Analyses of oxycodone-induced adverse effects based on the Japanese Adverse Drug Event Report Database

　Recently, the amount of oxycodone used for palliative care in the medical setting has markedly increased in Japan. As the beneficial effects and pharmacokinetic profile of oxycodone are dependent on patient characteristics such as gender and age, it is important to understand the relationships between adverse effects and patient characteristics when administering oxycodone therapy to patients suffering from cancer-related pain. Therefore, we used the Japanese Adverse Drug Event Report Database administered by the Pharmaceuticals and Medical Devices Agency, Japan, to analyze the frequencies of adverse events associated with oxycodone therapy. Furthermore, the statistical significance of the associations between adverse effects and background parameters, such as age and gender, was determined using Fisher’s exact test and odds ratio. As a result, it was found that delirium, nausea, and vomiting are the most common adverse events seen after oxycodone administration. These symptoms are also caused by morphine and fentanyl. Nausea and diarrhea in female and interstitial lung disease in male reported more frequently. On the other hand, somnolence and delirium in elderly patients reported more often than in young patients. These findings might be helpful for managing the adverse effects of pain therapy on an individual basis.

Analyses of opioid-induced adverse effects based on Japanese Adverse Drug Event Report database：Distinctive tendencies of the adverse events induced by morphine, fentanyl and oxycodone

Potent opioid analgesics are applicable for the treatment of severe pain, especially in cancer patients. Management of opioid-induced adverse effects is important to continue treatment with opioids because these drugs are associated with a variety of kinds of adverse effect, such as deliria and respiratory depression. However, information regarding these adverse effects in Japanese patients is limited. Therefore, we searched and analyzed a database for drug-induced adverse effects in Japan, the Japanese Adverse Drug Event Report database（JADER）, to acquire information related to the adverse effects induced by potent opioids such as morphine, fentanyl, and oxycodone. Cases with adverse effects associated with medications for palliative care were extracted from JADER, and types and frequencies of the events for each analgesic were analyzed. As a result, a lot of common adverse effects were found among the three opioids. However, the orders of their frequency differed among the analgesics. In principal component analysis, the property of morphine was intermediate between those of fentanyl and oxycodone. These findings may contribute to safe and effective pain control for patients receiving medical treatment with potent opioid analgesics.

Clinical Pharmacokinetics of Methadone

Methadone oral tablets initially became available on the Japanese market in MAR－2013. Methadone, which has different pharmacological properties from other opioids including morphine, can cause serious adverse drug reactions such as respiratory depression and QT prolongation. One of the causes of these reactions is its extremely complex pharmacokinetics. Methadone is mostly metabolized in the liver, with a variety of metabolic enzymes, including cytochrome P450 (CYP) 3A4, CYP2B6, and CYP2D6, being involved. The characteristics of methadone include self-induction of metabolism, delayed excretion due to alkaline urine, and an extremely long half-life requiring a long time to achieve a steady state. Without a full understanding of its complex pharmacokinetics, the blood concentration of methadone is not maintained at a constant level, and serious adverse events could happen due to an unexpected increase in its blood concentration. Herein, for safe clinical use by physicians and pharmacists, we summarize the pharmacokinetics of methadone.

A Study of the Evaluation of Drugs for the Introduction of Hospital Use / 薬剤疫学

Objective : The Pharmacy and Therapeutic Committee generally selects formulary drugs by evaluating the comparative data from non-clinical and clinical studies of pharmacologically similar type drugs. Usually there are few data from directly comparative studies among all similar type drugs, and there are only two types of studies, standard drug or placebo-control study. In this situation, it is very difficult to select the superior drug. <BR>Therefore, we conducted a retrospective cohort study to compare the efficiency among three 5-HT<SUB>3</SUB> antagonists and to investigate the possibility of data from this study, as a reference for decision making. <BR>Design : Retrospective cohort study. <BR>Methods : A retrospective cohort was assembled comprising in-patients of to Surgery, Obstetrics and Gynecology, Ophthalmology, Orthopedics, Dermatology, Psychiatry, or Thoracic Surgery Departments, who received chemotherapy and a 5-HT<SUB>3</SUB> receptor antagonist from January to June in 1996. We compared the side effects of nausea and vomiting among patients receiving various 5-HT<SUB>3</SUB> receptor antagonists. Physicians could freely prescribe three 5-HT<SUB>3</SUB> antagonists that were adopted in our hospital during the period. Pharmacists collected information regarding the efficacy of 5-HT<SUB>3</SUB> receptor antagonists on the first prescribed day by reviewing medical charts, nurses' reports and interviews with the nurses. <BR>Statistical Analysis : ANOVA was used for testing the age differences among patients receiving 5-HT<SUB>3</SUB> receptor antagonists. Chi-square was used for testing difference of sex, administration route, number of chemotherapy treatment. Kruskal-Wallis rank test was used for testing the difference of efficacy. Probabilities less than 5% (P<0.05) were considered significant. <BR>Results : Out of 68 patients, 35% received cisplatin and 65% received non-cisplatin anti-tumor drugs. The average age was 53.1±17.4 (49% male, 51% female). A total of 82% received intravenous drip injection. <BR>Percentage of non-changed cases in ingestion ratio was 32% of ramosetron, 50% of ondansetron and 53% of azasetron. There was no significant difference in the ingestion ratio (p = 0.026). <BR>Percentage of non-changed cases with regard to vomiting (complete control) was 80% of ramosetron, 50% of ondansetron, 79% of azasetron. There was a significant difference in vomiting (completecontrol) (p = 0.044). Ondansetron was less effective as an antiemetic function. <BR>Discussion : When no data from a directly comparative study are available to determine the adoption of a new medicine from among numerous candidate drugs, an observational study such as this appears useful.