Plasma Morphine Concentrations Research Articles

884 Once a day (i.e. 24 hourly) Kapanol™, a new sustained release morphine formulation, in the treatment of cancer pain: Morphine metabolite profiles

The role of the morphine metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in the analgesia observed following morphine administration is controversial. There is greater acceptance of the analgesic role ascribed to M6G while M3G is alternatively considered to be inactive or result in functional antagonism. Kapanol™/Kadian™ (Glaxo/Faulding) is a new sustained release morphine formulation consisting of polymer coated pellets in a capsule. Twenty-four patients completed a randomized, double-blind, two period, crossover study comparing 24 hourly Kapanol to 12 hourly MS Contino. The morphine metabolite profile was determined in a randomly selected subset of those patients (n=8). The Cmax, Cmin, AUC, time that the plasma morphine concentration was ≥ 0.75 Cmax (for that metabolite) and fluctuations in plasma morphine concentrations were not significantly different (<i>P</i>>0.05, repeated measures ANOVA) between the two formulations for either metabolite. However, the Tmax for both M6G (<i>P</i><0.001)and M3G (<i>P</i><0.05) was significantly longer following Kapanol administration compared to MS Contino. We conclude that the plasma metabolite profiles are very similar to the respective morphine profiles. Therefore, the release characteristics of morphine from the formulation has a major influence on the morphine metabolite profiles.

Cerebral uptake of morphine in the pig calculated from arterio-venous plasma concentration gradients: An alternative to tissue microdialysis

The aim of this study was to characterize the reversible cerebral uptake of morphine in the pig by measuring the changing arterio-venous plasma concentration gradient over the brain. Seven pigs were anaesthetized by continuous infusions of ketamine and pancuronium and ventilated with oxygen in nitrous oxide. During and after 5-min intravenous infusions of morphine hydrochloride, blood samples were drawn from a central artery and from the internal jugular vein. Concomitantly, cerebral blood flow (CBF) was repeatedly measured as clearance of 133Xe from the brain after intracarotid injection. Plasma concentrations of morphine and, in samples from two animals, morphine glucuronides were assayed by high-performance liquid chromatography. Drug flux (J net) from arterial blood to brain was calculated from the arterio-venous plasma concentration gradients, the blood: plasma concentration ratio and CBF. Uptake of morphine from arterial blood to brain was very rapid, with a maximal j net typically at 3 min after the beginning of the infusion. The initial cerebral extraction of morphine was close to 50%. When the arterial and jugular venous concentration curves crossed, 1–5 min after the end of the infusion, the initially rapid uptake of morphine changed into a slow and steady release. The cerebral extraction of morphine glucuronides was comparable to that of morphine, however, J net was lower due to lower plasma concentrations at time of maximal extraction. The findings demonstrate how the cerebral uptake and release of morphine and its metabolites can be studied with a method that is entirely non-invasive to the brain and permits very flexible sampling. Uptake and release of drug is observed directly and need not be inferred from cerebral concentration curves.

897 Once a day (i.e. 24 hourly) kapanol TM, a new sustained release morphine formulation, in the treatment of cancer pain: Pharmacokinetic aspects

Sustained release morphine formulations are now generally accepted as the formulations of choice in the treatment of severe cancer pain. Kapanol™/Kadian™ (Glaxo/Faulding), a new sustained release formulation consisting of polymer coated pellets in a capsule, has recently been shown to have a superior morphine release profile compared to the standard tablet, MS Contin. If fact, the release characteristics of morphine from Kapanol suggested the possibility that one oral dose of Kapanol per 24 hours could effectively treat severe cancer pain. Twenty four patients completed a randomised, double-blind, two period, crossover study comparing 24-hourly Kapanol to 12-hourly MS Contin. The morphine dose per 24 hours was identical for the two formulations and morphine pharmacokinetics were determined over 24 hours at steady state for each formulation (i.e. after 7 days). The Cmax, Cmin, AUC and fluctuations in plasma morphine concentrations were not significantly different between the two formulations ( P > 0.05, repeated measures ANOVA). Kapanol had significantly longer Tmax values (P

Morphine and morphine metabolite concentrations in cerebrospinal fluid and plasma in cancer pain patients after slow-release oral morphine administration

In 34 cancer patients treated with chronic slow-release oral morphine, plasma and cerebrospinal fluid (CSF) minimum steady-state concentrations of morphine (M), morpine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were determined by high-performance liquid chromatography (HPLC). Both plasma and CSF morphine, M3G and M6G, concentrations were linearly related to dose of morphine. At steady state, the mean ± SEM CSF/ plasma morphine concentration ratio was 0.8 ± 0.1. In plasma and CSF, the mean steady-state concentrations of M3G and M6G substantially exceeded those of morphine where the mean CSF M/M3G/M6G ratio was 1:47:5 (weight basis), 1:34:4 (molar basis) and the mean plasma ratio was M/M3G/M6G 1:150:23 (weight basis), 1:109:17 (molar basis). The mean M3G and M6G concentrations in CSF at steady state were 15–18% of those found in plasma. Pain relief, evaluated by a visual analogue scale (VAS), did not correlate with the CSF M3G concentrations or with the M3G/M ratio. Since CSF M6G concentrations were high, M6G could, however, contribute to pain relief. We conclude that after oral administration of slow-release morphine, there is a significant passage of the morphine glucuronide metabolites to the CSF and that the M3G and M6G metabolites in CSF are in the concentration range where they may have an influence on analgesia.

Plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide after intravenous and oral administration to healthy volunteers: relationship to nonanalgesic actions.

Healthy volunteers were given morphine as an i.v. infusion (10 mg), immediate release (IR) tablets (3 x 10 mg), and as a new controlled release (CR) tablet (30 mg) on separate occasions. Venous blood samples were analyzed for morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) using high-performance liquid chromatography (HPLC). Pupil size, salivation, and central nervous system (CNS) effects were evaluated serially. Pharmacokinetic parameters, calculated using a two-compartment model, were in accordance with previous results for i.v. administration of morphine. The absolute bioavailability of morphine in both IR and in CR tablets was, 32%, and the relative bioavailability of the CR tablet versus the IR tablets was 103% (91-115%, 95% confidence interval). Pupil size and unstimulated saliva production were significantly reduced and CNS effects most pronounced following i.v. infusion of morphine, but were only moderately affected after oral administration with IR or CR tablets. Miosis and reduction of salivation were observed at moderate concentrations of morphine and M6G. A pharmacokinetic/pharmacodynamic model based on previous studies of receptor binding and potency of morphine and its metabolites was used to assess the concentration-effect relationships. According to this model, M6G was four and eight times more potent than morphine in producing miosis and reduction of saliva production, respectively. The same model indicated that intrinsic activities of M6G and morphine were similar for both effect parameters, whereas M3G was either inactive or even opposed the effects of morphine and M6G.

Chronopharmacokinetic variability in plasma morphine concentrations following oral doses of morphine solution

Twenty-six patients with severe pain associated with cancer were entered into a study where they were required to take morphine mixture for 7 days. Prior to this, their morphine dose had been optimised to provide the most favourable balance between pain relief and side effects. After 6 days of taking their optimised morphine dose at 4-hourly intervals, the patients were admitted to the Pain Management Unit such that the doses from 18:00 h on day 6 were taken under direct nursing supervision. Frequent blood samples were collected after the 10:00 h (dose 1), 14:00 h (dose 2) and 18:00 h (dose 3) on day 7. There was a significant difference between the 3 doses with respect to C max values for morphine with dose 3 > dose 1 > dose 2. Further, there was considerable variability in the percentage change of either dose 1 or dose 3 C max. values relative to dose 2. The Cn max values of the active metabolite morphine-6-glucuronide (M6G), measured in 6 of the patients, for the 3 dosing intervals followed a similar trend to the parent drug; but only doses 1 and 2 differed significantly. Similar but less pronounced changes were observed in the area-under-curve parameter calculated for both morphine and M6G during the 3 dosing intervals. There were no significant differences in the C min or T max parameters for either morphine or M6G between the 3 dosing intervals. These results suggest intra-individual variation in the absorption of morphine or changes in the volume of distribution during the day. The clinical significance of these data concerns the possible mismatch between the chronopharmacokinetic variability in plasma morphine concentrations demonstrated in this communication and literature reports of circadian variability in patients' reports of pain.

Acute physical dependence: Time course and relation to human plasma morphine concentrations*

To characterize the postmorphine time course of precipitated withdrawal responses in comparison with the time course of opioid agonist effects and of plasma morphine concentrations. The study provides a more detailed and comprehensive assessment of the postagonist time course of acute dependence effects in humans than previously available. Opioid agonist effects, morphine plasma levels, and withdrawal effects precipitated by naloxone (10 mg/70 kg, administered intramuscularly) were examined at 1, 3, 6, 12, 18, 24, 30, 36, and 42 hours after a single dose of morphine (18 mg/70 kg, administered intramuscularly) in 10 nondependent opioid-experienced subjects. The intensity of subjectively reported precipitated withdrawal effects was greatest when testing was conducted at 6 hours after morphine administration, whereas peak intensity of agonist effects (pupil constriction and subjective ratings) and highest plasma morphine concentrations (57.3 ng/ml) were observed at the shortest test interval (1 hour) after morphine. Offset time course of naloxone-precipitated effects differed across specific measures, with hot and cold feelings elevated for the longest time after morphine (36 hrs), but significant effects were generally apparent for up to 24 hours after morphine pretreatment. Agonist effects lasted through only 12 hours; trace amounts of morphine were detected in plasma for up to 30 hours after administration. Results show that acute physical dependence engendered by a single dose of morphine peaks later and persists over a longer duration after morphine administration than do other agonist effects. This suggests that neuronal adaptations underlying physical dependence develop and decay gradually over time during a single episode of receptor occupancy. The presence of detectable morphine in plasma is consistent with a competitive displacement mechanism of precipitated effects, although noncompetitive actions of morphine or its metabolites are not ruled out.

Intravenous morphine pharmacokinetics in pediatric patients with sickle cell disease

To examine the pharmacokinetics of parenteral opioids, such as morphine, in patients with sickle cell disease, we determined the plasma morphine clearances in 18 patients (aged 6 to 19 years) who were receiving continuous intravenous infusions, and the pharmacokinetics of morphine in an additional six patients after single intravenous doses. Plasma morphine clearances ranged from 6.2 to 59.1 ml min - 1 kg - 1 (35.5 ± 12.4, mean ± SD) during steady-state infusions. There was a negative correlation between clearance values and age over the age range studied ( p = 0.013). A significant difference ( p = 0.042) was also observed in clearance values between patients who had serious adverse symptoms (23.4 ± 10.7 ml min - 1 kg -1) and those who had less serious symptoms (36.3 ± 6.4 ml min - 1 kg -1) when morphine was given at high dosage rates (≥0.15 mg kg - 1 hr -1). Pharmacokinetic modeling of plasma morphine concentrations adequately fit a two-compartment model with a short initial distribution phase (mean half-life = 4.5 minutes) and a rapid terminal elimination half-life (77.6 ± 19.2 minutes). These findings suggest that considerable individualization of morphine dosing may be necessary to achieve optimal analgesia and minimal adverse effects in these patients. (J P EDIATR 1995;126:461-7)

Modulation of Endogenous Opiate Production: Effect of Fasting

The endogenous opiate alkaloid content in tissues from fed, 24 h and 48 h fasted rats was determined. Plasma morphine and codeine concentrations did not change in response to fasting. Morphine levels in the spleen increased 3-fold after 24 h of fasting and were lower than fed rats by 48 h of fasting; no change was detected in spleen codeine levels. Brain morphine levels were elevated 5-fold after 24 h of fasting and were two-fold higher than those of fed rats after 48 h of fasting. Brain codeine levels did not change with fasting. These results indicate that opiate alkaloids are endogenously produced in rodent tissues, particularly in the spleen, liver, and adrenals. The synthesis of morphine, in the spleen and brain, is maximally stimulated after 24 h of fasting, without alterations in tissue codeine synthesis. These suggest differential regulation of the endogenous synthetic pathways of morphine and codeine in response to the stress of fasting.

No Relation of Plasma Morphine Level to the Severity of Naloxone-Induced Withdrawal in Acute Morphine-Dependent Rats

Plasma morphine concentration and naloxone-precipitated withdrawal body weight loss and plasma corticosterone (PCS) increase were determined at 12, 18 and 24 hr after i.v. infusion of morphine at a constant rate of 10 mg/kg/hr for 4 hr in Sprague-Dawley rats. Plasma morphine concentration declined 98.0% within 12 hr and further declined 58.8% during 12-24 hr after morphine infusion. There was a significant difference between plasma morphine concentrations at 12 and 24 hr after the morphine infusion. Naloxone (0.5 and 2.0 mg/kg)-precipitated withdrawal, but not spontaneous withdrawal, was elicited at 12-24 hr after the morphine infusion, and the severity of withdrawal precipitated by 2.0 mg/kg naloxone was the same at 12-24 hr after the morphine infusion. Furthermore, there was no significant correlation between plasma morphine concentration and body weight loss or PCS increase. The results suggest that a constant degree of morphine dependence is sustained during 12-24 hr after the morphine infusion and the severity of naloxone-precipitated withdrawal is not related to the plasma morphine concentration at the time of naloxone injection, that is, the rate of morphine removal from its receptor sites.

Efficacy and pharmacokinetics of a new controlled-release morphine sulfate 200-mg tablet

Nineteen of 25 patients (14 female) with advanced malignant disease completed a randomized controlled trial of a new high-dose (200 mg) tablet formulation of controlled-release morphine. Compared with the currently available 100-mg tablets there were no differences in pain severity or adverse effects with the new formulation.. In four patients, full 12-hr plasma morphine concentration profiles at steady state were obtained and showed no significant differences between the same dose provided as 100-mg and 200-mg tablets in C max , t max , or other pharmacokinetic indices.

Effects of diltiazem on morphine withdrawal and on plasma morphine concentration in rats.

Effects of diltiazem on morphine withdrawal and on plasma morphine concentration in rats.

Morphine and morphine‐glucuronide concentrations in plasma and CSF during long‐term administration of oral morphine.

Concentrations of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were measured by h.p.l.c. in plasma and cerebrospinal fluid (CSF) samples from 16 patients with cancer receiving oral (controlled-release) morphine. There was a close correlation between plasma and CSF morphine concentrations (r = 0.94, P = 0.0001) and both correlated with drug dosage (r = 0.61, P = 0.013 and r = 0.74, P = 0.0001, respectively). M3G and M6G in plasma and CSF were correlated (r = 0.81 and r = 0.82, both P = 0.0001). No relationship was apparent between M plus M6G concentrations in the CSF and pain scores.

Plasma and Cerebrospinal Fluid Concentrations of Morphine and Morphine Glucuronides after Oral Morphine

In patients with renal failure, morphine may cause prolonged narcosis and respiratory depression. Accumulation of the pharmacologically active metabolite morphine-6-glucuronide (M-6G) may explain this effect of morphine in patients with renal failure. After a single oral dose, morphine and its conjugates were measured in the plasma and the cerebrospinal fluid (CSF) in patients with renal failure. Eight patients with normal renal function and six patients with renal failure requiring dialysis were studied after operation under spinal anesthesia. Plasma and CSF concentrations of morphine, morphine-3-glucuronide (M-3G), and M-6G were measured by high-pressure liquid chromatography every 4 h for 24 h after an oral dose of 30 mg morphine. The area under morphine plasma concentration-time curve from 0 to 24 h increased from 38 +/- 4 ng.ml-1 x h in patients with normal renal function to 110 ng.ml-1 x h in those with renal failure (P < 0.01). In patients with renal failure, plasma concentrations of M-3G and M-6G were higher at 4 h and remained at an increased level until the end of the study. The peak CSF concentration of morphine at 8 h was similar in those with renal failure or normal renal function, 1.8 +/- 0.4 and 2.0 +/- 0.6 ng.ml-1 respectively. M-3G and M-6G in CSF reached a maximum at 12 h in patients with normal renal function, whereas in those with renal failure the concentrations gradually increased so that the highest concentrations were observed at 24 h. At 24 h, CSF M-6G concentration was 15 times greater in patients with renal failure than in those with normal renal function. We conclude that M-3G and M-6G readily cross the blood-brain barrier in patients with normal renal function or with renal failure. In patients with renal failure, the retention of plasma M-6G induces a progressive accumulation of this active metabolite in CSF; this accumulation may explain the increased susceptibility to morphine in patients with renal failure.

Psychotropic drug consumption and other factors associated with heroin overdose

In clinical or forensic practice there are few studies assessing which risk factors are associated with heroin overdoses. A series of 76 consecutive non-fatal heroin overdoses were compared to 22 consecutive subjects who self-injected heroin within 1 h before admission to the emergency room. Whereas blood levels of alcohol and IgE and urinary cocaine metabolite levels were similar in both groups, higher benzodiazepine plasma levels were detected in the heroin overdose group. The assessment of methadone, dextropropoxyphene, amphetamines and cannabis in urine analysis did not show differences between both groups. The interview revealed that only 48% of subjects in the heroin overdose group self-administered the last dose of heroin before admission in the usual setting as compared to 100% of subjects in the non-overdose group. The application of a log-linear regression model identified self-injection of heroin in an unusual place and plasma concentrations of total morphine and benzodiazepines as risk factors for heroin overdose.

CSF and Plasma Concentrations of Morphine and Morphine Glucuronides in Cancer Patients Receiving Epidural Morphine

Abstract Thirty-five cancer patients, treated with chronic epidural morphine, were assayed for plasma and cerebrospinal fluid (CSF) minimum steady-state concentrations (Css min) of morphine (M), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) by high performance liquid chromatography (HPLC). A linear dose-concentration relationship was found for the 3 substances in plasma and for morphine and M3G in CSF. The mean ± S.E.M. CSF/plasma morphine ratio was 158 ± 43. In CSF, the concentrations of morphine exceeded those of the metabolites substantially and, normalized to morphine, the mean CSF M M3G M6G ratio was 1:0.05:0.02. In plasma, the metabolite concentrations were higher than the parent drug and the plasma M M3G M6G ratio was 1:12:3. The mean M3G and M6G concentrations in CSF were 40–60% of those found in plasma. Indication of cerebral formation of M3G was found in 1 patient. Pain relief, evaluated by a visual analogue scale (VAS), did not correlate with the CSF M3G concentrations or with the M3G M ratio. CSF M6G concentrations were low and did not contribute to any detectable analgesia. We conclude that after epidural administration of morphine, the M3G and M6G metabolites in CSF are low compared to unchanged morphine and seem to have little influence on analgesia. Howewer, the fact that a significant passage of the glucuronide metabolites occurs to the CSF may indicate a role in morphine analgesia after other routes of administration.

Cognitive and motor function impairments during continuous opioid analgesic infusions

AbstractThis research was supported in part by grants from National Cancer Institute (CA 38552) and assistance from Janssen Research Foundation.Morphine and other opioid analgesics may interfere with normal cognition and motor function during long‐term treatment of cancer‐related pain. In this study, we used individually tailored steady‐state drug infusions to control plasma concentrations of morphine and alfentanil and measured the extent of cognitive and motor impairments produced by each drug in healthy volunteers. The tailored infusions allowed evaluation of cognitive and motor effects at three sequential, steady plasma concentrations of each opioid. During continuous infusion, both drugs caused significant, plasma concentration‐related impairments of ability to process serially‐presented information and of fine motor control at plasma drug concentrations within the usual therapeutic range. We found significant relationships between cognitive and motor function decrements and plasma opioid concentration with both morphine and alfentanil. We conclude that magnitudes of cognitive and motor function impairments are equivalent for these two mu receptor selective agonists at equianalgesic plasma concentrations.

Influence of inhaled anesthetics on the pharmacokinetics and pharmacodynamics of morphine.

We determined the magnitude and duration of the effect of morphine (1.0 mg/kg intravenous bolus) on isoflurane and halothane minimum alveolar concentration (MAC) in six dogs anesthetized on two occasions in cross-over fashion. Plasma morphine concentration-time profiles and changes in PaCO2 were determined after morphine injection. After morphine injection, the end-tidal anesthetic dose was manipulated over the course of a 4-h observation period to account for the decline in plasma morphine concentration and to maintain an anesthetic level equivalent to 1.0 MAC isoflurane or halothane alone. Morphine decreased the MAC of halothane and isoflurane. The magnitude of MAC decrease was related to time after morphine injection and was similar for a given time with both halothane and isoflurane. For example, at 28.8 +/- 3.6 (mean +/- SE) and 34.8 +/- 6.3 min after morphine injection, the MAC for halothane and isoflurane were reduced by 35.7% +/- 4.5% and 39.3% +/- 3.4%, respectively. By 4 h after morphine injection, the MAC reduction for both anesthetics was less than 10% in most of the animals. Except for systemic clearance of morphine during halothane and isoflurane (40.1 +/- 6.1 and 53.7 +/- 5.6 mL.min-1.kg-1, respectively), there were no differences in disposition kinetics of free morphine associated with the two inhaled anesthetics. Morphine increased PaCO2 to a similar degree with both halothane (from 42.2 +/- 2.1 mm Hg to 55.6 +/- 2.3 mm Hg) and isoflurane (46.2 +/- 2.4 mm Hg to 55.3 +/- 2.1 mm Hg). Respiratory depression was abolished by noxious stimulation (tail clamp) and naloxone in all animals with both anesthetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of Inhaled Anesthetics on the Pharmacokinetics and Pharmacodynamics of Morphine

We determined the magnitude and duration of the effect of morphine (1.0 mg/kg intravenous bolus) on isoflurane and halothane minimum alveolar concentration (MAC) in six dogs anesthetized on two occasions in cross-over fashion. Plasma morphine concentrationtime profiles and changes in Paco2 were determined after morphine injection. After morphine injection, the end-tidal anesthetic dose was manipulated over the course of a 4-h observation period to account for the decline in plasma morphine concentration and to maintain an anesthetic level equivalent to 1.0 MAC isoflurane or halothane alone. Morphine decreased the MAC of halothane and isoflurane. The magnitude of MAC decrease was related to time after morphine injection and was similar for a given time with both halothane and isoflurane. For example, at 28.8 ± 3.6 ( ± SE) and 34.8 ± 6.3 min after morphine injection, the MAC for halothane and isoflurane were reduced by 35.7% ± 4.5% and 39.3% ± 3.4%, respectively. By 4 h after morphine injection, the MAC reduction for both anesthetics was less than 10% in most of the animals. Except for systemic clearance of morphine during halothane and isoflurane (40.1 ± 6.1 and 53.7 ± 5.6 mL·min−1·kg−1, respectively), there were no differences in disposition kinetics of free morphine associated with the two inhaled anesthetics. Morphine increased PaCO2 to a similar degree with both halothane (from 42.2 ± 2.1 mm Hg to 55.6 ± 2.3 mm Hg) and isoflurane (46.2 ± 2.4 mm Hg to 55.3 ± 2.1 mm Hg). Respiratory depression was abolished by noxious stimulation (tail clamp) and naloxone in all animals with both anesthesics. We conclude that: 1) intravenous morphine (1.0 mg/kg) reduces the halothane and isoflurane MAC to the same extent and that the magnitude of reduction is time-dependent; 2) during conditions of a similar constant level of anesthesia (inhaled anesthetic plus morphine) there is little or no difference in disposition kinetics of morphine; and 3) there is no anesthetic-related difference in the magnitude of morphine-induced respiratory depression during inhaled anesthesia, a depression that can be abolished by noxious stimulation and naloxone. (Anesth Analg 1993;77:346-51)

Pharmacokinetics of morphine infusion in premature neonates.

Morphine pharmacokinetics were studied in 17 premature neonates (26-34 weeks' gestation) after intravenous infusion during the first 24 hours of life. Infants received either standard dose morphine that comprised of a 100 micrograms/kg/hour loading infusion for 2 hours followed by a maintenance infusion of 12.5 micrograms/kg/hour, or a high dose of 200 micrograms/kg/hour for 2 hours followed by 50 micrograms/kg/hour. Mean plasma concentrations of morphine (SD) after 2 and 24 hours were 99 (12.9) and 96.4 (3.2) ng/ml, and 184.2 (37.7) and 319 (71.2) ng/ml for the standard and high dose regimens, respectively. Morphine-3-glucuronide plasma concentrations achieved about 20% and 80% of morphine values at 2 and 24 hours respectively. Morphine-6-glucuronide could not be detected at 2 hours, but attained 20-25% of morphine plasma concentrations by 24 hours. The population mean morphine clearance was 2.4 ml/min/kg, the elimination half life was 8.75 hours and the volume of distribution was 1.82 1/kg. High plasma concentrations of morphine appeared to be well tolerated. Although mean arterial blood pressure decreased during the first six hours of treatment, this was not statistically significant; two infants experienced transient muscle rigidity, but no evidence of seizures was noted. There appears to be no clinical advantage in using the high dose regimen.