morphine-6-glucuronide and Renal-Insufficiency

Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindividual variability in patient response and no clear guidance on how to optimise morphine dosage regimen complicates treatment strategy for clinicians. Population pharmacokinetic-pharmacodynamic models can be used to quantify dose-response relationships for the population as well as interindividual and interoccasion variability. Additionally, relevant covariates for population subgroups that deviate from the typical population can be identified and help clinicians in dose optimisation. This review provides a detailed overview of the published human population pharmacokinetic-pharmacodynamic studies for morphine analgesia in addition to basic drug disposition and pharmacological properties of morphine and its analgesic active metabolite, morphine-6-glucuronide, that may help identify future covariates. Furthermore, based on simulations from key pharmacokinetic-pharmacodynamic models, the contribution of morphine-6-glucuronide to the analgesic response in patients with renal insufficiency was investigated. Simulations were also used to examine the impact of effect-site equilibration half-life on time course of response. Lastly, the impact of study design on the likelihood of determining accurate pharmacodynamic parameters for morphine response was evaluated.

Topics: Acute Pain; Analgesics, Opioid; Animals; Biological Availability; Biotransformation; Half-Life; Humans; Models, Biological; Morphine; Morphine Derivatives; Precision Medicine; Renal Insufficiency; Tissue Distribution

Topics: Animals; Half-Life; Humans; Morphine; Morphine Derivatives; Rats; Renal Insufficiency

Topics: Cancer Pain; Humans; Morphine; Morphine Derivatives; Neoplasms; Renal Insufficiency

Morphine-6-glucuronide, the active metabolite of morphine, and to a lesser extent morphine itself are known to accumulate in patients with renal failure. A number of cases on non-lethal morphine toxicity in patients with renal impairment report high plasma concentrations of morphine-6-glucuronide, suggesting that this metabolite achieves sufficiently high brain concentrations to cause long-lasting respiratory depression, despite its poor central nervous system penetration. We report a lethal morphine intoxication in a 61-year-old man with sickle cell disease and renal impairment, and we measured concentrations of morphine and morphine-6-glucuronide in blood, brain and cerebrospinal fluid. There were no measurable concentrations of morphine-6-glucuronide in cerebrospinal fluid or brain tissue, despite high blood concentrations. In contrast, the relatively high morphine concentration in the brain suggests that morphine itself was responsible for the cardiorespiratory arrest in this patient. Given the fatal outcome, we recommend to avoid repeated or continuous morphine administration in renal failure.

Topics: Anemia, Sickle Cell; Brain; Fatal Outcome; Heart Arrest; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Renal Insufficiency

The influence of experimentally induced renal failure on the disposition of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was examined in seven sheep infused intravenously with morphine for 6 hr. Between 5 and 6 hr, blood was collected from the aorta, pulmonary artery, hepatic, hepatic portal and renal veins and posterior vena cava. Additional samples from the aorta and urine were collected up to 144 hr. Morphine, M3G and M6G were determined in plasma and urine by high-performance liquid chromatography. Constant concentrations of morphine, but not of M3G and M6G, were achieved in plasma between 5 and 6 hr. Significant (P < .001) extraction of morphine by the liver (0.72 +/- 0.05) and kidney (0.42 +/- 0.15) occurred. Compared with sheep with normal kidneys (Milne et al., 1995), renal failure did not alter (P = .11) the mean total clearance of morphine (1.5 +/- 0.3 liters/min); clearance by the kidney was less (P < .001). However, a paired comparison using sheep common to this study and from the study when their kidneys were normal revealed a significant reduction in mean total clearance of 25%. The renal extraction of M3G and M6G and urinary recovery of the dose as summed morphine, M3G and M6G were reduced by renal failure. The kidney metabolized morphine to M3G. The data suggest that nonrenal elimination of M3G becomes more important during renal failure.

Topics: Animals; Area Under Curve; Chromatography, High Pressure Liquid; Infusions, Intravenous; Liver; Morphine; Morphine Derivatives; Renal Insufficiency; Sheep

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.

Topics: Administration, Oral; Aged; Aged, 80 and over; Blood-Brain Barrier; Body Weight; Humans; Kidney; Middle Aged; Morphine; Morphine Derivatives; Renal Insufficiency