morphine-6-glucuronide and Neoplasms

The chemical structures of morphine and its metabolites are closely related to the clinical effects of drugs (analgesia and side-effects) and to their capability to cross the Blood Brain Barrier (BBB). Morphine-6-glucuronide (M6G) and Morphine-3-glucuronide (M3G) are both highly hydrophilic, but only M6G can penetrate the BBB; accordingly, M6G is considered a more attractive analgesic than the parent drug and the M3G. Several hypotheses have been made to explain these differences. In this review we will discuss recent advances in the field, considering brain disposition of M6G, UDP-glucoronosyltransferases (UGT) involved in morphine metabolism, UGT interindividual variability and transport proteins.

Topics: Analgesics, Opioid; Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Blood-Brain Barrier; Brain; Glucuronosyltransferase; Humans; Liver; Mice; Morphine; Morphine Derivatives; Neoplasms; Pain; Rats; Receptors, Opioid, mu

Morphine metabolites are involved in various ways in determining the complex effects of morphine, both favourable and adverse, and may complicate the clinical use of morphine in the treatment of cancer pain. The production and effects of the principal morphine metabolites, morphine-3-glucuronide and morphine-6-glucuronide, in both normal and pathological states have been reviewed in the current literature. Therapeutic implications are also reviewed on the basis of experimental and clinical reports. The presence of these metabolites should be recognized in the chronic treatment of cancer pain with morphine, especially in the presence of renal impairment, and should be considered to have an important influence on opioid responsiveness, defined as a balance between the achievement of an optimal analgesia and the occurrence of adverse effects.

Topics: Analgesics, Opioid; Humans; Morphine; Morphine Derivatives; Neoplasms; Pain

Though many of the treatment strategies used in palliative care have never been subjected to clinical trial, it has been argued that advances in palliative care have outstripped those in many other specialties. This article is not a comprehensive review of therapeutic options, nor even of recent advances in this topic, but concentrates on the latest developments and controversies in the pharmacological treatment of four frequent and important symptoms: neuropathic pain, anorexia and cachexia, intestinal obstruction, and breathlessness. It is difficult to perform blinded, randomised trials in patients with advanced disease and poor performance status, yet it is these patients who may gain most from the adoption of new well evaluated treatment strategies.

Topics: Anorexia; Anti-Inflammatory Agents, Non-Steroidal; Cachexia; Humans; Intestinal Obstruction; Morphine Derivatives; Neoplasms; Pain; Palliative Care; Respiration Disorders

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

The well established use of oral morphine in the treatment of chronic cancer pain has developed empirically and a knowledge of its pharmacokinetics is not necessary in order to use the drug effectively. However recent information about the pharmacokinetics of morphine may help resolve the controversy about oral to parenteral relative potency ratios, and may also in the future shed some light on the problem of patients whose pain does not respond to morphine.

Topics: Administration, Oral; Drug Administration Schedule; Humans; Morphine; Morphine Derivatives; Neoplasms; Pain

Pain is one of the most prevalent and distressing symptoms in patients with cancer. There is evidence from observational studies that many patients do not get adequate relief. Although data in the literature confirm the effectiveness of most opioid drugs for the treatment of chronic pain, there is limited information about opioid titration.. The aim of this study was to evaluate the clinical pharmacokinetics of morphine (M) and their correlation with pharmacodynamic results (effective daily dose of M and side effects) during the M titration phase, in the management of chronic cancer pain. Fifty-two consecutive patients were administered Oramorph (Molteni Farmaceutici, Scandicci, Florence, Italy; beginning with 5 mg every 6 hours), to maintain pain intensity at low levels (visual analog scale <4). M, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) plasma concentrations were determined by a mass spectrometric assay.. Expected pharmacokinetic parameters were based on a pharmacokinetic profile extrapolated from 39 patients: M total clearance varied between 1.5 and 6.42 L·h(-1)·kg(-1); the median apparent volume of M distribution was 25.0 L/kg, and the elimination half-life was 4.4 hours. Over the entire period of treatment, a weak correlation between M and M3G or M6G concentrations was found, but the metabolite ratio (M3G/M6G) remained quite stable for each patient and at different sampling times. At the end of titration, the M6G/M ratio was significantly higher in the patients whose effective M concentration was below the median (5.2 ng/mL), than in patients in whom the concentration was above the median (M6G/M: 13.0 and 9.0, respectively).. This article presents the pharmacokinetic profiles of M and its metabolites: their concentration ratio could help clinicians to optimize individual therapies and tailor the dose to individual needs. Our results indicate that the relationship between M6G and M could represent a potentially useful parameter to personalize M dosing.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Analgesics, Opioid; Body Mass Index; Chromatography, High Pressure Liquid; Chronic Pain; Drug Monitoring; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain Measurement; Polymorphism, Genetic; Sex Factors; Tandem Mass Spectrometry

Our aim was to compare pharmacological aspects of two switching strategies from morphine/oxycodone to methadone; the stop and go (SAG) strategy in which methadone is started directly after the initial opioid has been stopped, and the 3-days switch (3DS), in which morphine/oxycodone is gradually changed to methadone by cross-tapering over 3 days.. Forty-two cancer patients with pain and/or opioid side effects were assessed in this randomised trial. Trough serum concentrations of methadone, morphine, morphine-6-glucuronide (M6G), and oxycodone were measured on days 1, 2, 3, 4, 7, and 14. Primary outcome was number of patients with methadone concentrations in apparent C(SS) on day 4. Secondary outcomes were exposure to opioids during the first 3 days, interindividual variation of opioid concentrations, and correlation between methadone concentrations and pain intensity (PI) day 3.. Thirty-five patients received methadone (16 in the SAG group, 19 in the 3DS group). The median preswitch morphine equivalent doses were 620 (range 350-2000) mg/day in the SAG group and 800 (range 90-3600) mg/day in the 3DS group (p = 0.43);42% reached C(SS) for methadone in the SAG group on day 4 compared with 22% in the 3DS group (p = 0.42). The SAG group was significantly less exposed to morphine/M6G/oxycodone and significantly more exposed to methadone in the first 3 days. Methadone showed a low correlation with PI. More patients dropped out after intervention in the SAG group than in the 3DS group (38% vs. 5%; p = 0.032). One SAG patient suffered from respiratory depression on day 5.. The SAG group was initially more exposed to methadone and less to the replaced opioids but without observed clinical benefit and with a higher dropout rate. Patients switched to methadone should be followed closely for the first 5 days, regardless of switching strategy.

Topics: Analgesics, Opioid; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Methadone; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Oxycodone; Pain; Palliative Care; Patient Dropouts

The aim of this study was to characterize the pharmacokinetics and pharmacodynamics of morphine and morphine 6-glucuronide (M6G) in children with cancer. Serum concentrations of morphine and M6G in children who received single oral or short term continuous intravenous morphine were determined by HPLC and ELISA assays, respectively. The serum C(max) of morphine and M6G after i.v. morphine administration was 560.5 and 309.0 nM and the T(max) was 61 and 65 min, respectively. The elimination half-life was 140.0 and 328.7 min, respectively. After oral administration of morphine, the serum C(max) of morphine and M6G was 408.34 and 256.3 nM and the T(max) was 40.0 and 60 min, respectively. The half-life was 131.0 and 325.8 min, respectively. The side effects were: drowsiness (100%), nausea and/or vomiting (57%), pruritus (28%) and urinary retention (14%). There were no reports of respiratory complications. This study showed that pharmacokinetics factors of morphine and M6G in children were significantly different from adults. Therefore the required dose for children should be different from that of adults and should be based on studies performed on children rather than on studies on adults. Some adverse effects, particularly nausea and pruritus, may be commoner than is usually thought, while others, particularly respiratory problems did not occur.

Topics: Administration, Oral; Adolescent; Biotransformation; Child; Child, Preschool; Female; Half-Life; Humans; Infusions, Intravenous; Male; Models, Biological; Morphine; Morphine Derivatives; Narcotics; Nausea; Neoplasms; Pain; Pain Measurement; Pruritus; Sleep Stages; Urinary Retention; Vomiting

We prospectively investigated the efficacy of opioid rotation from oral morphine to oral oxycodone in cancer patients who had difficulty in continuing oral morphine treatment because of inadequate analgesia and/or intolerable side effects.. Twenty-seven patients were enrolled and 25 were evaluated. The rate of patients who achieved adequate pain control, which provided an indication of treatment success, was evaluated as primary endpoint. The acceptability and pharmacokinetics of oxycodone were evaluated in addition to the assessment of analgesic efficacy and safety during the study period.. In spite of intense pain, the morphine daily dose could not be increased in most patients before the study because of intolerable side effects. However, switching to oral oxycodone allowed approximately 1.7-fold increase as morphine equivalent dose. Consequently, 84.0% (21/25) of patients achieved adequate pain control. By the end of the study, all patients except one had tolerated the morphine-induced intolerable side effects (i.e. nausea, vomiting, constipation, drowsiness). Common side effects (>10%) that occurred during the study were typically known for strong opioid analgesics, and most were mild to moderate in severity. A significant negative correlation between creatinine clearance (CCr) value and the trough concentrations of the morphine metabolites was observed. On the other hand, no significant correlation was found between CCr value and the pharmacokinetic parameters of oxycodone or its metabolites.. For patients who had difficulty in continuing oral morphine treatment, regardless of renal function, opioid rotation to oral oxycodone may be an effective approach to alleviate intolerable side effects and pain.

Topics: Administration, Oral; Aged; Analgesics, Opioid; Constipation; Drug Administration Schedule; Female; Humans; Linear Models; Male; Middle Aged; Morphinans; Morphine; Morphine Derivatives; Nausea; Neoplasms; Oxycodone; Pain; Prospective Studies; Renal Insufficiency, Chronic; Sleep Stages; Treatment Outcome; Vomiting

In order to make treatment decisions physicians should have knowledge about the relations between patient characteristics and drug disposition. Dose, route of administration, gender, age and renal function are reported to influence the serum concentrations of morphine, morphine-6-glucurnide (M6G) and morphine-3-glucuronide (M3G) during chronic treatment of cancer pain. These factors, however, are not evaluated in studies with a sample size sufficient to explore predictive factors.. Three hundred consecutive morphine users admitted because of a malignant disease were recruited. The relations of serum concentrations of morphine, M6G and M3G to patient characteristics (gender, age, weight, renal function, liver function, dose, route of administration) were explored, and regression analysis performed to investigate whether these characteristics predicted serum concentrations obtained during routine clinical drug monitoring.. Morphine dose was associated with serum concentrations of morphine (r = 0.69), M6G (r = 0.76) and M3G (r = 0.76). Oral morphine resulted in higher dose-adjusted M6G and M3G serum concentrations compared with s.c. morphine. Creatinine serum concentrations correlated with serum concentrations of M6G and M3G. Dose and route of administration predicted morphine serum concentrations, while dose and renal function predicted M6G and M3G serum concentrations. Age was an additional factor predicting M3G concentrations. Dose was the only factor that explained a clinically significant part of the observed variability.. Patient characteristics predict only minor parts of the variability of morphine, M3G and M6G serum concentrations observed during routine clinical drug-monitoring in cancer patients.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Biotransformation; Delayed-Action Preparations; Drug Monitoring; Female; Humans; Infusions, Intravenous; Liver Function Tests; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain; Prospective Studies

In 25 cancer patients treated with slow-release oral morphine and in 10 cancer patients treated with continuous infusion of morphine, plasma steady-state concentrations of morphine (M), morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G) were determined by high-performance liquid chromatography. Blood samples were withdrawn at 0, 2 and 6 h after oral administration in patients treated with slow-release oral morphine and once or twice a day in patients treated with continuous infusion of morphine. In four cancer patients treated with continuous infusion of morphine, in order to analyze chronopharmacokinetic variability, the M-3-G/M ratio was observed at 12:00 h and 24:00 h. No significant changes were observed in M-3-G/M ratios and M-6-G ratios at 0, 2, and 6 h after oral administration of morphine. The M-3-G/M ratio (38.6 +/- 25.7) in the oral morphine group was significantly higher than that (15.3 +/- 12.9) in the continuous infusion group (p < 0.01). There was an approximately 10-fold interindividual variation in the M-3-G/M ratio both in the continuous infusion group and in the oral morphine group. These results suggest that the activity of UDP glucuronosyltransferase 2B7 in the intestinal metabolism of morphine may play an active part in a large interindividual variation in the ratio of metabolites to morphine. Further studies are needed to clarify this hypothesis.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Alanine Transaminase; Aspartate Aminotransferases; Chromatography, High Pressure Liquid; Delayed-Action Preparations; Humans; Infusions, Intravenous; Liver; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain; Tablets

UDP-glucuronosyltransferase (UGT) 2B7 is the major UGT isoform responsible for the 3- and 6-glucuronidation of morphine in humans. Studies in rats have indicated that UGT1A1 may also contribute to the formation of morphine 3-glucuronide (M3G). Our objective was to investigate whether the UGT2B7 H268Y and UGT1A1*28 polymorphisms contribute to the variability in morphine glucuronide-to-morphine plasma ratios among cancer patients undergoing analgesic therapy with morphine.. Seventy patients with normal hepatic and renal function using slow-release morphine to relieve cancer pain were included. UGT2B7 genotyping was performed using restriction enzyme analysis of polymerase chain reaction (PCR)-amplified DNA fragments. Wild-type and variant alleles of the UGT1A1 gene were identified using sizing of PCR-amplified fragments. Morphine 6-glucuronide (M6G)/morphine, M3G/morphine, and M3G/M6G plasma ratios were compared between genotypes.. The M3G/morphine, M6G/morphine, and M3G/M6G plasma ratios varied 16-, 42-, and sevenfold, respectively, among individuals. No statistically significant differences in plasma ratios were found between individuals possessing UGT2B7 H/H ( n=20), H/Y ( n=30), or Y/Y ( n=20) genotypes. Five patients were homozygous for the UGT1A1 TA(7) allele, which is associated with reduced UGT1A1 gene expression. However, the mean M3G/M6G and M3G/morphine plasma ratios in TA(7) homozygous subjects did not differ significantly from those of heterozygous or homozygous wild-type (TA(6)) individuals.. The UGT2B7 H268Y polymorphism cannot account for the considerable variation in glucuronide-to-morphine ratios in cancer patients. Moreover, the contribution of UGT1A1 to the formation of M3G appears to be of minor biological significance, at least in a UGT2B7 background.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Genotype; Glucuronosyltransferase; Humans; Isoenzymes; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain; Reverse Transcriptase Polymerase Chain Reaction

Topics: Administration, Inhalation; Clinical Trials, Phase II as Topic; Dyspnea; Humans; Morphine Derivatives; Nebulizers and Vaporizers; Neoplasms

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

Oxycodone is an opioid analgesic that closely resembles morphine. Oxymorphone, the active metabolite of oxycodone, is formed in a reaction catalyzed by CYP2D6, which is under polymorphic genetic control. The role of oxymorphone in the analgesic effect of oxycodone is not yet clear. In this study, controlled-release (CR) oxycodone and morphine were examined in cancer pain. CR oxycodone and morphine were administered to 45 adult patients with stable pain for 3-6 days after open-label titration in a randomized, double-blind, cross-over trial. Twenty patients were evaluable. Both opioids provided adequate analgesia. The variation in plasma morphine concentrations was higher than that of oxycodone, consistent with the lower bioavailability of morphine. Liver dysfunction affected selectively either oxycodone or morphine metabolism. Three patients with markedly aberrant plasma opioid concentrations are presented. Significant individual variation in morphine and oxycodone metabolism may account for abnormal responses during treatment of chronic cancer pain.

Topics: Administration, Oral; Adult; Aged; Analgesics, Opioid; Cross-Over Studies; Cytochrome P-450 CYP2D6; Debrisoquin; Delayed-Action Preparations; Double-Blind Method; Female; Humans; Male; Middle Aged; Morphinans; Morphine; Morphine Derivatives; Neoplasms; Oxycodone; Pain; Pain Measurement; Phenotype

Eleven morphine naïve patients with cancer-related pain were given a single dose of either intravenous morphine (n = 5) or oral morphine (n = 6). Blood sampling was performed over a 24-hr period and serial pain assessments were made using a categorical scale. Plasma samples were analyzed for morphine, morphine-6-glucuronide (M-6-G), morphine-3-glucuronide (M-3-G), and normorphine using high-performance liquid chromatography. In neither the intravenous nor oral group was there a correlation between analgesia duration and the half-lives of morphine and M-6-G. There was no correlation between the time to peak analgesia and time to peak concentration for morphine or M-6-G. There was no significant difference in absolute concentrations of M-6-G or M-3-6 nor in the ratio of M-3-G to M-6-G at peak analgesia versus relapse.

Topics: Administration, Oral; Analgesics, Opioid; Area Under Curve; Chromatography, High Pressure Liquid; Half-Life; Humans; Injections, Intravenous; Morphine; Morphine Derivatives; Neoplasms; Pain; Pain Measurement

The relationships between plasma morphine and metabolite (M3G and M6G) concentrations and analgesic efficacy were investigated in an open study of 39 cancer pain patients receiving chronic oral morphine therapy with either morphine sulfate solution or controlled-release morphine tablets. There were no differences in morphine, metabolite kinetics, or analgesic efficacy between equivalent doses of conventional or controlled-release formulations. The increase in morphine plasma concentration after a dose (1 hr for normal release, 2 hr for controlled release) was correlated significantly with the dose of morphine (r = 0.914, P < 0.001). There was a significant reduction in pain intensity (P < 0.05) and increase in pain relief (P < 0.001) after the dose of morphine administration, when compared with the predose score. One-half of the patients had mild and tolerable adverse effects. Patients were classified by mean pain relief between doses as having optimal, moderate, or poor pain control. No simple relationship was found between morphine plasma concentration and pain control. Morphine plus M6G concentrations in the "optimal control" group (751.2 +/- 194 nmol/L), however, were more than twice those found in the "moderate control" group (276.9 +/- 41.9 nmol/L) (P < 0.05), and no patient in the moderate control group had a morphine plus M6G concentration greater than 405 nmol/L. These results support the importance of M6G in morphine analgesia. For these hospitalized patients, there appeared to be a therapeutic range of morphine plus M6G plasma concentrations for optimal pain control with a lower limit of 400 nmol/L predose.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain

Ten patients who suffered from severe cancer-related pain participated in a randomised, double-blind and cross-over study to compare the effectiveness and acceptability of epidural and subcutaneous administration of morphine. The patients titrated themselves pain-free in 48 h using a patient controlled analgesia system. The median daily doses calculated from the consumption of the last 4-h study period were 372 mg for subcutaneous and 106 mg for epidural administration. The two modes of morphine administration turned out to be comparable in terms of both effectiveness and acceptability. Both treatments provided better pain relief with less adverse effects compared with the prestudy oral morphine treatment.

Topics: Adult; Aged; Analgesia, Patient-Controlled; Analgesics, Opioid; Blood Chemical Analysis; Cross-Over Studies; Double-Blind Method; Evaluation Studies as Topic; Female; Humans; Injections, Epidural; Injections, Subcutaneous; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Palliative Care

Plasma and cerebrospinal fluid (CSF) steady-state concentrations (Css) of morphine (M) and the main metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), were determined by high performance liquid chromatography (HPLC) in 21 cancer patients treated with chronic subcutaneous morphine infusion. There was a moderate, but statistically significant correlation between the daily dose of morphine and the concentrations of morphine, M3G and M6G in CSF. A poorer correlation to concentrations were seen in plasma. The mean +/- SEM CSF/plasma morphine concentration ratio was 0.36 +/- 0.07. In plasma and CSF, the mean steady state concentration of M3G but not M6G substantially exceeded that of morphine where the mean CSF M/M3G/M6G ratio was 1:15:0.5 (molar basis), and the mean plasma ratio was M/M3G/M6G 1:31:3 (molar basis). The mean M3G and M6G concentrations in CSF were approximately 8 and 10% of those found in plasma, but there was a wide interindividual variation. Plasma concentrations of both morphine glucuronides were positively correlated to serum creatinine. Neither pain intensity, evaluated by visual analogue scale (VAS), nor side effects showed any relationship to the CSF M3G concentrations, M3G/M or the M3G/M6G ratios. We conclude that during steady state subcutaneous administration of morphine, there is a large interindividual variation in plasma morphine with poor relationship to the daily administered dose. In CSF this correlation was more evident. Plasma and CSF concentrations of M3G and CSF concentrations of M6G correlated with administered morphine dose. There was an accumulation of both morphine glucuronides in patients with elevated serum creatinine. Measurements of morphine, M3G and M6G in CSF did not show any overt relationship to analgesia or side effects.

Topics: Aged; Aged, 80 and over; Analgesics, Opioid; Creatinine; Dose-Response Relationship, Drug; Female; Humans; Infusions, Parenteral; Kidney Function Tests; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain

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.

Topics: Administration, Oral; Adult; Aged; Chromatography, High Pressure Liquid; Delayed-Action Preparations; Dose-Response Relationship, Drug; Female; Humans; Linear Models; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain; Pain Measurement

Sustained-release morphine (MST) given by the rectal route was compared with oral MST in an open randomised cross-over trial in ten patients with cancer who received stable doses of MST. No significant difference was found in the areas under the curve of the concentration-time profiles (AUC) following oral or rectal administration for parent morphine. The AUCs determined for morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) after oral administration were approximately twice those obtained following rectal administration. The maximal concentration achieved was lower and the time to maximal concentration was longer following rectal administration for morphine, M6G and M3G. The relative mean arrival times following rectal administration were significantly longer for morphine and M3G but not for M6G. These findings suggest slower absorption but less first-pass metabolism of MST after rectal administration. No significant difference was noted between the oral and the rectal route in measurements on visual-analogue scales for pain or side effects. We recommend the rectal route as being suitable for MST administration when the oral route is no longer available. In changing from oral to rectal administration, the same dose and dose interval may be used, but dose adjustment may be needed.

Topics: Administration, Oral; Administration, Rectal; Adult; Aged; Aged, 80 and over; Delayed-Action Preparations; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain; Pain Measurement; Time Factors

The single-dose and steady state kinetics of morphine given as controlled-release tablets (30 mg every 12 h) and as a solution (15 mg every 6 h) have been compared in 11 cancer patients with chronic pain. The concentrations of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were analyzed by HPLC. There were no significant differences between the tablets and solution in the mean steady state concentrations of morphine, M3G or M6G. The tmax was 3.3 h for the tablets compared to 1.1 h for the solution. After giving the controlled-release tablets every 12 h there was a significantly higher fluctuation index of the morphine concentrations than after the solution. Urinary recovery at steady state was comparable between the two preparations, with averages of 57% and 47%, respectively. Thus, no major differences were found in the pharmacokinetics of morphine and its glucuronidated metabolites after 30 mg morphine as controlled-release tablets every 12 h or 15 mg of morphine solution every 6 h, except for a significantly longer tmax and greater fluctuation in morphine concentrations after the controlled-release tablets.

Topics: Adenocarcinoma; Administration, Oral; Aged; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Delayed-Action Preparations; Female; Half-Life; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Solutions; Tablets

Clinical studies on the effectiveness of morphine administered through different routes are contradictory. In order to further elucidate this point, the plasma concentrations of morphine and its 3- and 6-glucuronated metabolites were measured after short-term oral, sublabial, rectal and subcutaneous administration of the opiate. The bioavailability of free morphine and the 6-glucuronated active metabolite was comparable through the different routes. It was concluded that the choice of the route of morphine administration should be mainly guided by the needs of each individual patient.

Topics: Aged; Drug Administration Routes; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain

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

The feasibility and clinical implication of drug monitoring of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) need further investigation. This study aimed to determine what predicts serum concentrations of morphine in cancer patients receiving continuously intravenous morphine, the relationships between serum concentration of morphine/its metabolites and urinary concentrations, and the relation between morphine concentrations and with clinical outcomes.. We collected serum and urine samples from 24 patients with advanced cancer undergoing continuously intravenous morphine therapy. Serum samples were obtained at day one. Spot urine samples were collected once daily on three consecutive days. Pain and adverse drug events were assessed using the Korean version of MD Anderson Symptom Inventory.. A total of 96 samples (72 urine and 24 serum samples) were collected. Median dose of morphine was 82.0 mg/24 h. In a multivariate analysis, total daily morphine dose was the most significant predictors of both serum and urine concentration of morphine. Morphine, M6G, and M3G in serum and urine were statistical significantly correlated (correlation coefficient = 0.81, 0.44, 0.56; p values < 0.01, 0.03, 0.01, respectively).. Spot urine concentrations of morphine and its metabolites were highly correlated to those of serum. Total dose of daily morphine was related to both serum and urine concentration of morphine and its metabolites.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Republic of Korea

This study was undertaken to investigate the relationship between the plasma concentration of morphine, morphine-3-glucuronide and morphine-6-glucuronide and pain in cancer patients receiving oral morphine.. The trough value of plasma concentrations of morphine and its metabolites were measured by high performance liquid chromatography using an ultraviolet detector. Using this assay system, the plasma concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide in 26 cancer pain patients were measured and compared with pain intensity. The pain intensity was assessed at the time of blood sampling using the visual analog scale.. The trough value of morphine and morphine-6-glucuronide did not show a significant correlation with pain intensity by visual analog scale assessment, but morphine-3-glucuronide and the ratio of morphine-3-glucuronide/morphine showed a significantly positive correlation (r = 0.528, P = 0.006 and r = 0.671, P < 0.001, respectively). By dividing the group according to low (≤ median value) or high (> median value) VAS scores a significant difference was found between the two groups in morphine-3-glucuronide and the ratio of morphine-3-glucuronide/morphine (P = 0.045 and P = 0.007, respectively).. These results indicated that the level of morphine-3-glucuronide is related to the patient's perception of morphine effect, and the plasma concentration of morphine-3-glucuronide and the ratio of morphine-3-glucuronide/morphine indicated potency to assess clinical effect.

Topics: Administration, Oral; Aged; Analgesics, Opioid; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain; Pain Measurement

The aim of this study was to contrast protein binding of morphine and morphine-6 glucuronide in cord blood and children with adults and examine impact of chemotherapy and other factors. Morphine binding was measured in spiked samples from 18 adults and 18 neonates (cord blood), and compared with six children with cancer receiving morphine. The influence of the following was examined: Human serum albumin (HSA), alpha-1 acid glycoprotein (AAG), non-esterified fatty acids (NEFA); palmitic acid and oleic acid, pH, vincristine, methotrexate, 6-mercaptopurine and M6G. binding correlated with concentrations of albumin and alpha1 acid glycoprotein. In vitro, binding was not altered by vincristine, 6-mercaptopurine, methotrexate or M6G. Compared with HSA alone, AAG increased binding, palmitic acid reduced it and oleic acid had no effect. Binding was unaffected by pH in samples from patients. Morphine binding was influenced by concentrations of albumin, AAG and morphine itself, but not by age.

Topics: Adolescent; Adult; Age Factors; Analgesics, Opioid; Antineoplastic Agents; Blood Proteins; Child; Child, Preschool; Fatty Acids, Nonesterified; Female; Fetal Blood; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Infant, Newborn; Male; Mercaptopurine; Methotrexate; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Orosomucoid; Protein Binding; Serum Albumin; Vincristine

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

In patients with pain of malignant origin morphine may be administered in high and often increasing doses during extended periods of time. In patients with chronic pain of non-malignant origin morphine may be an important remedy, and in these cases the goal is to keep the morphine dose stable. The pharmacokinetic as well as the pharmacodynamic consequences of long-term morphine treatment with special reference to the two most important metabolites of morphine morphine-6-glucuronide (M-6-G) and morphine-3-glucuronide (M-3-G) remain to be settled.. Assessments for pain, sedation and other morphine induced side effects were made several times for 19 cancer patients treated with changing doses of oral sustained release (SR) morphine and twice for 17 non-cancer patients treated with stable doses of SR morphine. Blood samples were obtained simultaneously and analysed for contents of morphine, M-3-G and M-6-G by high-performance liquid chromatography (HPLC).. Significant correlations were found between the daily dose of SR morphine and plasma morphine (r = 0.469, p < 0.01), plasma M-6-G (r = 0.677, p < 0.01), and plasma M-3-G ((r = 0.827, p < 0.01), in the cancer patient group, but only between the daily dose of SR morphine and plasma M-3-G (0.662, p < 0.01) and plasma M-6-G (0.571, p < 0.01) in the non-cancer patient group. Normalised M-3-G/M and M-6-G/M ratios for the cancer patient group were independent of duration of treatment and daily dose of SR morphine. Likewise in the non-cancer patient group duration of treatment did not influence the metabolite ratios. Correlations between pain score and plasma morphine, M-6-G and M-6-G/M were weak in the cancer patient as well as in the non-cancer patient group making it impossible to draw any conclusion regarding the potential contributory analgesic effect of M-6-G. Dryness of the mouth was the most frequent adverse effect reported in the non-cancer as well as the cancer patient group. In the latter group patients complaining of dryness of the mouth had significantly higher plasma morphine and M-6-G concentrations than patients who did not suffer from this side effect. This difference persisted (or was close to significance) when excluding patients receiving antidepressants.. In the cancer patient group neither dose nor treatment period seems to influence morphine glucuronidation. Likewise in the non-cancer patient group receiving stable doses of morphine duration of treatment does not seem to influence morphine glucuronidation. Dryness of the mouth was positively correlated to high plasma concentrations of morphine and M-6-G.

Topics: Adult; Aged; Analgesics, Opioid; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain; Pain Measurement; Salivary Glands; Xerostomia

The feasibility of drug monitoring of serum concentrations of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) during chronic morphine therapy is not established. One important factor relevant to drug monitoring is to what extent morphine, M6G and M3G serum concentrations fluctuate during stable morphine treatment.. We included twenty-nine patients admitted to a palliative care unit receiving oral morphine (n = 19) or continuous subcutaneous (sc) morphine infusions (n = 10). Serum concentrations of morphine, M6G and M3G were obtained at the same time on four consecutive days. If readmitted, the patients were followed for another trial period. Day-to-day variations in serum concentrations and ratios were determined by estimating the percent coefficient of variation (CV = (mean/SD) x100).. The patients' median morphine doses were 90 (range; 20-1460) mg/24 h and 135 (range; 30-440) mg/24 h during oral and sc administration, respectively. Intraindividual fluctuations of serum concentrations estimated by median coefficients of day-to-day variation were in the oral group for morphine 46%, for M6G 25% and for M3G 18%. The median coefficients of variation were lower in patients receiving continuous sc morphine infusions (morphine 10%, M6G 13%, M3G 9%).. These findings indicate that serum concentrations of morphine and morphine metabolites fluctuate. The fluctuations found in our study are not explained by changes in morphine doses, administration of other drugs or by time for collection of blood samples. As expected the day-to-day variation was lower in patients receiving continuous sc morphine infusions compared with patients receiving oral morphine.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Palliative Care; Prospective Studies

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

Morphine, the recommended drug for the management of moderate to severe cancer pain, is metabolized predominantly to the glucuronides morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). The quantitative clinical importance of these metabolites following the administration of oral morphine is unclear. This study investigates the relationship between plasma concentrations of morphine (M), M6G, M3G and clinical effects in patients receiving sustained release oral morphine for cancer-related pain. Peak and trough plasma concentrations of morphine and its metabolites were determined by high-performance liquid chromatography (HPLC). At corresponding time points, pain [Visual Analogue Scales (VAS), Verbal Rating Scales (VRS), Pain Relief Scores (PRS)] and toxicity (VAS and VRS) were assessed. Renal and liver function tests were performed. Forty-six patients were included in the study. There was a significant correlation between dose and both peak and trough plasma M, M6G and M3G (r > 0.60, P < 0.001 for each). Differences between peak and trough M, M6G, M3G, M+M6G, M6G:M, M3G:M and M3G:M6G were all significant (P < 0.001 for each). Pain was generally well controlled in the group, with a median VAS of 15 mm at the peak blood sampling time point. The differences between peak and trough values for VAS pain, VAS nausea and VAS drowsiness were not statistically significant (P = 0.078, 0.45 and 0.099, respectively). There were no differences in peak or trough morphine and metabolite concentrations or ratios between patients with low (< median) or high pain scores. Similarly, there was no significant relationship between high and low plasma concentrations and clinical effect. This study did not identify a simple relationship between plasma concentrations of morphine, morphine metabolites or metabolite ratios and clinical effects in patients with cancer and pain who were receiving chronic oral morphine therapy. Although overall pain control was good, there was marked interpatient variability in the dose of morphine and the plasma concentrations necessary to achieve this degree of analgesia.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Central Nervous System Stimulants; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain; Pain Measurement

To provide additional pharmacokinetic evidence for the oral-to-parenteral relative potency ratio of 1:2 to 1:3 for chronic morphine use in a palliative care setting, we determined the plasma concentrations of morphine and its major metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), in hospitalized advanced cancer patients maintained on long-term oral or intravenous morphine. There were significant linear correlations between daily doses of morphine and plasma concentrations (molar base) of morphine, M3G and M6G for both routes of administration. The oral-to-intravenous relative ratios of the regression coefficients were 2.9 for morphine and 1.8 for morphine + M6G. The morphine kinetic variables were not significantly influenced by any hepato-renal biochemical markers. These results support the commonly used oral-to-intravenous relative potency ratio of 1:2 to 1:3 in patients with cancer pain receiving chronic morphine treatment.

Topics: Administration, Oral; Aged; Analgesics, Opioid; Chronic Disease; Dose-Response Relationship, Drug; Female; Humans; Infusions, Parenteral; Injections, Intravenous; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain; Palliative Care

The clinical importance of routine drug monitoring of serum concentrations of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) during chronic morphine therapy is not established. We measured morphine, M6G and M3G serum concentrations in cancer pain patients receiving oral (n = 263, median dose 80 mg/24 hours) or subcutaneous (sc) (n = 35, median dose 110 mg/24 hours) morphine. Regression analyses were performed to investigate if serum concentrations of morphine, M3G and M6G predicted pain intensity (Brief Pain Inventory), health-related quality-of-life variables (EORTC QLQ-C30) and cognitive function (Mini-Mental Score). Serum concentrations were also compared in patients categorized as morphine 'treatment successes' and 'treatment failures'. We observed that serum concentrations of morphine, M6G or M3G did not predict pain intensity, cognitive function, nausea or tiredness. 'Treatment failures' caused by nausea, tiredness, cognitive failure or constipation did not have statistically significant different morphine, M6G and M3G serum concentrations than patients classified as 'treatment successes'. In conclusion, this study did not observe any concentration-effect relationships of morphine, M3G or M6G with pain intensity, nausea, constipation, tiredness or cognitive failure in blood samples obtained during routine clinical drug monitoring in cancer patients. This result suggests that therapeutic drug monitoring as a routine tool during chronic morphine treatment has limited value for clinical decision making.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Cognition Disorders; Dose-Response Relationship, Drug; Drug Monitoring; Fatigue; Female; Humans; Infusions, Parenteral; Male; Middle Aged; Morphine; Morphine Derivatives; Nausea; Neoplasms; Pain; Pain Measurement; Palliative Care

Morphine-6-glucuronide (M-6-G) and morphine-3-glucuronide (M-3-G) are the two most important metabolites of morphine. Both are pharmacologically active, however, with different effects. M-6-G has been demonstrated capable of inducing anti-nociception and sedation, and M-3-G may induce behavioural excitation and possibly antagonise anti-nociception. Their impact on pharmacodynamics in patients in long-term treatment with oral morphine remains to be settled.. Forty-two cancer patients treated with oral sustained-release (SR) morphine were assessed for pain, sedation and other side effects related to morphine treatment. Blood samples were analysed for morphine, M-3-G and M-6-G by high-performance liquid chromatography (HPLC).. Significant correlations were found between the daily dose of SR morphine and plasma morphine (M) (r = 0.535, P < 0.001), plasma M-6-G (r = 0.868, P < 0.001) and plasma M-3-G (r = 0.865, P < 0.001). There was no relationship between plasma morphine, M-6-G, M-6-G/M and pain and sedation scores. Seventy-nine percent of the patients suffered from dryness of the mouth, which was the most frequent side effect observed. Patients in this group had higher plasma morphine and M-6-G concentrations than patients who did not suffer from this side effect.. The plasma concentrations of morphine and its metabolites, M-3-G and M-6-G, are significantly correlated to the daily dose of SR morphine. Although M-6-G has analgesic properties, no associations were found between pain and plasma morphine and morphine metabolites. This may be due to the multitudinous factors affecting the dose-effect relationship. Patients with dryness of the mouth had higher concentrations of morphine and M-6-G than patients without this side effect.

Topics: Adult; Aged; Analgesics, Opioid; Delayed-Action Preparations; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain

To investigate the serum concentrations of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) and the relationships between serum concentrations and clinical effects associated with start of morphine treatment in cancer patients.. Forty patients with malignant disease and intolerable pain on weak opioids (codeine/dextropropoxyphen) were included. After a wash-out period, titration with immediate-release (IR) morphine was started. When a stable dose was achieved, the morphine treatment was changed to slow-release (SR) morphine in equivalent daily dosages. Clinical data and serum concentrations of morphine, M3G and M6G were obtained at the end of the IR and SR morphine treatment periods.. The mean trough serum morphine concentration associated with pain relief was 66 nmol/l. The corresponding mean concentrations of M6G and M3G were 257 nmol/l and 1943 nmol/l, respectively. Morphine serum trough concentrations showed a 33-fold variation. Seventy percent of the variation was predicted in a model including age, daily morphine dose and M6G/morphine ratio as independent variables. No associations were observed between side effects and serum concentrations of morphine and its metabolites.. In this study, a mean serum trough morphine concentration of 66 nmol/l was associated with satisfactory pain relief when disease progression required an increase in intensity of pain therapy from step II to step III in the World Health Organization pain ladder. An increased ratio of M6G to morphine serum concentrations predicted lower effective serum morphine concentrations at the time of satisfactory pain relief. This observation supports that M6G contributes to the pain control produced by oral morphine in patients with pain caused by malignant disease.

Topics: Adult; Age Factors; Aged; Analgesics, Opioid; Delayed-Action Preparations; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain; Palliative Care; Time Factors

Twenty-three patients treated with intracerebroventricular (ICV) morphine in this study not only obtained excellent pain relief without rapid increases in dose, but also experienced a reduction in morphine-related side effects. By 24 h after initiation of ICV morphine, the mean trough cerebrospinal fluid (CSF) morphine concentration (approximately 20 microM) was 50-fold higher than the baseline concentration (approximately 0.4 microM), and the CSF concentration of morphine-6-glucuronide (M6G) was undetectable (<0.01 microM). The mean CSF concentration of morphine-3-glucuronide (M3G) decreased 90%, from a baseline concentration of 1 microM to 0.1 microM by Day 7 postventriculostomy. Thereafter, the mean trough CSF M3G concentration remained relatively constant while ICV morphine was continued, although the concomitant M3G plasma concentrations were undetectable (<0.01 microM). The large increase in the CSF morphine concentration in patients receiving ICV morphine strongly suggests that increased CSF morphine levels are unlikely to be the primary cause of analgesic tolerance or undesirable excitatory side effects (hyperalgesia, myoclonus, seizures) experienced by some patients receiving chronic large-dose systemic morphine.. After initiation of intracerebroventricular morphine, cancer patients experienced excellent pain relief. Although the mean morphine concentration in cerebrospinal fluid increased 50-fold relative to preventriculostomy levels, rapid dose increases did not occur, which suggests that increased cerebrospinal fluid morphine levels are unlikely to be the main cause of analgesic tolerance.

Topics: Administration, Oral; Adult; Aged; Analgesics, Opioid; Female; Humans; Individuality; Injections, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain

Intracerebroventricular (ICV) morphine administration is effective for the management of refractory cancer pain. Recent preclinical observations of acute depletion of the major endogenous intracellular antioxidant glutathione (GSH) in brain and peripheral organs after ICV morphine in rodents led us to apply microchemical methods to profile the neurochemical effects of ICV morphine in three patients treated for intractable cancer pain. Assessment of morphine, morphine-6-glucuronide, and a panel of endogenous compounds and metabolites in ventricular and cisternal cerebrospinal fluid (CSF) demonstrated transient, postdose increases in morphine and morphine-6-glucuronide in ventricular and cistemal CSF, accompanied by acute decreases in CSF GSH levels. Significant changes were also observed in the CSF levels of 4-hydroxybenzoic acid, homovanillic acid, 5-hydroxyphenyllactic acid, and uric acid. These pilot clinical observations of acute central GSH depletion after ICV morphine suggest a novel mechanism for neuropsychiatric toxicity or preclinical findings, such as hyperalgesia or increased motoric activity observed in nonhuman species after central morphine administration. Because ICV morphine is a mainstay of treatment for refractory cancer pain, elucidation of a mechanism's (or mechanisms') mediating a potential pro-oxidant state in the central nervous system induced by ICV morphine is important.. We observed acute decreases in glutathione levels in cerebrospinal fluid sampled from patients after intracerebroventricular doses of morphine for intractable cancer pain. Such doses may, by depleting the antioxidant glutathione, render the central nervous system vulnerable to damage from oxidative stress.

Topics: Chromatography, High Pressure Liquid; Glutathione; Humans; Injections, Intraventricular; Morphine; Morphine Derivatives; Neoplasms; Pain, Intractable

The active morphine metabolite, morphine-6-glucuronide (M-6-G), may contribute to both the analgesia and the adverse effects observed during morphine (MOR) therapy. To evaluate the relationship between M-6-G and adverse effects, we measured steady-state plasma concentrations of MOR and M-6-G and concurrently noted the presence or absence of moderate to severe cognitive impairment or myoclonus in 109 cancer patients who were receiving either oral (n = 71) or parenteral (n = 38) morphine. MOR and M-6-G plasma concentrations were determined by HPLC with electrochemical detection. The presence of cognitive impairment or myoclonus was analyzed in relation to molar M-6-G/MOR ratio, age, morphine dose, the use of other centrally acting drugs, renal function (blood urea nitrogen (BUN) and serum creatinine), hepatic function (serum bilirubin, serum glutamic oxalacetic transaminase (SGOT), and alkaline phosphotase) and serum lactate dehydrogenase (LDH). The patient population consisted of 60 women and 49 men. The mean age was 51.5 years (range: 10-85 years). The mean morphine dose (total dose-prior 48 h) was 486 mg (range: 40-4800 mg) for the oral group and 931 mg (range: (10-9062 mg) for the parenteral group. The mean molar M-6-G/MOR ratios were 6.1 (SD: 18.2; range: 0.01-153.3) for the oral treatment group and 2.7 (SD: 4.16; range: 0.05-23.8) for the parenteral treatment group. Overall, the M-6-G/MOR ratio demonstrated a moderate but significant correlation with BUN (r = 0.4; P < 0.001) and creatinine (r = 0.45; P < 0.001) levels, but not with the other clinical variables examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Cognition Disorders; Drug Administration Routes; Evaluation Studies as Topic; Female; Health Surveys; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Myoclonus; Neoplasms; Pain; Regression Analysis

A rapid and selective assay of morphine and its 3- and 6-glucuronides in serum, based on high-performance liquid chromatography-electrospray mass spectrometry has been developed. The analytes and the internal standard, codeine or naltrexone, were subjected to solid-phase extraction, using ethyl solid-phase extraction columns, prior to chromatography. A reversed-phase column and a gradient mobile phase consisting of water and methanol were used. The mass spectrometer was operated in the selected-ion monitoring mode. The following ions were used: m/z 286 for morphine, m/z 300 for codeine, m/z 342 for naltrexone, and m/z 462 for morphine 3- and 6-glucuronides. The limit of quantitation observed with this method was 10 ng/ml morphine, 50 ng/ml morphine-6-glucuronide and 100 ng/ml morphine-3-glucuronide. The present method proved useful for the determination of serum levels of the parent drug and its metabolites in pain patients, heroin addicts and in morphine-treated mice.

Topics: Animals; Calibration; Chromatography, High Pressure Liquid; Heroin Dependence; Humans; Male; Mass Spectrometry; Mice; Mice, Inbred C57BL; Morphine; Morphine Derivatives; Neoplasms; Reference Standards

In 34 cancer patients treated with chronic slow-release oral morphine, plasma and cerebrospinal fluid (CSF) minimum steady-state concentrations of morphine (M), morphine-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.

Topics: Administration, Oral; Analgesics, Opioid; Delayed-Action Preparations; Dose-Response Relationship, Drug; Humans; Lumbosacral Region; Morphine; Morphine Derivatives; Neoplasms; Pain

Recent studies have suggested that morphine-3-glucuronide (M3G) may antagonize the analgesic effects of morphine and morphine-6-glucuronide (M6G). To investigate this hypothesis, steady-state concentrations of morphine, M6G and M3G in serum and cerebrospinal fluid (CSF) were measured in 11 patients receiving chronic morphine therapy (9 orally and 2 subcutaneously) for treatment of cancer-related pain. All patients appeared to have morphine-resistant pain and had elected to proceed to intrathecal bupivacaine or percutaneous cordotomy. Morphine, M6G and M3G concentrations were measured by high-performance liquid chromatography. The concentrations (median and range) for morphine, M6G and M3G in serum were 193 (14-1086) nmol/l, 847 (210-4113) nmol/l and 4553 (1324-24035) nmol/l, respectively, while in CSF concentrations of morphine, M6G and M3G were 200 (21-1461) nmol/l, 115 (30-427) nmol/l and 719 (249-3252) nmol/l, respectively. Median molar ratios of M6G/morphine and M3G/morphine in serum were 3.79 and 22.1, respectively, while in CSF the same ratios were 0.42 and 2.39, respectively. Median molar ratios of M3G/M6G in serum and CSF were 5.84 and 6.61, respectively. The median molar ratios for CSF/serum distribution of morphine, M6G and M3G were 1.23, 0.12 and 0.14, respectively. Thus, despite their relatively poor ability to penetrate into the CSF, the high serum concentrations of M6G and M3G resulted in substantial concentrations of these metabolites in the CSF. Nevertheless, M3G/M6G ratios in our morphine-resistant patients were similar to published values in patients with well-controlled pain, suggesting that the hypothesis that M3G plays a major role in morphine-resistance is not correct.

Topics: Adult; Aged; Chromatography, High Pressure Liquid; Drug Resistance; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain

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

1. The pharmacokinetics, cardio-respiratory effects and analgesic effects of intravenous morphine-6-glucuronide were studied in 20 cancer patients with pain. Four different dose levels (0.5, 1, 2, and 4 mg 70 kg-1) were studied. Plasma concentrations of morphine-6-glucuronide were measured for 12 h after dosing. Pulse rate, respiratory rate and blood pressure were monitored, and pain relief was measured using two rating scales and a visual analogue scale. 2. The mean elimination half-life (+/- s.d.) of morphine-6-glucuronide was 3.2 +/- 1.6 h. The mean AUC standardised to a dose of 1 mg 70 kg-1 was 390 +/- 263 nmol l-1 h. Mean morphine-6-glucuronide clearance was 96 +/- 38 ml min-1. There was a direct relationship between morphine-6-glucuronide plasma clearance and calculated creatinine clearance (r = 0.81, P less than 0.001). 38 +/- 22% of the dose of morphine-6-glucuronide was recovered unchanged in the urine in 24 h. No morphine or morphine-3-glucuronide was detected in the plasma or urine of any patient after morphine-6-glucuronide treatment. 3. Morphine-6-glucuronide exerted a useful analgesic effect in 17/19 assessable patients for periods ranging between 2 and 24 h. No correlation was observed between dose or plasma morphine-6-glucuronide concentrations, and duration or degree of analgesia. No clinically significant changes in cardio-respiratory parameters were observed. No patients reported sedation or euphoria. Nausea and vomiting were notably absent in all cases. 4. Morphine-6-glucuronide is an effective and well-tolerated analgesic. It is likely that the majority of the therapeutic benefit of morphine is mediated by morphine-6-glucuronide.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Analgesics; Blood Pressure; Half-Life; Humans; Male; Middle Aged; Morphine Derivatives; Neoplasms; Pain Measurement; Pain, Intractable; Respiration

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

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

Topics: Humans; Injections, Spinal; Morphine Derivatives; Neoplasms; Pain

Morphine-6-glucuronide (M-6-G) is an active metabolite that may contribute to the clinical effects produced by systemic administration of morphine. To help clarify the extent to which M-6-G may cross the blood-brain barrier and exert effects, we employed high-performance liquid chromatography with electrochemical detection to measure the concentrations of M-6-G and morphine in the plasma and either ventricular (three patients) or lumbar (eight patients) CSF of cancer patients receiving chronic morphine therapy. The mean ratio of morphine in ventricular CSF:morphine in plasma was 0.71; the same ratio for M-6-G was only 0.077. The average molar ratio of M-6-G: morphine in ventricular CSF was 0.207, and the average molar ratio in plasma was 1.89. Although sampling problems render the lumbar CSF results less reliable, they were very similar. Thus, plasma contained approximately twice as much M-6-G as morphine, whereas CSF contained only one-fifth to one-third as much. These data confirm that M-6-G in plasma is distributed into CSF, but to a far lesser extent than morphine. They help explain animal data demonstrating much higher potency of M-6-G on administration into CSF than systemic administration and indicate that the degree to which M-6-G contributes to morphine effects in humans remains an unresolved question.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain

A convenient and sensitive analytical method for determination of plasma morphine and its metabolites in cancer patients was established using HPLC with a column-switching technique. Sample plasma which has been deproteinized with trichloroacetic acid is injected onto a precolumn, then the compounds of interest are preferentially introduced into the analytical column for separation and detection after washing out the unnecessary plasma components from the precolumn. Detection was simultaneously performed with coulometry for unchanged morphine and morphine-6-glucuronide and with UV analysis for morphine-3-glucuronide. Analytical recoveries were greater than 99% for these compounds, and the averaged coefficients of within-day or between-day variation did not exceed 5.5%. Detection limits were 0.2 ng/mL for morphine, 0.5 ng/mL for morphine-6-glucuronide, and 10 ng/mL for morphine-3-glucuronide. Correlation between the previously reported solid extraction method and this method was satisfactory in plasma samples after administration of morphine.

Topics: Chromatography, High Pressure Liquid; Humans; Morphine; Morphine Derivatives; Neoplasms; Palliative Care

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

One hundred fifty-one patients with chronic cancer pain were studied during chronic treatment with oral morphine. Plasma concentrations of morphine and metabolites (M3G and M6G) were measured. The ratio of plasma morphine to metabolites was not affected by dose. Generalized linear interactive modeling analysis using morphine dose, age, sex, renal and hepatic dysfunction, and concomitant medication as explanatory variables accounted for 70% of the variance in plasma concentrations of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Increasing morphine dose was a significant factor for increased plasma concentrations of morphine, M3G, and M6G. Other significant factors were: age greater than 70 years (increased M3G and M6G plasma concentrations), plasma creatinine greater than 150 mumol/L (increased M3G and M6G plasma concentrations), male sex (decreased morphine and M6G plasma concentrations), raised creatinine plus coadministration of tricyclic antidepressants (increased M3G plasma concentrations), ranitidine (increased morphine plasma concentrations), and raised creatinine plus coadministration of ranitidine (increased M6G plasma concentrations).

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain; Sex Factors

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

The kinetics of morphine and formation of the main metabolite, morphine-3-glucuronide (M3G) after single and intravenous doses of morphine were studied in six cancer patients and compared with the formation rate of M3G in vitro in microsomes isolated from liver biopsies obtained from the same patients at palliative laparotomy. The results showed that high formation rates of M3G in vitro in microsomes isolated from liver biopsies were associated both with high apparent oral clearance values and high M3G/morphine AUC (area under the concentration vs time curve) ratios as measured in vivo in the same patients. In accordance with previous results marked interindividual differences were seen in the kinetics of morphine; the oral bioavailability varied between 30 and 69% and the systemic plasma clearance between 18.6 and 34.0 ml min-1 kg-1. This variation correlated with the variation in morphine metabolism as assessed in vitro. In vivo, a high M3G/morphine AUC ratio predicted a high oral clearance. Hepatic UDP-glucuronyl transferase activity is thus an important determinant of the in vivo kinetics of orally administered morphine.

Topics: Administration, Oral; Aged; Glucuronates; Half-Life; Humans; In Vitro Techniques; Injections, Intravenous; Kinetics; Liver; Male; Microsomes, Liver; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain

Topics: Chromatography, High Pressure Liquid; Humans; Morphine; Morphine Derivatives; Neoplasms; Reference Values