Morphine and morphine-6-glucuronide plasma concentrations and effect in cancer pain

Faura, Clara C.; Moore, R Andrew; Horga, J.F.; Hand, C.W.; McQuay, Henry J

doi:10.1016/0885-3924(95)00148-4

Cited by 66 publications

(49 citation statements)

References 19 publications

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“…This is at odds with the hypothesis of "toxic" concentrations of either the opioid or its metabolites as major contributors to the pathogenesis of AE [5]. Conversely, individual patterns in opioid metabolism and in the distribution of opioid receptors and their functional networks should be discussed as relevant (perhaps genetically fixed) factors influencing individual responsiveness to or tolerability of opioids as suggested by the number of patients requiring multiple changes [6,15,27]. In the present study, 6 out of 8 patients changing opioids because of AE received morphine in spite of impaired renal function.…”

Section: Discussionmentioning

confidence: 93%

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Toxicity and/or insufficient analgesia by opioid therapy: risk factors and the impact of changing the opioid. A retrospective analysis of 273 patients observed at a single center

Kloke¹,

Rapp²,

Bosse

et al. 2000

Support Care Cancer

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The charts of 273 cancer patients were retrospectively analyzed in order (1) to evaluate the frequency of opioid change (OCH) when adjuvants (antiemetics/laxatives) were administered on a regular basis and co-analgesic medication as indicated by the specific type of pain, (2) to define risk factors for the request of OCH, and (3) to reveal settings in which OCH may not be recommended as a first-line therapeutic intervention. Opioids used included morphine, fentanyl, 1-methadone, and buprenorphine. Out of 273 patients, 103 changed opioids at least once, with a success rate of 65%. The indications for the OCH were insufficient analgesia in 43%, intolerable side effects in 20%, both in 15%, and other reasons in 22% of patients. The frequency of OCH was not influenced by the routine use of adjuvants or co-analgesics except corticosteroids, which raises queries about the concept of an opioid-sparing effect of co-analgesics. The occurrence of intolerable side effects is thought not to be dose dependent so much as to reflect differences in the individual tolerability of a distinct opioid for whatever reason (genetically fixed or individually acquired pharmacodynamic or kinetic properties). Moreover, there was strong evidence for the existence of an unpredictable and incomplete cross-tolerance between opioids, which meant careful titration of the new opioid was required after OCH. The overall frequency of OCH was similar to that observed in previous studies in spite of the documented addition of adjuvants and co-analgesics. This retrospective study supports the notion that opioid rotation must be retained as an essential therapeutic option even with optimized adjuvant and co-analgesic regimens.

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Section: Discussionmentioning

confidence: 93%

“…The involvement of active metabolites in the development of opioid side effects has been shown for morphine-3-glucuronide and morphine-6-glucuronide, which accumulate in patients with renal injury [2, 15,34,35]. The impact of an individualized pharmacodynamic is obvious for methadone and for oral morphine [11,37,38].…”

Section: Introductionmentioning

confidence: 98%

Toxicity and/or insufficient analgesia by opioid therapy: risk factors and the impact of changing the opioid. A retrospective analysis of 273 patients observed at a single center

Kloke¹,

Rapp²,

Bosse

et al. 2000

Support Care Cancer

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“…One study suggested, for example, that up to 89% of plasma methadone is protein bound (Inturrisi et al, 1987), thereby possibly reducing the in vivo amount of methadone available to inhibit I HERG to 11% (free fraction) and raising the therapeutic index for methadone approximately 10-fold. Drug metabolites may also play a role, because the metabolites for some opioid compounds can attain plasma concentrations that are Ͼ60-fold higher than those achieved by the parent drug (Faura et al, 1996). In addition, one has to consider drug formulations.…”

Section: Discussionmentioning

confidence: 99%

Influence of Opioid Agonists on Cardiac HumanEther-a-go-go-related Gene K⁺Currents

Katchman

McGroary²,

Kilborn³

et al. 2002

J Pharmacol Exp Ther

239

185

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We have evaluated the ability of various opioid agonists, including methadone, L-␣-acetylmethadol (LAAM), fentanyl, meperidine, codeine, morphine, and buprenorphine, to block the cardiac human ether-a-go-go-related gene (HERG) K ϩ current (I HERG ) in human cells stably transfected with the HERG potassium channel gene. Our results show that LAAM, methadone, fentanyl, and buprenorphine were effective inhibitors of I HERG , with IC 50 values in the 1 to 10 M range. The other drugs tested were far less potent with respect to I HERG inhibition. Compared with the reported maximal plasma concentration (C max ) after administration of therapeutic doses of these drugs, the ratio of IC 50 /C max was highest for codeine and morphine (Ͼ455 and Ͼ400, respectively), thereby indicating that these drugs have the widest margin of safety (of the compounds tested) with respect to blockade of I HERG . In contrast, the lowest ratios of IC 50 /C max were observed for LAAM and methadone (2.2 and 2.7, respectively). Further investigation showed that methadone block of I HERG was rapid, with steady-state inhibition achieved within 1 s when applied at its IC 50 concentration (10 M) for I HERG block. Results from "envelope of tails" tests suggest that the majority of block occurred when the channels were in the open and/or inactivated states, although ϳ10% of the available HERG K ϩ channels were apparently blocked in a closed state. Similar results were obtained for LAAM. These results demonstrate that LAAM and methadone can block I HERG in transfected cells at clinically relevant concentrations, thereby providing a plausible mechanism for the adverse cardiac effects observed in some patients receiving LAAM or methadone.Torsades de pointes is a potentially fatal form of ventricular arrhythmia that typically occurs under conditions where cardiac repolarization is delayed (as indicated by prolonged QT intervals from electrocardiographic recordings) (Goodman and Peter, 1995;Viskin, 1999). These conditions can be precipitated by drugs that block the cardiac potassium channels responsible for mediating ventricular repolarization. Remarkably, many different types of drugs, including some antiarrhythmics, antihistamines, antibiotics, gastrointestinal prokinetics, and antipsychotics (Faber et al., 1994;De Ponti et al., 2001), have been shown to cause QT prolongation, primarily through interference with the rapid component of the delayed rectifier potassium current, I Kr (Antzelevitch et al., 1996;January et al., 2000;Tamargo, 2000;Tseng, 2001). The human ether-a-go-go-related gene (HERG) gene encodes for the major channel protein that underlies I Kr , and a recently developed cell line that was stably transfected with the HERG gene (Zhou et al., 1998) has proven useful for evaluating drugs suspected of causing delays in cardiac repolarization (Mohammad et al., 1997;Ferreira et al., 2001).In April 2001, the United States Food and Drug Administration issued a new warning about adverse cardiac events (Deamer et al., 2001) associated with th...

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“…Inhibition of morphine clearance would result in increased plasma morphine concentrations, which would be expected to increase analgesia. However, M6G is a more potent µ opioid agonist [1] and a number of studies have shown its contribution to analgesia, particularly after a high dose or during chronic morphine therapy [2,3,51,52]. In contrast, several animal studies have shown that M3G attenuates the opioid effects of morphine [5,6,53,54], although this has yet to be well demonstrated in humans.…”

Section: Tablementioning

confidence: 99%

Differential in vitro inhibition of M3G and M6G formation from morphine by (R)‐ and (S)‐methadone and structurally related opioids

Morrish

Foster

Somogyi

2005

Brit J Clinical Pharma

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Differential in vitro inhibition of M3G and M6G formation from morphine by (R)-and (S)-methadone and structurally related opioids Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, Australia AimsTo determine the in vitro kinetics of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) formation and the inhibition potential by methadone enantiomers and structurally related opioids. MethodsM3G and M6G formation kinetics from morphine were determined using microsomes from five human livers. Inhibition of glucuronide formation was investigated with eight inhibitors (100 µ M ) and the mechanism of inhibition determined for (R)-and (S)-methadone (70-500 µ M ) using three microsomal samples. ResultsGlucuronide formation displayed single enzyme kinetics. The M3G V max (mean ± SD) was 4.8-fold greater than M6G V max (555 ± 110 vs. 115 ± 19 nmol mg − 1 protein h − 1 ; P = 0.006, mean of difference 439; 95% confidence interval 313, 565 nmol mg − 1 protein h − 1 ). K m values for M3G and M6G formation were not significantly different (1.12 ± 0.37 vs. 1.11 ± 0.31 m M ; P = 0.89, 0.02; − 0.29, 0.32 m M ). M3G and M6G formation was inhibited ( P < 0.01) with a significant increase in the M3G/M6G ratio ( P < 0.01) for all compounds tested. Detailed analysis with (R)-and (S)-methadone revealed noncompetitive inhibition with (R)-methadone K i of 320 ± 42 µ M and 192 ± 12 µ M for M3G and M6G, respectively, and (S)-methadone K i of 226 ± 30 µ M and 152 ± 20 µ M for M3G and M6G, respectively. K i values for M3G inhibition were significantly greater than for M6G for (R)-methadone ( P = 0.017, 128; 55, 202 µ M ) and (S)-methadone ( P = 0.026, 75; 22, 128 µ M ). ConclusionsBoth methadone enantiomers noncompetitively inhibited the formation of morphine's primary metabolites, with greater inhibition of M6G formation compared with M3G. These findings indicate a mechanism for reduced morphine clearance in methadonemaintained patients and reduced relative formation of the opioid active M6G compared with M3G. IntroductionMorphine is the gold standard opioid for the treatment of moderate to severe acute and chronic pain. Morphine is primarily cleared via glucuronidation to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). M6G is a potent µ -opioid agonist [1] with clinical studies suggesting it contributes to analgesia after the administration of morphine [2,3]. M3G has no anal- [11,12,14]. Investigations with expressed recombinant human UDPglucuronosyltransferase (UGT) enzymes have shown UGT1A1, 1A3, 1A6, 1A8, 1A9, 1A10 and 2B7 all metabolize morphine to M3G [15][16][17]. However, only UGT2B7 has been shown to form M6G [17,18]. The relative contribution of these isoforms to the overall glucuronidation of morphine is still unknown. Only one investigation using human liver microsomes has shown the possible involvement of more than one UGT isoform in M3G formation, with the suggested involvement of a high-affinity, low-capacity enzyme (with a mean K m and V max of 5.3 µ M and 18 nmol mg − 1 protein h...

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Morphine and morphine-6-glucuronide plasma concentrations and effect in cancer pain

Cited by 66 publications

References 19 publications

Toxicity and/or insufficient analgesia by opioid therapy: risk factors and the impact of changing the opioid. A retrospective analysis of 273 patients observed at a single center

Toxicity and/or insufficient analgesia by opioid therapy: risk factors and the impact of changing the opioid. A retrospective analysis of 273 patients observed at a single center

Influence of Opioid Agonists on Cardiac HumanEther-a-go-go-related Gene K⁺Currents

Differential in vitro inhibition of M3G and M6G formation from morphine by (R)‐ and (S)‐methadone and structurally related opioids

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Morphine and morphine-6-glucuronide plasma concentrations and effect in cancer pain

Cited by 66 publications

References 19 publications

Toxicity and/or insufficient analgesia by opioid therapy: risk factors and the impact of changing the opioid. A retrospective analysis of 273 patients observed at a single center

Toxicity and/or insufficient analgesia by opioid therapy: risk factors and the impact of changing the opioid. A retrospective analysis of 273 patients observed at a single center

Influence of Opioid Agonists on Cardiac HumanEther-a-go-go-related Gene K+Currents

Differential in vitro inhibition of M3G and M6G formation from morphine by (R)‐ and (S)‐methadone and structurally related opioids

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Influence of Opioid Agonists on Cardiac HumanEther-a-go-go-related Gene K⁺Currents