The influence of drug polarity on the absorption of opioid drugs into CSF and subsequent cephalad migration following lumbar epidural administration: application to morphine and pethidine

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Abstract
This study examines the influence of drug polarity on the rate and extent of drug absorption into cerebrospinal fluid (CSF) following lumbar epidural administration. Twelve patients with pain secondary to cancer were simultaneously administered both morphine (10 mg) and pethidine (50 mg) in 10 ml of normal saline via an epidural catheter inserted in the lumbar region (usually L2.3) and attached to a subcutaneously implanted portal reservoir. Frequent blood samples were collected to characterise the vascular uptake of both opioids. In addition, a single CSF sample was collected in each patient from the C7-T1 interspace at one of the following times: 10,30,60,120,180 and 240 min. There was a rapid vascular uptake of morphine from the epidural space with a mean (.+-.S.D.) peak concentration of 173 .+-. 80 ng/ml (range 52-345 ng/ml) and a time-to-peak concentration of 8 .+-. 6 min (range 2-17 min). In contrast, the vascular uptake of pethidine was more variable with a mean (.+-. S.D.) concentration of 274 .+-. 294 ng/ml (range 80-1113 ng/ml) and the time-to-peak concentration was 21 .+-. 26 min (range 2-75 min). There was a rapid absorption of pethidine across the dura mater into the CSF with peak CSF concentration between 1400 and 1650 ng/ml occurring between 10 and 60 min in samples collected cephalad (C7-T1 interspace) from the administration point in the lumbar region. However, the peak morphine concentration in CSF was delayed relative to the pethidine peak and occurred in 120 min. The min sample to approximately 0.6-0.8:1 in the CSF samples obtained between 120 and 240 min. A ratio of approximately 5 (ratio of the two opioids in the injection solution) would be expected if both pethidine and morphine were absorbed from the epidural space and underwent cephalad migration at the same rate. This study suggests that drug polarity is an important variable in controlling absorption from the epidural space into CSF.