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Albert Dahan - One of the best experts on this subject based on the ideXlab platform.

  • Influence of Morbid Obesity on the Pharmacokinetics of Morphine, Morphine-3-Glucuronide, and Morphine-6-Glucuronide.
    Clinical Pharmacokinectics, 2017
    Co-Authors: Sjoerd De Hoogd, Simone Van Kralingen, Michael M. W. Coughtrie, Pyry A. J. Välitalo, Eric P A Van Dongen, Albert Dahan, Bert Van Ramshorst, Catherijne A J Knibbe
    Abstract:

    Introduction Obesity is associated with many pathophysiological changes that may result in altered drug metabolism. The aim of this study is to investigate the influence of obesity on the pharmacokinetics of Morphine, Morphine-3-Glucuronide (M3G), and Morphine-6-Glucuronide (M6G) through a combined analysis in morbidly obese patients and non-obese healthy volunteers.

  • Influence of Morbid Obesity on the Pharmacokinetics of Morphine, Morphine-3-Glucuronide, and Morphine-6-Glucuronide
    2017
    Co-Authors: Hoogd, De S., Albert Dahan, Välitalo P.a.j., Kralingen, Van S., Coughtrie M.m.w., Dongen, Van E.p.a., Ramshorst, Van B., Knibbe C.a.j.
    Abstract:

    Obesity is associated with many pathophysiological changes that may result in altered drug metabolism. The aim of this study is to investigate the influence of obesity on the pharmacokinetics of Morphine, Morphine-3-Glucuronide (M3G), and Morphine-6-Glucuronide (M6G) through a combined analysis in morbidly obese patients and non-obese healthy volunteers.\n for 1 h. Population pharmacokinetic modeling was performed using NONMEM 7.2.\nIn morbidly obese patients, elimination clearance of M3G and M6G was decreased substantially compared with healthy volunteers (p 

  • a randomised controlled trial on the efficacy and side effect profile nausea vomiting sedation of Morphine 6 Glucuronide versus Morphine for post operative pain relief after major abdominal surgery
    European Journal of Pain, 2011
    Co-Authors: Alexander R Binning, Terry Smith, Krzysztof Przesmycki, Piotr Sowinski, Lachlan M M Morrison, Paul Marcus, James P Lees, Albert Dahan
    Abstract:

    Morphine is the first choice of treatment of severe post-operative pain, despite the occurrence of often discomforting (post-operative nausea or vomiting (PONV)) and sometimes dangerous (sedation, respiratory depression) side effects. Literature data indicate that Morphine's active metabolite, Morphine-6-Glucuronide (M6G), is a powerful analgesic with a possibly more favourable side-effect profile. In this multi-centre randomised controlled clinical trial patients undergoing major abdominal surgery were randomised to M6G or Morphine treatment. Treatment started 30-60 min prior to the end of surgery and was continued postoperatively, after patients were titrated to comfort, via patient-controlled analgesia (PCA) for 24-48 h. Pain intensity, nausea, vomiting and sedation scores were collected at regular intervals. In the study 268 patients were randomised to M6G and 249 to Morphine. Withdrawal due to insufficient pain relief occurred predominantly just after surgery and was higher in the M6G group (16.8%) than in the Morphine group (8.8%), suggesting a slower onset of analgesia for M6G compared to Morphine. Subjects who continued on PCA remained equi-analgesic throughout the study. During the first 24h, nausea levels showed a 27% difference in favour of M6G which narrowly failed to reach statistical significance (P=0.052). Sub-analysis showed a significant reduction in nausea levels in females on M6G (30% difference, P=0.034). In all patients, similar reductions of 30-35% were observed in anti-emetic use, vomiting, PONV (a combined measure of nausea and vomiting) in favour of M6G, persisting for the first 24h postoperatively. Reductions in sedation were observed in the first 4h post-operative period for M6G patients.

  • Arterial and venous pharmacokinetics of Morphine-6-Glucuronide and impact of sample site on pharmacodynamic parameter estimates.
    Anesthesia & Analgesia, 2010
    Co-Authors: Erik Olofsen, René Mooren, Eveline Van Dorp, Terry Smith, Albert Dahan, Jan Den Hartigh, Leon Aarts, Elise Sarton
    Abstract:

    BACKGROUND: In pharmacokinetic-pharmacodynamic modeling studies, venous plasma samples are sometimes used to derive pharmacodynamic model parameters. In the current study the extent of arteriovenous concentration differences of Morphine-6-Glucuronide (M6G) was quantified. We used simulation studies to estimate possible biases in pharmacodynamic model parameters when linking venous versus arterial concentrations to effect. METHODS: Seventeen healthy volunteers received an IV 90-second infusion of 0.3 mg/kg Morphine-6-Glucuronide (M6G). Arterial and venous blood samples, from the radial artery and cubital vein, respectively, were obtained. An extended pharmacokinetic model was constructed linking arterial and venous compartments. The extent of bias in pharmacodynamic model parameter estimates was explored in simulation studies with NONMEM, simulating M6G effect using first-order effect-compartment-inhibitory sigmoid E MAX models. M6G effect was simulated at various values for the arterial blood-effect-site equilibration half-lifes (t½k EO ), ranging from 5 to 240 minutes. RESULTS: Arteriovenous concentration differences were apparent, with higher arterial plasma concentrations just after infusion, whereas at later times (>60 minutes) venous M6G concentrations exceeded arterial concentrations. The extended pharmacokinetic model adequately described the data and consisted of 3 arterial compartments, 1 central venous compartment, and 1 peripheral venous compartment. The simulation studies revealed large biases in model parameters derived from venous concentration data. The biases were dependent on the value of t½k EO . Assuming that the true values of M6G t½k EO range from 120 to 240 minutes (depending on the end point measured), we would have underestimated t½k EO by 30%, whereas the potency parameter would have been overestimated by about 40%, when using venous plasma samples. CONCLUSIONS: Because of large arteriovenous differences in M6G plasma, concentration biases in pharmacodynamic model parameters will occur when linking venous concentration to effect, using a traditional effect-compartment model.

  • naloxone reversal of Morphine and Morphine 6 Glucuronide induced respiratory depression in healthy volunteers a mechanism based pharmacokinetic pharmacodynamic modeling study
    Anesthesiology, 2010
    Co-Authors: Erik Olofsen, Terry Smith, Albert Dahan, Leon Aarts, Eveline L A Van Dorp, Luc J Teppema, Elise Sarton
    Abstract:

    Background Opioid-induced respiratory depression is antagonized effectively by the competitive opioid receptor antagonist naloxone. However, to fully understand the complex opioid agonist-antagonist interaction, the effects of various naloxone doses on Morphine and Morphine-6-Glucuronide (M6G)-induced respiratory depression were studied in healthy volunteers. Methods Twenty-four subjects received 0.15 mg/kg Morphine intravenously at t = 0 followed by placebo, 200 or 400 microg naloxone at t = 30 min. Thirty-two subjects received 0.3 mg/kg M6G intravenously at t = 0 followed by placebo, 25, 100, or 400 microg naloxone at t = 55 min. There were a total of 8 subjects per treatment group. Respiration was measured on a breath-to-breath basis at constant end-tidal Pco2. A mechanism-based pharmacokinetic-pharmacodynamic model consisting of a part describing biophase equilibration and a part describing receptor association-dissociation kinetics was used to analyze the data. Results Naloxone reversal of M6G-induced respiratory depression developed more slowly than reversal of the respiratory effect of Morphine. A simulation study revealed that this was related to the slower receptor association-dissociation kinetics of M6G (koff M6G = 0.0327 +/- 0.00455 min versus Morphine 0.138 +/- 0.0148 min; values are typical +/-SE). Duration of naloxone reversal was longer for M6G. This was related to the three- to fourfold greater potency of naloxone as an antagonist against M6G compared with Morphine. Increasing the naloxone dose had no effect on the speed of reversal, but it did extend reversal duration. Conclusions Naloxone reversal of the opioid effect is dependent on the receptor association-dissociation kinetics of the opioid that needs reversal with respect to the rate of reversal. The pharmacodynamics of naloxone determines reversal magnitude and duration.

Kathleen M Foley - One of the best experts on this subject based on the ideXlab platform.

  • Morphine 6 Glucuronide concentrations and opioid related side effects a survey in cancer patients
    Pain, 1995
    Co-Authors: Paul J Tiseo, Kathleen M Foley, Russell K. Portenoy, Charles E Inturrisi, Howard T Thaler, Jeanne Lapin
    Abstract:

    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)

  • the metabolite Morphine 6 Glucuronide contributes to the analgesia produced by Morphine infusion in patients with pain and normal renal function
    Clinical Pharmacology & Therapeutics, 1992
    Co-Authors: Kathleen M Foley, Russell K. Portenoy, Charles E Inturrisi, Howard T Thaler, Hamutal Friedlanderklar
    Abstract:

    Morphine-6-Glucuronide is a metabolite of Morphine that binds to the opioid receptor and is analgesic in animals and humans. Although accumulation of Morphine-6-Glucuronide in patients with renal insufficiency has been implicated in Morphine toxicity, the contribution of the metabolite to Morphine analgesia in patients with normal renal function has not been established. To evaluate this contribution, we repeatedly sampled blood and assessed effects during and after a loading infusion with Morphine (mean duration, 168 minutes) in 14 patients with chronic pain, all of whom had normal serum creatinine levels. Plasma concentrations of Morphine and Morphine-6-Glucuronide were assayed by use of high performance liquid chromatography with electrochemical detection. Patients were divided into three groups on the basis of the molar concentration ratio of Morphine-6-Glucuronide:Morphine from the start of the infusion until 240 minutes later: Group 1 (n = 5) had a mean ratio greater than or equal to 0.7:1; group 2 (n = 4) had a mean ratio less than 0.7:1 but greater than or equal to 0.4:1; and group 3 (n = 5) had a mean ratio less than 0.4:1. Time-effect plots revealed that average and peak relief were greater in group 1 than group 2 and greater in group 2 than group 3. For all patients, mean Morphine-6-Glucuronide:Morphine ratio throughout the study was significantly correlated with mean pain relief (r = 0.611, p less than 0.02). These data suggest that Morphine-6-Glucuronide contributes to Morphine analgesia in patients with normal renal function. The role of the metabolite should be considered when Morphine is used clinically.

  • plasma Morphine and Morphine 6 Glucuronide during chronic Morphine therapy for cancer pain plasma profiles steady state concentrations and the consequences of renal failure
    Pain, 1991
    Co-Authors: Russell K. Portenoy, Daniel J. Cerbone, Kathleen M Foley, E Khan, Mary Layman, James Stulman, Jean Adelhardt, Charles E Inturrisi
    Abstract:

    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.

  • chronic Morphine therapy for cancer pain plasma and cerebrospinal fluid Morphine and Morphine 6 Glucuronide concentrations
    Neurology, 1991
    Co-Authors: Russell K. Portenoy, Daniel J. Cerbone, Kathleen M Foley, Howard T Thaler, E Khan, Mary Layman, Jeanne Lapin, M G Malkin, Charles E Inturrisi
    Abstract:

    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.

  • Chronic nausea and Morphine-6-Glucuronide.
    Journal of Pain and Symptom Management, 1991
    Co-Authors: Neil A. Hagen, Daniel J. Cerbone, Kathleen M Foley, Russell K. Portenoy, Charles E Inturrisi
    Abstract:

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

Charles E Inturrisi - One of the best experts on this subject based on the ideXlab platform.

  • Morphine 6 Glucuronide concentrations and opioid related side effects a survey in cancer patients
    Pain, 1995
    Co-Authors: Paul J Tiseo, Kathleen M Foley, Russell K. Portenoy, Charles E Inturrisi, Howard T Thaler, Jeanne Lapin
    Abstract:

    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)

  • the metabolite Morphine 6 Glucuronide contributes to the analgesia produced by Morphine infusion in patients with pain and normal renal function
    Clinical Pharmacology & Therapeutics, 1992
    Co-Authors: Kathleen M Foley, Russell K. Portenoy, Charles E Inturrisi, Howard T Thaler, Hamutal Friedlanderklar
    Abstract:

    Morphine-6-Glucuronide is a metabolite of Morphine that binds to the opioid receptor and is analgesic in animals and humans. Although accumulation of Morphine-6-Glucuronide in patients with renal insufficiency has been implicated in Morphine toxicity, the contribution of the metabolite to Morphine analgesia in patients with normal renal function has not been established. To evaluate this contribution, we repeatedly sampled blood and assessed effects during and after a loading infusion with Morphine (mean duration, 168 minutes) in 14 patients with chronic pain, all of whom had normal serum creatinine levels. Plasma concentrations of Morphine and Morphine-6-Glucuronide were assayed by use of high performance liquid chromatography with electrochemical detection. Patients were divided into three groups on the basis of the molar concentration ratio of Morphine-6-Glucuronide:Morphine from the start of the infusion until 240 minutes later: Group 1 (n = 5) had a mean ratio greater than or equal to 0.7:1; group 2 (n = 4) had a mean ratio less than 0.7:1 but greater than or equal to 0.4:1; and group 3 (n = 5) had a mean ratio less than 0.4:1. Time-effect plots revealed that average and peak relief were greater in group 1 than group 2 and greater in group 2 than group 3. For all patients, mean Morphine-6-Glucuronide:Morphine ratio throughout the study was significantly correlated with mean pain relief (r = 0.611, p less than 0.02). These data suggest that Morphine-6-Glucuronide contributes to Morphine analgesia in patients with normal renal function. The role of the metabolite should be considered when Morphine is used clinically.

  • plasma Morphine and Morphine 6 Glucuronide during chronic Morphine therapy for cancer pain plasma profiles steady state concentrations and the consequences of renal failure
    Pain, 1991
    Co-Authors: Russell K. Portenoy, Daniel J. Cerbone, Kathleen M Foley, E Khan, Mary Layman, James Stulman, Jean Adelhardt, Charles E Inturrisi
    Abstract:

    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.

  • chronic Morphine therapy for cancer pain plasma and cerebrospinal fluid Morphine and Morphine 6 Glucuronide concentrations
    Neurology, 1991
    Co-Authors: Russell K. Portenoy, Daniel J. Cerbone, Kathleen M Foley, Howard T Thaler, E Khan, Mary Layman, Jeanne Lapin, M G Malkin, Charles E Inturrisi
    Abstract:

    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.

  • Chronic nausea and Morphine-6-Glucuronide.
    Journal of Pain and Symptom Management, 1991
    Co-Authors: Neil A. Hagen, Daniel J. Cerbone, Kathleen M Foley, Russell K. Portenoy, Charles E Inturrisi
    Abstract:

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

Russell K. Portenoy - One of the best experts on this subject based on the ideXlab platform.

  • Morphine 6 Glucuronide concentrations and opioid related side effects a survey in cancer patients
    Pain, 1995
    Co-Authors: Paul J Tiseo, Kathleen M Foley, Russell K. Portenoy, Charles E Inturrisi, Howard T Thaler, Jeanne Lapin
    Abstract:

    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)

  • the metabolite Morphine 6 Glucuronide contributes to the analgesia produced by Morphine infusion in patients with pain and normal renal function
    Clinical Pharmacology & Therapeutics, 1992
    Co-Authors: Kathleen M Foley, Russell K. Portenoy, Charles E Inturrisi, Howard T Thaler, Hamutal Friedlanderklar
    Abstract:

    Morphine-6-Glucuronide is a metabolite of Morphine that binds to the opioid receptor and is analgesic in animals and humans. Although accumulation of Morphine-6-Glucuronide in patients with renal insufficiency has been implicated in Morphine toxicity, the contribution of the metabolite to Morphine analgesia in patients with normal renal function has not been established. To evaluate this contribution, we repeatedly sampled blood and assessed effects during and after a loading infusion with Morphine (mean duration, 168 minutes) in 14 patients with chronic pain, all of whom had normal serum creatinine levels. Plasma concentrations of Morphine and Morphine-6-Glucuronide were assayed by use of high performance liquid chromatography with electrochemical detection. Patients were divided into three groups on the basis of the molar concentration ratio of Morphine-6-Glucuronide:Morphine from the start of the infusion until 240 minutes later: Group 1 (n = 5) had a mean ratio greater than or equal to 0.7:1; group 2 (n = 4) had a mean ratio less than 0.7:1 but greater than or equal to 0.4:1; and group 3 (n = 5) had a mean ratio less than 0.4:1. Time-effect plots revealed that average and peak relief were greater in group 1 than group 2 and greater in group 2 than group 3. For all patients, mean Morphine-6-Glucuronide:Morphine ratio throughout the study was significantly correlated with mean pain relief (r = 0.611, p less than 0.02). These data suggest that Morphine-6-Glucuronide contributes to Morphine analgesia in patients with normal renal function. The role of the metabolite should be considered when Morphine is used clinically.

  • plasma Morphine and Morphine 6 Glucuronide during chronic Morphine therapy for cancer pain plasma profiles steady state concentrations and the consequences of renal failure
    Pain, 1991
    Co-Authors: Russell K. Portenoy, Daniel J. Cerbone, Kathleen M Foley, E Khan, Mary Layman, James Stulman, Jean Adelhardt, Charles E Inturrisi
    Abstract:

    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.

  • chronic Morphine therapy for cancer pain plasma and cerebrospinal fluid Morphine and Morphine 6 Glucuronide concentrations
    Neurology, 1991
    Co-Authors: Russell K. Portenoy, Daniel J. Cerbone, Kathleen M Foley, Howard T Thaler, E Khan, Mary Layman, Jeanne Lapin, M G Malkin, Charles E Inturrisi
    Abstract:

    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.

  • Chronic nausea and Morphine-6-Glucuronide.
    Journal of Pain and Symptom Management, 1991
    Co-Authors: Neil A. Hagen, Daniel J. Cerbone, Kathleen M Foley, Russell K. Portenoy, Charles E Inturrisi
    Abstract:

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

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  • analgesic effects of Morphine and Morphine 6 Glucuronide in a transcutaneous electrical pain model in healthy volunteers
    Clinical Pharmacology & Therapeutics, 2003
    Co-Authors: Carsten Skarke, Gerd Geisslinger, Jutta Darimont, Helmut Schmidt, Jörn Lötsch
    Abstract:

    Objective Our objective was to quantify the extent and time course of the effects of Morphine-6-Glucuronide and Morphine on pain threshold, pain tolerance, pupil diameter, and side effects. Methods In a double-blind, placebo-controlled, randomized, 3-way crossover study, 12 healthy volunteers (6 men and 6 women) received 63 to 112 mg of Morphine-6-Glucuronide or 26 to 66 mg of Morphine as an intravenous bolus, followed by an infusion of the same medication for 1.8 to 6.4 hours. Analgesia was assessed every 30 minutes for up to 16 hours by means of transcutaneous electrical stimulation (sine wave, 5 Hz; intensity, 0–9.99 mA). Pupil diameter and side effects were recorded concomitantly. Results At the administered doses, Morphine-6-Glucuronide and Morphine had comparable effects on pain tolerance, pupil diameter, and side effects. The delay between the time course of the plasma concentrations and the time course of the effects was longer for Morphine-6-Glucuronide than for Morphine (transfer half-life, 8.2 hours versus 2.6 hours for pain tolerance and 7.7 hours versus 2.8 hours for pupil diameter). The slope of the linear concentration versus effect relationship for pain tolerance was flatter for Morphine-6-Glucuronide than for Morphine (0.05% versus 0.6% increase in pain tolerance per nanomole per liter of Morphine-6-Glucuronide and Morphine at effect site, respectively). Morphine-6-Glucuronide was less potent than Morphine in producing pupil constriction (mean concentration at half-maximum effect, 745 nmol/L versus 26.4 nmol/L for Morphine-6-Glucuronide and Morphine, respectively). In carriers of the mutated G118 allele of the μ-opioid receptor, the potency of the pupil-constricting effects of Morphine-6-Glucuronide and Morphine was significantly smaller, and carriers of the G118 allele reported less nausea and vomited less often after administration of Morphine-6-Glucuronide. Conclusions Morphine-6-Glucuronide clearly produced analgesic effects in healthy volunteers. However, the high amounts of systemic Morphine-6-Glucuronide needed to produce the same effects as Morphine suggest that Morphine-6-Glucuronide barely contributes to the central nervous opioid effects after administration of analgesic doses of Morphine. Clinical Pharmacology & Therapeutics (2003) 73, 107–121; doi: 10.1067/mcp.2003.5

  • does the a118g polymorphism at the μ opioid receptor gene protect against Morphine 6 Glucuronide toxicity
    Anesthesiology, 2002
    Co-Authors: Jörn Lötsch, Carsten Skarke, Jutta Darimont, Michael Zimmermann, Claudia Marx, Rafael Dudziak, Gerd Geisslinger
    Abstract:

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

  • increased cns uptake and enhanced antinociception of Morphine 6 Glucuronide in rats after inhibition of p glycoprotein
    Journal of Neurochemistry, 2002
    Co-Authors: Jörn Lötsch, Gerd Geisslinger, Helmut Schmidt, Rodolfo Schmidt, Gregor Vetter, Ellen Niederberger, Irmgard Tegeder
    Abstract:

    Morphine-6-Glucuronide (M6G) is a substrate of P-glycoprotein (P-gp), which forms an outward transporter at the blood–brain barrier. Inhibition of P-gp may therefore be expected to cause increased CNS uptake of M6G. We directly assessed the spinal concentrations of M6G and its antinociceptive effects in rats following pharmacological inhibition of P-gp. Spinal cord tissue concentrations of M6G were assessed by microdialysis with probes transversally implanted through the dorsal horns of the spinal cord at level L4. Ten rats received M6G intravenously (0.018 mg/kg loading dose plus 0.00115 mg/kg/min for an 8-h infusion), five of them together with PSC833 to inhibit P-gp (32-h infusion, starting 24 h before the addition of M6G). Antinociceptive effects were explored by means of formalin tests. After having obtained evidence for enhanced CNS uptake and antinociception of M6G in the presence of PSC833, additional behavioural experiments were performed in another 32 rats to assess the dose dependency of the antinociceptive effects of M6G either with or without PSC833 in comparison with both PSC833 alone and placebo. Inhibition of P-gp increased the M6G concentrations in the spinal cord approximately three-fold whereas the plasma concentrations were increased only by a factor of 1.4, which resulted in a more than doubled spinal cord/plasma concentration ratio (from 0.08 ± 0.03 for M6G alone to 0.17 ± 0.08 for M6G plus PSC833). Antinociceptive effects of M6G were significantly enhanced by inhibition of P-gp. Inhibition of P-gp alters the transport of M6G across the blood–brain barrier, resulting in enhanced spinal cord uptake and enhanced antinociception.

  • pharmacokinetic modeling to predict Morphine and Morphine 6 Glucuronide plasma concentrations in healthy young volunteers
    Clinical Pharmacology & Therapeutics, 2002
    Co-Authors: Jörn Lötsch, Carsten Skarke, Helmut Schmidt, Jurgen Liefhold, Gerd Geisslinger
    Abstract:

    Objective This investigation focused on the development of a predictive model of Morphine, including Morphine-6-Glucuronide (M6G) for healthy young volunteers after Morphine administration. Methods Population compartmental pharmacokinetic modeling with NONMEM was applied to the plasma concentration-time data of Morphine and M6G obtained from 8 healthy volunteers (4 men and 4 women; age range, 23 to 30 years) after intravenous bolus injection of 5.64 mg Morphine base (7.5 mg Morphine sulfate) and of 1 mg deuterium-labeled M6G. Results Two models were identified that described the plasma concentration versus time courses of Morphine and M6G after administration of Morphine. The model consisted of a standard 3-compartment model for Morphine and a standard 2-compartment model for M6G, with input into and output from the central compartments. The formation of M6G from Morphine was modeled as a fraction of Morphine clearance of about 14%, which accounted forthe formation of M6G, and a delay of the appearance of M6G in plasma modeled as afirst-order process, with a mean metabolic transit time of 17.2 minutes. An alternative model assigned the formation of M6G among the first peripheral compartment of Morphine andthe central compartment of M6G. Therefore the alternative 3-compartment model of Morphinehad the input into the central compartment and renal excretory elimination from the central compartment, but the metabolic clearance of Morphine started from the first peripheralcompartment. M6G was again modeled with a standard 2-compartment model. Both models predicted Morphine and M6G plasma concentrations available from an independent study with acceptable accuracy and without bias. Conclusions Two models are provided that can predict plasma concentrations of Morphine and M6G with acceptable accuracy in healthy young volunteers. Clinical Pharmacology & Therapeutics (2002) 72, 151–162; doi: 10.1067/mcp.2002.126172

  • the polymorphism a118g of the human mu opioid receptor gene decreases the pupil constrictory effect of Morphine 6 Glucuronide but not that of Morphine
    Pharmacogenetics, 2002
    Co-Authors: Jörn Lötsch, Carsten Skarke, Jutta Darimont, Helmut Schmidt, Sabine Grosch, Gerd Geisslinger
    Abstract:

    Large individual differences in the clinical response to Morphine therapy have been known for a long time by clinicians. The recent advances in genomic research encourage the search for pharmacogenetic causes of that variability. As a measure of central opioid effects, pupil diameters were assessed every 20 min for 18 h after administration of Morphine or its active metabolite Morphine-6-Glucuronide (M6G) in a two-way crossover study. The opioid effects were compared between six subjects with a single-nucleotide polymorphism (SNP) A118G in the mu-opioid receptor gene (five heterozygous, one homozygous) and six control subjects. Non-parametric pharmacokinetic-pharmacodynamic modelling was employed to identify the influence of the A118G SNP on the concentration-response relationship of M6G and Morphine, which was described by a sigmoid Emax model. As a measure of potency, the EC50 of the pupil constrictory effects of M6G was 714 +/- 197 nmol/l in wild-type and 1475 +/- 424 nmol/l in heterozygous carriers of the A118G SNP. In the homozygous carrier of the SNP, it had an EC50 of 3140 nmol/l. In addition, the dose-response relationship was flatter in the A118G carriers than in control subjects (shape factor of the sigmoid Emax model: gamma = 3.3 +/- 1.2, 1.7 +/- 0.5 and 1.6 for wild-type, heterozygous and the homozygous A118G carriers, respectively). In contrast, the concentration-response relationship of Morphine was not affected by this specific SNP. The A118G SNP in the mu-receptor gene significantly reduces the potency of M6G in humans.