Urine and plasma pharmacokinetics of codeine in healthy volunteers: implications for drugs-of-abuse testing

Thirteen healthy volunteers participating in an open and randomized study received two single doses (25 and 50 mg) of codeine orally two weeks apart. Urine concentrations of opiates were studied for 96 h, and plasma concentrations of codeine and the metabolites codeine-6-glucuronide (C6G), morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were monitored for 24 h. Plasma was analyzed by high-performance liquid chromatography. Measurements of urine were made with the EMIT opiate-screening assay and with gas chromatography-mass spectrometry for total (conjugates liberated by acid hydrolysis) codeine, morphine, and norcodeine. In urine, the ratio between total recovered morphine and codeine as expressed in percent ranged from 2.3 to 23.3% with a mean value of 9.8%. This ratio increased with time, and, in all but three subjects, rose to greater than 1 after 22-36 h. In 58% of cases, this occurred within the detection time in the EMIT assay. The detection time in the EMIT screening assay was found to be 20-39 h after the 25-mg dose and 30-52 h after the 50-mg dose. Elimination rates calculated from urine data corrected for creatinine concentration showed that morphine was eliminated more slowly than codeine. In plasma, the highest concentrations and area-under-curve values were observed for C6G, followed by codeine and M3G. All compounds had peak plasma values 1-2 h after dosing. The elimination of M3G was slower than that of C6G. We concluded that the relative proportion of codeine and morphine varies both between individuals and as a function of time and that morphine may be present in concentrations above those of codeine even after moderate and single doses of codeine. This must be taken into consideration when interpreting the presence of opiates during drugs-of-abuse testing.