morphine-6-glucuronide and Kidney-Failure--Chronic

A 57-year-old woman with metastasizing ovarian cancer and chronic renal failure was admitted for morphine treatment of an acute lumbospinal pain syndrome, ambulant treatment with analgesics having failed provide adequate pain relief. On admission due to pain the conscious patient presented with reduced general condition and lumbal pain sensitive to tapping. Lasègue's sign was positive on both sides, no other disturbed neurological functions were found.. On the 7th day of morphine administration she became somnolent and breathing became markedly depressed, indicating overdosage, metabolic and intracranial causes having been excluded. Naloxone, an opioid antagonist, was given i.v. and the breathing pattern improved. But drowsiness continued for another 48 hours and only regressed after repeated doses of naloxone.. Morphine-6-glucuronide (M6G), formed from morphine in the liver, accumulates in blood and penetrates the blood-brain barrier, binding with strong affinity to opiate receptors and exerts a strong analgesic effect. As M6G is excreted by the kidney, its concentration rises in renal failure and can lead to severe intoxication. Morphine dosage must therefore be carefully controlled in patients with renal failure.

Topics: Analgesics, Opioid; Diagnosis, Differential; Female; Humans; Kidney Failure, Chronic; Middle Aged; Morphine; Morphine Derivatives; Naloxone; Narcotic Antagonists; Ovarian Neoplasms; Pain, Intractable; Poisoning

Topics: Humans; Kidney Failure, Chronic; Morphine; Morphine Derivatives; Neoplasms; Pain

A morphine plasma concentration/respiratory rate relationship has been described for both adults and children although that of its metabolite, morphine-6-glucuronide, remains uncertain. We describe this relationship in a child with end-stage renal failure who received repeat morphine administration over two days. An EMAX model for additive morphine and morphine-6-glucuronide respiratory effects described respiratory rate better than models describing either alone. Failure to clear morphine-6-glucuronide renally led to respiratory depression episodes occurring later than those predicted by modelling morphine levels only. These findings support the use of alternative analgesics (e.g. fentanyl) that are cleared by non-renal pathways and have no active metabolites in patients with end-stage renal disease.

Topics: Analgesics, Opioid; Child; Humans; Kidney Failure, Chronic; Male; Models, Biological; Morphine; Morphine Derivatives; Respiration

We studied the influence of three factors on drug disposition: genetic polymorphism, impaired renal excretion of drug metabolites, and the possible elimination by hemodialysis (HD), using codeine as a model drug.. Based on the genotyping of three CYP2D6 polymorphisms in 228 HD patients, nine extensive metabolizers (EMs) and two poor metabolizers (PMs) were given a single oral dose of 50 mg codeine phosphate. Plasma concentrations of its metabolites codeine-6-glucuronide (C6G), morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were determined after 2, 4, 6, 8 and 24 h (beginning of the HD session) and again after 4 h of HD (28 h). Codeine metabolites in plasma were quantitated by liquid chromatography-mass spectrometry (LC-MS).. The concentrations of C6G in plasma were high and similar in EMs and PMs. Two hours after the codeine intake, the mean concentration of M3G was 210 nM in EMs vs. 3.5 nM in PMs. The M6G metabolite concentrations could be quantitated in EMs but were below the limit of quantification in PMs (<1 nM). All three codeine metabolites/glucuronides remained unchanged or even increased until the start of HD, and thereafter, the concentrations decreased dramatically during the HD procedure.. Formation of the codeine metabolites M3G and M6G was dependent on the CYP2D6 genotype, as previously shown in healthy individuals. Elimination of glucuronides in these patients was absent until HD was performed. These factors need to be taken into consideration when drugs metabolized by CYPs are prescribed in HD patients.

Topics: Administration, Oral; Aged; Biotransformation; Chromatography, Liquid; Codeine; Cytochrome P-450 CYP2D6; Female; Gene Frequency; Genotype; Humans; Kidney Failure, Chronic; Male; Middle Aged; Morphine Derivatives; Phenotype; Polymorphism, Genetic; Renal Dialysis; Spectrometry, Mass, Electrospray Ionization

Some, but not all, patients with renal dysfunction suffer from side effects after morphine administration because of accumulation of the active metabolite morphine-6-glucuronide (M6G). The current study aims to identify genetic causes that put patients at risk for, or protect them from, opioid side effects related to high plasma M6G. Candidate genetic causes are the single nucleotide polymorphism (SNP) A118G of the mu-opioid-receptor gene (OPRM1), which has recently been identified to result in decreased potency of M6G, and mutations in the MDR1-gene coding P-glycoprotein, of which morphine and M6G might be a substrate.. Two men, aged 87 and 65 yr, with renal failure (creatinine clearance of 6 and 9 ml/min) received 30 mg/day oral morphine for pain treatment. Both patients had sufficient analgesia from morphine. However, while one patient tolerated morphine well despite high plasma M6G of 1735 nM, in the patient with M6G plasma concentrations of 941 nM it caused severe sleepiness and drowsiness. Patients were genotyped for known SNPs of the OPRM1 and MDR1 genes.. The patient who tolerated morphine well despite high plasma M6G was a homozygous carrier of the mutated G118 allele of the mu-opioid-receptor gene, which has been previously related to decreased M6G potency. In contrast, the patient who suffered from side effects was "wild-type" for this mutation. No other differences were found between the OPRM1 and MDR1 genes.. The authors hypothesize that the A118G single nucleotide polymorphism of the mu-opioid-receptor is among the protective factors against M6G-related opioid toxicity. The observation encourages the search for pharmacogenetic reasons that cause interindividual variability of the clinical effects of morphine.

Topics: Aged; Aged, 80 and over; Analgesics, Opioid; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Chromosomes, Human, Pair 6; Genotype; Humans; Kidney Failure, Chronic; Male; Morphine; Morphine Derivatives; Pain; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Receptors, Opioid, mu; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors

Topics: Adult; Analgesia, Patient-Controlled; Blood-Brain Barrier; Humans; Kidney Failure, Chronic; Male; Morphine; Morphine Derivatives; Nephrectomy; Pain, Postoperative; Renal Dialysis; Unconsciousness

Twelve patients with chronic renal failure (dialysis-dependent) and six with good renal function after renal transplantation received i.v. morphine-6-glucuronide (M6G) 30 micrograms kg-1 as part of a standardized anaesthetic technique for minor surgery. Continuous peritoneal dialysis was commenced 6 h after M6G administration in six of the dialysis-dependent patients. Serum was sampled for up to 12 h and analysed for morphine and M6G by high pressure liquid chromatography. Morphine was not detected. Mean (SD) derived pharmacokinetic variables for the three groups (transplant, renally impaired non-dialysed and renally impaired dialysed, respectively) were: elimination half-life 2.14 (0.69) h, 27.10 (15.8) h, 17.33 (4.6) h; clearance 96.0 (34.9) ml min-1, 10.57 (5.57) ml min-1, 14.3 (6.2) ml min-1; volume of distribution 0.19 (0.03) litre kg-1, 0.25 (0.06) litre kg-1, 0.27 (0.06) litre kg-1. The elimination half-life was shorter (P < 0.01) and the clearance greater (P < 0.01) for the transplanted group compared with the dialysed and non-dialysed groups. Peritoneal dialysis for the second 6 h after drug administration had little effect on M6G disposition as assessed by comparison with data obtained from the non-dialysed group.

Topics: Adolescent; Adult; Aged; Anesthesia, General; Creatinine; Half-Life; Humans; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Minor Surgical Procedures; Morphine Derivatives; Peritoneal Dialysis; Time Factors

The pharmacokinetics of morphine and its glucuronide metabolites were investigated in three groups of patients with kidney failure (nondialyzed, receiving dialysis, and transplantation) and compared with a group of normal healthy volunteers. Patients in all three renal groups were undergoing surgical procedures (nondialyzed group undergoing arteriovenous fistula formation, dialysis group undergoing placement of a peritoneal dialysis catheter, and the transplant group undergoing live donor kidney transplant). A sensitive, specific high-performance liquid chromatographic assay was used to quantitate morphine, morphine-3-glucuronide, and morphine-6-glucuronide. Patients with kidney failure had a significantly increased morphine area under the curve (AUC) compared with control subjects. There was also an increase in the metabolites morphine-3-glucuronide and morphine-6-glucuronide that was severalfold greater than the increase in morphine AUC. This metabolite accumulation was reversed by kidney transplantation, providing an elegant confirmation on the role of the kidney in morphine pharmacology.

Topics: Adult; Humans; Kidney Failure, Chronic; Kidney Transplantation; Metabolic Clearance Rate; Middle Aged; Morphine; Morphine Derivatives; Peritoneal Dialysis

Morphine-6-glucuronide (M-6-G) is an active metabolite of morphine that may contribute to drug effects. To understand better the relationship between morphine and M-6-G in cancer patients receiving chronic therapy, we employed high performance liquid chromatography with electrochemical detection to measure: (1) morphine and M-6-G plasma concentrations following discontinuation of dosing in 2 patients, one receiving oral therapy and the other an intravenous infusion; (2) morphine and M-6-G concentrations in random blood samples taken at apparent steady state from 8 patients, 7 with normal renal function and 1 with mild renal insufficiency, who were receiving continuous morphine infusions; and (3) morphine and M-6-G concentrations in random blood samples taken over a period of weeks from 4 patients, 2 with stable and 2 with declining renal function. Results demonstrated a slightly slower decline in plasma M-6-G than morphine concentrations following drug discontinuation, as would be expected for metabolite and parent relationship; roughly similar M-6-G: morphine ratios (mean molar ratio = 1.22) across a broad range of morphine doses in patients with normal renal function; and an increase in this ratio over time in patients with progressive renal dysfunction. These data illustrate the kinetics of M-6-G in cancer patients receiving chronic morphine therapy and confirm the importance of renal function in determining the concentration of the metabolite.

Topics: Adult; Aged; Female; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain

Morphine-6-glucuronide is an active metabolite of morphine that has analgesic properties and is measurable in the plasma and cerebrospinal fluid of patients treated with this opioid. Decreased clearance of the compound has been observed in patients with renal insufficiency, and this has been associated with an increase in the ratio of morphine-6-glucuronide to morphine. Clinical effects from accumulation of morphine-6-glucuronide have not been described with the exception of case reports in which patients with renal failure were noted to develop opioid toxicity with high plasma levels of the metabolite and low levels of the parent drug. We describe a patient who experienced chronic nausea and an episode of confusion while treated with a small, stable dose of oral morphine in the setting of mild renal insufficiency. Relatively high levels of morphine-6-glucuronide were measured and all symptoms resolved promptly as the concentration of this metabolite declined. This case provides suggestive evidence that morphine-6-glucuronide can produce clinically significant effects in patients with mild renal insufficiency.

Topics: Adenocarcinoma; Confusion; Female; Humans; Kidney Failure, Chronic; Middle Aged; Morphine; Morphine Derivatives; Nausea; Pain; Pancreatic Neoplasms

The influence of renal failure on the disposition of morphine and its metabolites was studied in nine patients with end-stage renal failure undergoing transplantation, and compared with five healthy anaesthetized patients. All patients received morphine sulphate pentahydrate 10 mg i.v. over 30 s, as part of a balanced anaesthetic technique. Venous blood samples were collected for up to 24 h, and plasma concentrations of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) assayed by a differential radioimmunoassay method. There were no differences between the two groups for morphine elimination half-life (renal failure: 290 min; anaesthetized controls: 286 min), or clearance (renal failure: 533 ml min-1; controls 741 ml min-1). However, the volume of distribution at steady state was greater in the control group (241 litre v. 141 litre; P = 0.002). The peak concentrations of M3G and M6G were greater in the renal transplant patients (P = 0.001 and P = 0.01, respectively), as were the AUC (0-24 h) (P = 0.002 and P = 0.002). M6G has been shown to possess analgesic properties in both man and experimental animals, and therefore the increased AUC for M6G may contribute to the prolonged effect seen with morphine when given to patients with impaired renal function.

Topics: Adult; Anesthesia, General; Half-Life; Humans; Kidney Failure, Chronic; Kidney Transplantation; Metabolic Clearance Rate; Middle Aged; Morphine; Morphine Derivatives

Patients with impaired renal function may experience severe and prolonged respiratory depression when treated with morphine. This has been attributed to accumulation of the drug during renal failure. Three patients are described who had classical signs of intoxication with morphine in the absence of measurable quantities of morphine in the plasma. The observed clinical effect is attributed to accumulation of the pharmacologically active metabolite morphine-6-glucuronide, which is usually renally excreted. It is concluded that morphine does not accumulate in patients with renal failure but that accumulation of metabolites does occur. The previously reported observations of morphine accumulation during renal failure probably result from the use of radioimmunoassays that cannot distinguish between morphine and morphine-6-glucuronide. Thus the apparent morphine concentration measured with these assays in fact reflects the total quantity of morphine and morphine-6-glucuronide present.

Topics: Acute Kidney Injury; Adult; Aged; Female; Humans; Kidney; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Morphine; Morphine Derivatives; Respiratory Insufficiency

Topics: Humans; Kidney Failure, Chronic; Kinetics; Morphine; Morphine Derivatives