Effect of oral contraceptive on plasma concentration of codeine

MR Sattari1,3, SO Mashayekhi2,3, M Mortazavi3. 1Tabriz University of Medical Sciences, Neurosciences Research Centre, 5166414766, Iran, 2Tabriz University of Medical Sciences, NPMC, 5166414766, Iran, 3Tabriz University of Medical Sciences, Faculty of Pharmacy, 5166414766, Iran

Addiction to opiates is one of the most critical social problems in Iran rising day by day. It is reported that a number of opiate addicts may obtain false negative results from the laboratories by manipulating their urine samples with citric acid or lactose, or taking few oral contraceptive or probenecid tablets few hours before addiction test to break out the law. Bibliography did not reveal any previous study on the interaction between contraceptives and opiates in human. Only two studies had been performed on the rat which rejected such an interaction. Consequently, we decided to study the probable masking effect of oral contraceptives on plasma concentration of codeine. Six healthy male volunteers (aged 20-28 years) were recruited for the study to participate in a three-phase trial with one week intervals. At the first phase they received only two tablets of acetaminophen-codeine (300mg acetaminophen and 20mg codeine) in fast condition. Blood samples were taken from their brachial vein (5ml each) in 1, 2, and 4 hours after the codeine tablets intake. At the second and third phases they were pre-treated with two oral contraceptive tablets (HD) two hours and 24 hours respectively before codeine intake. Blood samples were taken at the same times after codeine intake. The blood samples were quickly centrifuged and the supernatants were frozen in -20ºC until analysis. Plasma concentration of codeine was determined using an HPLC developed method. Data were analysed using one-way ANOVA test. We showed that, the mean plasma concentration of codeine in the first sample of phase 1 (1h after codeine intake) declined significantly (P<0.05) from 150.9ng/ml±20.6 (SEM) in the first phase to 54.9ng/ml±21.7 in the second phase. However, the decline to 11.9ng/ml±71.5 in the third phase was not significant (P>0.05). Therefore, we hypothesised that if the oral contraceptive can reduce the plasma concentration of free form of codeine, it might be due to its enzyme induction effects pre-treating 24 hours before codeine intake. Whereas, the maximum reduction in plasma concentration of free codeine was with the second phase. This shows that the mechanism of the interaction is different from enzyme induction and needs further investigations. Advance studies also are needed to investigate the chronic effects of oral contraceptives on the plasma concentrations of free and conjugated codeine and morphine.