Does intravenous methadone provide longer lasting analgesia than intravenous morphine?
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Analgesia↗
Biomedical subjects
John L Plummer
Publications and source records attributed to John L Plummer.
The transdermal administration of fentanyl in the treatment of postoperative pain: pharmacokinetics and pharmacodynamic effects.
A transdermal formulation of fentanyl (TTS-fentanyl, Alza Corp., Palo Alto, CA) was evaluated in 13 surgical patients after an abdominal operation. An intraoperative dose of fentanyl (100-200 micrograms i.v.) was administered at the same time as the TTS-fentanyl systems (50-125 micrograms/h) were applied to the antero-lateral chest wall. The TTS-fentanyl systems remained in situ for 24 h and were then removed and a second lot of systems were applied to the contra-lateral chest wall. There was a mean (S.D.) delay time of 12.7 (9.6) h before minimum effective blood fentanyl concentrations (MEC) were obtained from the systems and pseudo-steady state was reached between 36 and 48 h. There was a decay time of 16.1 (7.1) h after the systems were removed for the blood fentanyl concentration to decrease to less than the mean MEC for the control of postoperative pain. There was marked variability between patients in the actual hourly fentanyl dose rate determined from the residual amount of fentanyl remaining in the system and the duration of application. Significantly more supplementary pethidine was administered for inadequate postoperative analgesia between 0 and 12 h compared to the 12-24, 24-36 and 36-48 h periods; this was consistent with the observed delay time. Three patients required a reduction in the hourly fentanyl dose rate because of bradypnoea while 1 patient required an increase in dose because of inadequate pain relief. Nausea was the most frequently reported side effect (85% of patients) while bradypnoea, drowsiness, unpleasant dreams and headache were also reported. These effects were due to the combined effects of a sustained blood fentanyl concentration and the intermittent supplementary pethidine doses. Side effects due to the topical formulation were transient and included erythema (8 patients) and a minor rash (2 patients) in the area occluded by the systems. The TTS-fentanyl systems provided a significant contribution to postoperative pain control but, at the TTS dose rates used, supplementary doses of pethidine were required by all patients probably to control 'incident' pain.
Administration, Cutaneous↗
Pharmacokinetics of fentanyl in lumbar and cervical CSF following lumbar epidural and intravenous administration.
Fentanyl (1 microgram/kg body weight) was administered intravenously and via a lumbar epidural catheter (in random order) on 2 separate occasions to 6 patients with chronic pain associated with non-terminal disease states. Frequent blood samples were collected from an indwelling intravenous catheter and CSF samples were collected via spinal needles inserted in the cervical (C7-T1 interspace) and lumbar (L3.4 interspace) regions at 0, 5, 10, 20, 30 and 45 min after fentanyl administration. The concentration of fentanyl in blood and CSF samples were quantified by a sensitive and selective gas-liquid chromatography assay. Visual analogue pain scores (VAPS) were recorded every 5 min for the first hour. Coded syringes (one containing the appropriate fentanyl dose while the other contained an equivalent volume of saline) allowed the investigator administering the fentanyl and assessing VAPS to remain blinded as to which route of administration actually contained the fentanyl. There was minimal vascular uptake of fentanyl following epidural administration. Similarly, the permeation of fentanyl into cervical and lumbar CSF following intravenous administration was minimal and erratic such that only 4 of the 60 CSF samples had detectable fentanyl concentrations. In contrast, there was a rapid penetration of fentanyl across the dura mater following lumbar epidural administration. There was significantly fentanyl in lumbar CSF samples by 10 min in 5 patients, and by 20 min in all 6 patients. The mean maximum lumbar CSF concentration was 19.1 ng/ml, while the time associated with these maximum concentrations was 22.5 min. The mean maximum cervical CSF fentanyl concentrations were 10% of the lumbar CSF concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Fentanyl↗
Estimation of methadone clearance: application in the management of cancer pain.
The long half-life and wide inter-patient variability in clearance of methadone make this drug difficult to use optimally. If a patient's methadone clearance is known, however, dose regimens can be devised to maintain any desired blood concentration and hence, since the effect of methadone is related to its concentration in the blood, pain relief. We investigated methods for determining methadone clearance. In 25 patients, clearance was estimated by monitoring blood methadone concentrations following an intravenous infusion. Estimates of clearance adequate for clinical purposes could be obtained by assaying only 10-12 blood samples collected over 30 h following the infusion. The blood sampling schedules were such that it was not necessary to collect samples during the night, so the procedure could be done on an outpatient basis. An advantage of this procedure is that it also allows estimation of the blood methadone concentration required to relieve pain. We also conducted a retrospective study of data from 185 patients whose methadone clearance we had determined, to identify factors which may give rise to the large inter-patient variation in clearance. Clearance tended to be high in patients taking phenytoin, spironolactone, verapamil or oestrogens, and low in patients taking amitriptyline. Patients with malignant disease as opposed to chronic benign pain, and patients 65 years of age or older, tended to have low clearance. Clearance was positively associated with haematocrit. An equation was constructed allowing methadone clearance to be predicted from knowledge of these factors. The predicted clearance, however, showed only a moderately strong correlation with measured clearance (r = 0.75), indicating that factors not investigated also had a major influence on methadone clearance.
Blood Specimen Collection↗
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.
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 concentrations 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 at 120 min.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood-Brain Barrier↗