreatment Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 0 was linked to significantly longer OS than ECOG PS = 1 (median: 20.1 vs. 6.5 months, respectively; p < 0.001). There was a higher incidence of nivolumab-related pneumonitis in patients with a history of interstitial pneumonia than in those without it (p = 0.008). During treatment, the level of albumin gradually decreased prior to PD and onset of nivolumab-related pneumonitis. CONCLUSION: These results suggest that the pretreatment ECOG PS is the determining factor that is associated with OS, whereas history of interstitial pneumonia is the factor associated with nivolumab-related pneumonitis. A decrease in albumin during treatment may be associated with both PD and nivolumab-related pneumonitis.

Evaluation of thromboembolic events in cancer patients receiving bevacizumab according to the Japanese Adverse Drug Event Report database.

Purpose We aimed to examine the risk factors, time of onset, incidence rates, and outcomes of thromboembolic events induced by bevacizumab in patients with cancer using the Japanese Adverse Drug Event Report (JADER) database of the Pharmaceuticals and Medical Devices Agency. Methods Adverse event data recorded in the JADER database between January 2004 and January 2015 were used. After screening the data using the generic drug name bevacizumab, patient data were classified into two groups by age and five groups by cancer type. The histories of disorders were also categorized. Arterial thromboembolic event and venous thromboembolic event were classified as "favorable" or "unfavorable" outcomes. Results In total, 6076 patients were reported to have developed adverse events during the sample period, of which 233 and 453 developed arterial thromboembolic event and venous thromboembolic event, respectively. Logistic analysis suggested that the presence of cancer was a significant risk factor for both arterial thromboembolic event and venous thromboembolic event. Age (≥70 years), histories of either hypertension or diabetes mellitus were also risk factors for arterial thromboembolic event. Median cumulative times of onset for arterial thromboembolic event and venous thromboembolic event were 60 and 80 days, respectively, and were not significantly different by the log-rank test. By the chi-square test, the rate of unfavorable outcomes was found to be higher after developing arterial thromboembolic event than after venous thromboembolic event. Conclusion Thromboembolism is a leading cause of mortality in patients with cancer. Patients should be monitored for the symptoms of thromboembolic events right from the initial stages of bevacizumab treatment.

Time-Series Modeling and Simulation for Comparative Cost-Effective Analysis in Cancer Chemotherapy: An Application to Platinum-Based Regimens for Advanced Non-small Cell Lung Cancer.

The purpose of this study was to propose a time-series modeling and simulation (M&S) strategy for probabilistic cost-effective analysis in cancer chemotherapy using a Monte-Carlo method based on data available from the literature. The simulation included the cost for chemotherapy, for pharmaceutical care for adverse events (AEs) and other medical costs. As an application example, we describe the analysis for the comparison of four regimens, cisplatin plus irinotecan, carboplatin plus paclitaxel, cisplatin plus gemcitabine (GP), and cisplatin plus vinorelbine, for advanced non-small cell lung cancer. The factors, drug efficacy explained by overall survival or time to treatment failure, frequency and severity of AEs, utility value of AEs to determine QOL, the drugs' and other medical costs in Japan, were included in the model. The simulation was performed and quality adjusted life years (QALY) and incremental cost-effectiveness ratios (ICER) were calculated. An index, percentage of superiority (%SUP) which is the rate of the increased cost vs. QALY-gained plots within the area of positive QALY-gained and also below some threshold values of the ICER, was calculated as functions of threshold values of the ICER. An M&S process was developed, and for the simulation example, the GP regimen was the most cost-effective, in case of threshold values of the ICER=$70000/year, the %SUP for the GP are more than 50%. We developed an M&S process for probabilistic cost-effective analysis, this method would be useful for decision-making in choosing a cancer chemotherapy regimen in terms of pharmacoeconomic.

Analysis of Adverse Drug Reaction Risk in Elderly Patients Using the Japanese Adverse Drug Event Report (JADER) Database.

In general, the risk of adverse drug reactions (ADRs) is higher in elderly patients than in younger patients. In this study, we performed a comprehensive assessment of the risks of possible drug-ADR combinations in elderly patients using the Japanese Adverse Drug Event Report (JADER) database of the Pharmaceutical and Medical Devices Agency (PMDA, Japan) using the reporting odds ratio (ROR) as an index. Data recorded from April 2004 to September 2015 in the JADER database were downloaded from the PMDA website. The patients were classified into younger (≤69 years old) and elderly (≥70 years old) groups. The ROR and 95% confidence interval (CI) were calculated for all combinations of drugs and ADRs for which there were three or more reports in the database, focusing particularly on the combinations where more than 100 cases had been reported in elderly and younger patients. The most frequently reported drug-ADR combination was methotrexate with interstitial lung disease (646 cases). The combination with the highest ROR was methotrexate with lymphoproliferative disorder (ROR: 484.6, 95% CI: 334.1-702.9). In total, 27 drug-ADR combinations were found to have high risk in elderly patients. In conclusion, the findings of this comprehensive assessment of drug-ADR combinations using the JADER database will be valuable for updating the ADR risks for elderly patients in clinical setting.

Daphnetin inhibits invasion and migration of LM8 murine osteosarcoma cells by decreasing RhoA and Cdc42 expression.

Daphnetin, 7,8-dihydroxycoumarin, present in main constituents of Daphne odora var. marginatai, has multiple pharmacological activities including anti-proliferative effects in cancer cells. In this study, using a Transwell system, we showed that daphnetin inhibited invasion and migration of highly metastatic murine osteosarcoma LM8 cells in a dose-dependent manner. Following treatment by daphnetin, cells that penetrated the Transwell membrane were rounder than non-treated cells. Immunofluorescence analysis revealed that daphnetin decreased the numbers of intracellular stress fibers and filopodia. Moreover, daphnetin treatment dramatically decreased the expression levels of RhoA and Cdc42. In summary, the dihydroxycoumarin derivative daphnetin inhibits the invasion and migration of LM8 cells, and therefore represents a promising agent for use against metastatic cancer.

Population Pharmacodynamic Model for Bayesian Prediction of Myelosuppression Profiles Based on Routine Clinical Data after Gemcitabine and Carboplatin Treatment.

BACKGROUND: Hematological toxicity is a serious adverse event and is often a dose-limiting factor in anticancer drugs. The objective of the present study was to develop a modeling and simulation (M&S) procedure for predictions of time course profiles of blood cell counts that reflect myelosuppression profiles. METHODS: A method for Bayesian prediction of myelosuppression profiles during chemotherapy using a population pharmacodynamic model is proposed, and predictabilities of nadir values and times to nadir (Tnadir) after gemcitabine and carboplatin treatment were evaluated. The model is based on an equation for Erlang distribution, which we previously proposed, and it explains time course profiles of platelet (PLT), red blood cell (RBC) and white blood cell (WBC). RESULTS AND CONCLUSION: PLT, RBC and WBC counts were retrospectively collected from 61 time courses (a total of 472 points) of 27 cancer patients. Predictive performance by a one-point Bayesian prediction was evaluated using data from day 8 in consideration of applicability to outpatients. Some good predictability was obtained for nadir values with some exceptions for PLT and RBC, whereas the predictability of Tnadir was insufficient. Although the predictability was not acceptable enough, this M&S approach could be used for supportive care during cancer chemotherapy.

Population Pharmacokinetics and Therapeutic Efficacy of Febuxostat in Patients with Severe Renal Impairment.

The aim of the present study was to determine the influence of severe renal dysfunction (estimated glomerular filtration rate <30 ml/min/1.73 m(2), including hemodialysis) on the pharmacokinetics and therapeutic effects of febuxostat using a population pharmacokinetic analysis. This study recruited patients with hyperuricemia who were initially treated with allopurinol, but were switched to febuxostat, and it consists of 2 sub-studies: a pharmacokinetic study (26 patients) and retrospective efficacy evaluation study (51 patients). The demographic and clinical data of patients were collected from electronic medical records. Plasma febuxostat concentrations were obtained at each hospital visit. Population pharmacokinetic modeling was performed with NONMEM version 7.2. A total of 128 plasma febuxostat concentrations from 26 patients were used in the population pharmacokinetic analysis. The data were best described by a 1-compartment model with first order absorption. Covariate analysis revealed that renal function did not influence the pharmacokinetics of febuxostat, whereas actual body weight significantly influenced apparent clearance and apparent volume of distribution. The retrospective efficacy analysis showed the favorable therapeutic response of febuxostat switched from allopurinol in patients with moderate to severe renal impairment. No serious adverse event associated with febuxostat was observed irrespective of renal function. The population pharmacokinetic analysis and therapeutic analysis of febuxostat revealed that severe renal dysfunction had no influence on the pharmacokinetic parameters of febuxostat. These results suggest that febuxostat is tolerated well by patients with severe renal impairment.

Reduction in gastrointestinal toxicity by gastric secretion inhibitors during S-1 monotherapy for patients with gastric cancer.

The purpose of this study was to retrospectively examine the effect of concomitant administration of gastric secretion inhibitors or gastrectomy on the frequency of gastrointestinal toxicity caused by 5-fluorouracil (5-FU) in gastric cancer patients receiving chemotherapy with S-1. In 62 gastric cancer patients treated with S-1 alone, data relating to the occurrence of gastrointestinal toxicity (diarrhea, vomiting, and nausea) and possible contributing factors were retrospectively collected, and logistic regression analysis was performed. Time-to-event data relating to the occurrence of gastrointestinal toxicity were also collected, and the effect of gastric secretion inhibitors on the time-to-event profiles was examined using a log-rank test. Logistic regression analysis suggested that the frequency of gastrointestinal toxicity was significantly reduced by the administration of gastric secretion inhibitors (p=0.01; odds ratio, 0.197; 95% confidence interval (CI), 0.056-0.694) and that gastrointestinal toxicity correlated with the estimated glomerular filtration rate (p=0.04; odds ratio, 0.956; 95% CI, 0.916-0.997). The median time-to-event of gastrointestinal toxicity was 85 d for patients that received gastric secretion inhibitors, which was significantly different from the 42 d for patients that did not receive the inhibitors (p=0.02, log-rank test). No clear effect of gastrectomy was found in the present study. The prophylactic use of gastric secretion inhibitors in gastric cancer patients treated with S-1 may decrease and delay the occurrence of gastrointestinal toxicity.

Analysis of Barriers to Medical Opioid Pain Medication Using the Japanese Version of the Barriers Questionnaire II (JBQ-II): Pharmacists and Nurses Perspective in Japan.

BACKGROUND: Some Japanese patients with cancer pain have negative beliefs regarding opioid therapy. The Japanese version of the Barriers Questionnaire II (JBQ-II) determines barriers to cancer pain management. Few studies reported JBQ-II scores in Japan, and none focused on pharmacists. Accordingly, we aimed to explore the relationship between health care professionals' knowledge of and willingness to use opioids, and their JBQ-II scores. Additionally, the variances in JBQ-II scores among nurses, hospital pharmacists, and pharmacy pharmacists were assessed. METHODS: This cross-sectional survey employed the JBQ-II for nurses and pharmacists in hospitals and pharmacies across Japan. Participants were requested to respond to the JBQ-II concerning their affiliation, knowledge of opioid analgesics, and willingness to utilize these drugs for medical practice. RESULTS: A total of 55 hospital pharmacists, 25 pharmacy pharmacists, and 24 nurses responded to the survey. The group-knowledgeable about medical use of narcotics had significantly lower total JBQ-II scores (25.43, standard deviation [SD]: 15.11) than those had by the group with insufficient knowledge (34.50, SD: 18.41). There was no statistically significant difference in total JBQ-II scores among those willing to use opioids medically. The total JBQ-II scores of hospital pharmacists, pharmacy pharmacists, and nurses were 31.00 (SD: 15.11), 33.96 (SD: 19.25), and 27.21 (SD: 15.56), respectively. However, the differences were not statistically significant. CONCLUSIONS: Health care professionals in Japan with knowledge about opioids for medical purposes had a significantly lower total JBQ-II score than those with insufficient knowledge. Thus, health care professionals' knowledge plays a crucial role in reducing barriers to using narcotic drugs.

Cost-Effectiveness Analysis of Atezolizumab versus Platinum-Based Chemotherapy as First-Line Treatment for Patients with Unresectable Advanced Non-small Cell Lung Cancer with PD-L1 Expression Status in Japan.

BACKGROUND AND OBJECTIVES: Atezolizumab has demonstrated safety and efficacy in patients with metastatic non-small cell lung cancer (NSCLC) in the IMpower110 trial. The aim of this study was to evaluate the cost-effectiveness of atezolizumab as the first-line treatment for patients with unresectable advanced NSCLC, including programmed cell death ligand-1 (PD-L1)-positive probability testing, from the perspective of healthcare costs in Japan. METHODS: A cost-effectiveness analysis model for atezolizumab, including PD-L1-positive probability testing, was used to construct a partitioned survival model with three health states. To assess the robustness, a probabilistic sensitivity analysis (PSA) was conducted. The acceptable probability was defined as the probability of willingness-to-pay (WTP) over the incremental cost-effectiveness ratio (ICER). Multiple repetitions at WTP thresholds were calculated by continuously reducing the atezolizumab price. RESULTS: The ICER per quality-adjusted life year (QALY) for atezolizumab therapy only for patients with high PD-L1 expression compared to platinum-based chemotherapy for all patients was 31,975,792 yen per QALY. This is higher than the WTP threshold of 15,000,000 yen. If the cost of atezolizumab were reduced to 54% of the original cost (563,917 yen), the strategy of using atezolizumab for patients with high PD-L1 could become more cost-effective. CONCLUSIONS: The results indicated that atezolizumab was not cost-effective compared to platinum-based chemotherapy as a first-line treatment for patients with unresectable advanced NSCLC. However, we suggest that the price of atezolizumab should be reduced to 54% of the original cost to meet the WTP threshold of 15,000,000 yen per QALY.

The Occurrence of Encephalitis Due to Immune Checkpoint Inhibitors: A Pharmacovigilance Study.

PURPOSE: Immune checkpoint inhibitors (ICIs) are associated with peculiar adverse events related to the mechanism of action. Less than 1% of patients treated with ICIs develop autoimmune encephalitis. The aim of this study was to compare the frequency of encephalitis development due to ICIs with encephalitis due to other drugs using the Japanese Adverse Drug Event Report (JADER) database and Bayesian confidence propagation neural networks for signal detection. METHODS: Data from the JADER database from April 2004 to December 2020 were downloaded via the Pharmaceuticals and Medical Devices Agency (PMDA) website. The Information Component (IC) values were calculated as an index of signal detection based on the Bayesian method. RESULTS: The lower bound of the 95% credible interval (CI) of the IC values for atezolizumab and pembrolizumab were greater than 0 in most of the periods. Thus, encephalitis occurred more frequently for atezolizumab and pembrolizumab than for other drugs. For nivolumab and ipilimumab, a significant signal was detected only for recent data. In contrast, the lower bounds of the 95% CIs for avelumab and durvalumab were smaller than 0 in most of the periods because encephalitis was seldom reported for avelumab and durvalumab. CONCLUSIONS: We showed that encephalitis occurs more frequently for atezolizumab, pembrolizumab, nivolumab, and ipilimumab compared with the frequency for other drugs. The time of onset varied widely, and patients should be monitored for more than 1 year after the last administration of ICIs.

Cost-effectiveness Analysis of Atezolizumab Plus Nab-Paclitaxel for Advanced PD-L1 Positive Triple-Negative Breast Cancer in Japan.

BACKGROUND AND OBJECTIVES: Atezolizumab is an anti-programmed death ligand 1 (PD-L1) antibody that shows good safety and efficacy for patients with PD-L1-positive triple-negative breast cancer (TNBC). The cost of atezolizumab therapy is expensive, and its economic burden is an important problem. In this study, we evaluated the cost effectiveness of atezolizumab plus nab-paclitaxel therapy (AnP) compared with nab-paclitaxel monotherapy (nP) for PD-L1-positive TNBC under Japanese medical conditions and environments using a Markov model. METHODS: The medical information was collected from data published by the IMpassion130 trial. A Markov model was established to simulate the number of patients in each disease state after AnP or nP therapy during each time period. As indices for cost effectiveness, total cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER) were calculated. Probabilistic sensitivity analysis (PSA) was used to assess the uncertainty of the model using 10,000 Monte Carlo simulations with difference parameters. RESULTS: The QALYs for AnP treatment were longer than for nP treatment (1.12 vs 0.82 QALYs), but the total cost of AnP treatment was more expensive than that of nP treatment (¥11,070,143 vs ¥2,056,164). The ICER values comparing AnP treatment with nP treatment were ¥30,208,143/QALY. The ICER/QALY was more expensive than the willingness-to-pay (WTP) of ¥15,000,000 per QALY. To achieve a 50% cost-effective probability with a WTP threshold, the price of the atezolizumab should be reduced by 55.1%. CONCLUSIONS: AnP was not cost effective compared to nP for PD-L1-positive inoperable TNBC under the Japanese condition.

Prediction of Apparent Oral Clearance of Small-Molecule Inhibitors in Pediatric Patients.

The purpose of this study was to build regression models for the prediction of apparent oral clearance (CL/F) for small-molecule inhibitors in the pediatric population using data obtained from adults. Two approaches were taken; a simple allometric regression model which considers no interdrug or interindividual variability and an allometric regression model with mixed-effects modeling where some variability parameters are included in the model. Average CL/F values were obtained for 15 drugs at various dosages from 31 literatures (a total of 139 data sets) conducted in adults and for 15 drugs from 26 literatures (62 data sets) conducted in children. Data were randomly separated into the "modeling" or "validation" data set, and the 2 allometric regression models were applied to the modeling data set. The predictive ability of the models was examined by comparing the observed and model-predicted CL/F in children using the validation data set. The percentage root mean square error was 17.2% and 26.3% in the simple allometric regression model and the allometric regression model with mixed-effects modeling, respectively. The predictive ability of the 2 models seems acceptable, suggesting that they could be useful for predicting the CL/F of new small-molecule inhibitors and for determining adequate doses in clinical pharmacotherapy for children.

Bone-Marrow-Derived Microglia-Like Cells Ameliorate Brain Amyloid Pathology and Cognitive Impairment in a Mouse Model of Alzheimer's Disease.

Microglia, the primary immune cells in the brain, sense pathogens and tissue damage, stimulate cytokine production, and phagocytosis to maintain homeostasis. Accumulation of amyloid-ß peptides (Aß) in the brain triggers the onset of Alzheimer's disease (AD). Accordingly, promotion of Aß clearance represents a promising strategy for AD therapy. We previously demonstrated that primary-cultured rat microglia phagocytose Aß, and that transplantation of these cells ameliorates the Aß burden in brains of Aß-injected rats. In this study, we demonstrate that stimulation with colony-stimulating factor-1 efficiently differentiates mouse bone marrow cells into bone marrow-derived microglia-like (BMDML) cells that express markers for microglia, including the recently identified transmembrane protein 119. BMDML cells effectively phagocytose Aß in vitro, with effects comparable to primary-cultured mouse microglia and greater than peritoneal macrophages. RT-qPCR analysis for cytokine mRNA levels revealed that BMDML cells polarize to a relatively anti-inflammatory state under non-stimulated and inflammatory conditions but exert a pro-inflammatory reaction after lipopolysaccharide treatment. Moreover, BMDML cells hippocampally injected into a mouse model of AD are morphologically similar to the ramified and amoeboid types of residential microglia. Comparisons with simulations assuming a uniform distribution of cells suggest that BMDML cells migrate directionally toward Aß plaques. We also detected Aß phagocytosis by BMDML cells, concomitant with a reduction in the number and area of Aß plaques. Finally, we observed amelioration of cognitive impairment in a mouse model of AD after hippocampal injection of BMDML cells. Our results suggest that BMDML cells have potential as a cell-based disease-modifying therapy against AD.

Indication of Adequate Transdermal Fentanyl Dose in Opioid Switching From Oral Oxycodone in Patients With Cancer.

OBJECTIVE: The present study aimed to examine affecting factors for conversion ratio and to predict adequate fentanyl dose for patients with cancer pain in opioid switching from oral oxycodone. METHODS: Patient characteristics, biochemical parameters, daily oxycodone dose, and reasons for opioid switching were retrospectively collected. The effect of variables on the conversion ratio was analyzed by multiple regression analysis. RESULTS: Regression analysis for the data from 122 patients suggested that the typical conversion ratio was 95:1; however, this ratio was significantly reduced in patients taking a daily oral morphine-equivalent dose of <45 mg/d and in patients with poor pain control to 52:1 and 64:1, respectively. CONCLUSION: We should carefully and rapidly control pain in opioid switching based on the adequate dose indicated in this study.

Opioid analgesics increase incidence of somnolence and dizziness as adverse effects of pregabalin: a retrospective study.

BACKGROUND: Pregabalin, a gabapentinoid, is an adjuvant analgesic for treatment of neuropathic pain, but it has serious adverse effects such as somnolence and dizziness, particularly in elderly patients. Although decreased renal function is considered to the contributing factor for high frequency of these adverse effects in elder patients, only a few systematic clinical investigations, especially for hospitalized patients, have been performed on factors that might affect the incidence of its adverse effects. In this study, we performed a retrospective study on the effect of concomitant drugs on induction of somnolence and dizziness as adverse effects of pregabalin in hospitalized patients. METHODS: The subjects were all pregabalin-administered patients in Shiga University of Medical Science Hospital from September 2010 to September 2012, and the subject number was 195. Multivariate logistic regression analysis was performed to determine predictors of the adverse effects, creatinine clearance, duration of pregabalin therapy, initial and maintenance doses of pregabalin, and concomitant drugs, including hypoglycemic drugs, anti-hypertensive ones, non-steroidal anti-inflammatory ones, opioids and central nervous system depressants, being used as independent variables. RESULTS: The median initial doses of pregabalin in each renal function group were the same with the case of the defined dose. Although renal function is a well-known factor for prediction of development of adverse effects of pregabalin, we did not detect significant contribution of it. Alternatively, it was demonstrated that concomitant administration of opioids was the significant factor of the incidence of somnolence and dizziness. The first onset date of the adverse effects was frequently detected in the early days of the pregabalin therapy. CONCLUSIONS: The fine tuning of pregabalin dosage schedule based on the renal function appeared to be critical for prevention of development of its adverse effects. Adverse effects tended to develop in the initial phase of pregabalin therapy. Concomitant administration of opioids with pregabalin has the potential to increase the incidence of adverse effects, and thus much more careful attention has to be paid especially in those situations.