morphine-3-glucuronide and Pain--Intractable

To compare the efficacy, safety and pharmacokinetics of a newly developed controlled-release suppository (MSR) with MS Contin tablets (MSC) in cancer patients with pain.. In a double-blind, randomised, two-way cross-over trial, 25 patients with cancer pain were selected with a morphine (M) demand of 30 mg every 12 h. Patients were divided into two groups. Group 1 received active MSC (30 mg) and placebo MSR, followed by placebo MSC and active MSR (30 mg) each for a period of 5 days. Group 2 started with active MSR and placebo MSC, followed by active MSC and placebo MSR, each for a period of 5 days. Blood for determination of plasma concentration of morphine (M) and its 3- and 6-glucuronides (M3G, M6G) was collected, and area under the plasma concentration-time curve (AUC)0-12 h, peak plasma concentration (Cmax), time to reach Cmax (tmax), and CO and C12 of M, M6G and M3G were determined on day 5 and day 10. Intensity of pain experienced by each patient was assessed every 2 h on a 0-10 scale, while side effects and rescue medication were recorded.. Twenty patients (ten patients in each group) completed the study. A pronounced inter-patient variability in plasma concentrations of M, M3G and M6G was observed after administration of both forms. Apart from the C0 and C12, no significant differences in AUC0-12 h, tmax and Cmax of morphine between the rectal and oral route of administration were found. In the case of the metabolites, it was found that AUC0-12 h and Cmax of M6G, and AUC0-12 h, Cmax, C0 and C12 of M3G after rectal administration were significantly lower than after oral administration. However, apart from the tmax of M6G, none of the pharmacokinetic parameters of M, M6G or M3G met the criteria for bioequivalence. There were no significant (P = 0.44) differences in pain intensity score between the oral and rectal forms within the two groups, regardless of the treatment sequence. No treatment differences in nausea, sedation or the demand on escape medication (acetaminophen tablets) between the rectal and oral forms were observed.. The newly developed controlled-release M suppository is safe and effective and may be a useful alternative for oral morphine administration in patients with cancer pain.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Biological Availability; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain, Intractable; Suppositories

A simultaneous determination of morphine (M) and its two metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), by HPLC in the serum of oncological patients is described. The compounds are extracted from the serum by means of Chromabond C18--EC solid-phase-extraction cartridges, separated on a Symmetry C18 analytical column (150 x 4.9 mm, 5 microm) and detected by a UV detector at 210 nm. The mobile phase consisted of 8% acetonitrile in water, 30 mmol/l phosphate buffer (pH 3) and 1 mmol/l octane sulfonic acid as the ion pairing agent; its flow-rate was 0.8 ml/min. Under these conditions, the detection limits were 10 ng/ml, 60 ng/ml and 90 ng/ml for M, M3G, and M6G, respectively. This paper concerns blood serum concentration levels of M, M3G and M6G in oncological patients, their ratios and their role in pain resistance.

Topics: Adult; Aged; Analgesics, Opioid; Biotransformation; Chromatography, High Pressure Liquid; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain, Intractable; Sex Characteristics; Spectrophotometry, Ultraviolet

Dispositions for genes encoding opioid receptors may explain some variability in morphine efficacy. Experimental studies show that morphine and morphine-6-glucuronide are less effective in individuals carrying variant alleles caused by the 118 A > G polymorphism in the mu-opioid receptor gene (OPRM1). The purpose of the study was to investigate whether this and other genetic polymorphisms in OPRM1 influence the efficacy of morphine in cancer pain patients.. We screened 207 cancer pain patients on oral morphine treatment for four frequent OPRM1 gene polymorphisms. The polymorphisms were the -172 G > T polymorphism in the 5'untranslated region of exon 1, the 118 A > G polymorphism in exon 1, and the IVS2 + 31 G > A and IVS2 + 691 G > C polymorphisms, both in intron 2. Ninety-nine patients with adequately controlled pain were included in an analysis comparing morphine doses and serum concentrations of morphine and morphine metabolites in the different genotypes for the OPRM1 polymorphisms.. No differences related to the -172 G > T, the IVS2 + 31 G > A and the IVS2 + 691 G > C polymorphisms were observed. Patients homozygous for the variant G allele of the 118 A > G polymorphism (n = 4) needed more morphine to achieve pain control, compared to heterozygous (n = 17) and homozygous wild-type (n = 78) individuals. This difference was not explained by other factors such as duration of morphine treatment, performance status, time since diagnosis, time until death, or adverse symptoms.. Patients homozygous for the 118 G allele of the mu-opioid receptor need higher morphine doses to achieve pain control. Thus, genetic variation at the gene encoding the mu-opioid receptor contributes to variability in patients' responses to morphine.

Topics: Aged; Alleles; Analgesics, Opioid; Dose-Response Relationship, Drug; Female; Genetic Testing; Genotype; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain Measurement; Pain, Intractable; Polymorphism, Genetic; Quality of Life; Receptors, Opioid, mu; Reverse Transcriptase Polymerase Chain Reaction

A 32-year-old man with chronic intractable right lower extremity pain unresponsive to multiple neurosurgical and pharmacologic treatments, including intrathecal morphine administration, was successfully treated with sciatic nerve block, discontinuance of opioid therapy, and psychologic interventions. Plasma and urine ratios of morphine metabolites morphine-3-glucuronide and morphine-6-glucuronide were analyzed at the beginning of our interventions, and the results indicated that morphine-3-glucuronide levels were significantly higher than morphine-6-glucuronide levels. The possible association between the observed morphine metabolite ratio and the intractable pain in patients resistant to opioids may have potential clinical implications.

Topics: Adult; Analgesics, Opioid; Drug Resistance; Humans; Injections, Spinal; Male; Morphine; Morphine Derivatives; Nerve Block; Pain, Intractable; Treatment Failure

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. However, 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.

Topics: Analgesia, Epidural; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Humans; Morphine; Morphine Derivatives; Neoplasms; Pain Measurement; Pain, Intractable

The plasma concentrations and renal clearance values of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were determined in 11 adult cancer patients maintained on a long term oral morphine dosage (10 to 100mg every 4h). Concentrations in plasma and urine were determined by a specific high performance liquid chromatography assay. In this group of patients, whose creatinine clearance values ranged from 52 to 180 ml/min (3.12 to 10.8 L/h), average steady-state plasma concentrations of morphine, M3G and M6G were related (p < 0.01) to the morphine dose per kilogram of bodyweight. The mean total urinary recovery as morphine, M3G and M6G was 74.6 +/- 26.5% of the dose. Renal clearance values for M3G and M6G were closely related (r2 = 0.80; p < 0.0005). It was not possible to detect a relationship between the renal clearance of morphine, M3G and M6G, and that of creatinine. The renal tubular handling of all 3 compounds showed wide interindividual variation, and there was evidence of either net renal tubular secretion or reabsorption. There was no apparent relationship between plasma morphine and M6G concentrations and pain relief.

Topics: Adult; Aged; Aged, 80 and over; Chromatography, High Pressure Liquid; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain, Intractable; Regression Analysis

Plasma morphine concentrations were measured in five cancer patients receiving long-term epidural morphine administration. Peak concentrations were observed within 1 h of dosage and concentrations then declined biexponentially. Plasma morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) concentrations were measured in two patients and plasma M3G concentrations were observed to be much higher than plasma M6G and morphine concentrations. Peak plasma M6G concentrations occurred within 1.0 h of dosing and plasma M6G concentrations then remained higher than plasma morphine concentrations.

Topics: Analgesia, Epidural; Chromatography, High Pressure Liquid; Humans; Male; Morphine; Morphine Derivatives; Neoplasms; Pain, Intractable; Spectrometry, Fluorescence

After intracerebroventricular administration of morphine in four cancer patients, cerebrospinal fluid (CSF) was analyzed by two morphine radioimmunoassays (RIA), liquid chromatography (LC) and radioreceptor assay (RRA) to evaluate the presence of morphine metabolites. Immunoreactive morphine-like substances were detected by differential RIA's. The maximum concentrations of these compounds were achieved 3 hours after drug administration. These concentrations, according to the specificity of the antiserum, represent a mixture of several metabolites in which only morphine 3-glucuronide(M 3-G) and morphine 6-glucuronide (M 6-G) were identified by LC, and M 6-G by LC-RRA. These results confirm that brain is able to metabolize morphine to inactive (M 3-G) or more potent (M 6-G) derivatives.

Topics: Chromatography, Liquid; Humans; Injections, Intraventricular; Male; Morphine; Morphine Derivatives; Pain, Intractable; Radioimmunoassay; Radioligand Assay

There is growing evidence that renally-impaired patients receiving morphine therapy are at greater risk of developing opiate toxicity, due to the accumulation of an active metabolite, morphine-6-glucuronide (M6G), which is usually excreted by the kidneys. This study examined the relationships between morphine dosage, renal function, and trough plasma concentrations of morphine and its glucuronide metabolites in 21 patients (aged mean: 68.5 years: 11 males) receiving either oral or subcutaneous morphine for terminal cancer pain. The median daily morphine dosages (mg.kg-1) were: orally 1.87 (range 0.37-6.82) and subcutaneously 1.64 (range 0.22-3.60). The median plasma concentrations of morphine, morphine-3-glucuronide (M3G), and M6G (ng.ml-1) were: 36.0, 1035.2, and 142.3, respectively. The plasma concentrations of morphine, M3G and M6G were each significantly related to the daily morphine dosage (n = 21, Spearman r = 0.79, 0.91, and 0.88 respectively). Accumulation of the morphine glucuronides was dependent on renal function. The plasma concentrations of M3G and M6G, when divided by the morphine concentration, were significantly related to the calculated creatinine clearance of the patient. Patients receiving oral morphine had higher plasma concentration ratios of glucuronide/morphine than those receiving subcutaneous therapy, presumably due to first-pass glucuronidation. The results of this study confirm that accumulation of the pharmacologically active M6G is related to renal function, which probably explains the observation that morphine dosage requirements are generally reduced in patients with renal impairment.

Topics: Aged; Aged, 80 and over; Creatinine; Female; Humans; Kidney; Kidney Function Tests; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain, Intractable

The bioavailability of oral controlled release morphine tablets (MST, Napp Laboratories) and oral morphine sulphate in aqueous solution (MSS) was compared in 10 patients with advanced cancer. Serum samples were analysed for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) using a specific HPLC assay. The relative bioavailability of morphine with MST was significantly less than that with MSS (mean 80%, range 50-110%) although there was no difference between the formulations in the relative availability of M3G and M6G. There was no significant difference between the formulations in the serum concentration of morphine at 12 h. The mean ratios morphine: M6G:M3G (comparing areas under the serum concentration-time curves) were 1:9:56. There was a highly significant linear relationship between the dose administered and AUC for morphine, M3G and M6G after MSS; and for morphine after MST. Median tmax for morphine was 0.5 h with MSS and 2.5 h with MST; for M3G 1.5 h with MSS and 3.0 h with MST; and for M6G 1.5 h with MSS and 3.25 h with MST. A secondary peak of unconjugated morphine, which may represent enterohepatic circulation, was seen in several patients 2-4 h after administration of elixir and 4-6 h after administration of MST.

Topics: Adult; Aged; Biological Availability; Delayed-Action Preparations; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain, Intractable