Pharmacokinetic aspects of spinal morphine analgesia.

Epidural (E.D.) and intrathecal (I.T.) morphine (M) analgesia were studied in patients with pain after thoracotomy. The role of the pharmacokinetic properties of M. for the associated analgesia was also evaluated. M. concentrations in CSF and plasma were assayed using gas chromatography with EC detection. Analgesia was evaluated as the time postoperative until the patients again required analgetics and were given meperidine intramuscularly (I.M.) for thoracic pain. A lumbar site of E.D. and I.T. injection of M. resulted in a variable but in general longlasting postoperative analgesia although delayed after I.T. administration. The mean duration of analgesia after E.D. administration was dose-related (8.6 +/- 2.0 h, 13.0 +/- 3.5 h, and 15.6 +/- 2.6 h; means +/- SEM for the 2, 4 and 6 mg groups, respectively), which was comparable to that achieved after I.T. administration of 0.25 to 0.50 mg M. M. concentrations in plasma after E.D. administration were comparable in variability and magnitude to those found after I.M. administration. The concentrations of M. in plasma were not related to the long duration of analgesia and may only contribute to analgesia shortly after the E.D. administration. The reported time course of analgesia after E.D. injection with a delayed onset corresponded with the appearance of M. in the CSF. Fifteen min after E.D. administration, M. was found in higher concentrations in CSF than in plasma, but peak levels were not seen until 2 h after the injection. Both the high content of M. in CSF as expressed by AUC, as well as peak concentrations in CSF, were related to the longlasting analgesia after E.D. administration. A protracted clearance of M. from the CSF as a cause of longlasting analgesia was not found, M. was eliminated with a similar half-life from CSF and plasma. The high CSF concentrations of M. seen after E.D. administration were the result of a direct uptake across the dura. In contrast, the appearance of M. in CSF after I.M. administration of 10 mg was slower. Maximal concentration of M. in the CSF was reached after 3 h and the peak levels were on average about 100 times less than those found after E.D. injection of 6 mg morphine. CSF and plasma reached pseudoeliquilibrium at a ratio around 0.9 after I.M. administration. This is to be compared with a CSF/plasma concentration ratio around 100 after E.D. administration. A comparison of M. concentrations in the CSF after thoracic and lumbar E.D. injection showed that spinal CSF rapidly yielded comparable concentrations at the lumbar level.(ABSTRACT TRUNCATED AT 400 WORDS)