Peak Plasma Concentrations After Oral Morphine

Collins, Sally; Faura, Clara C.; Moore, R Andrew; McQuay, Henry J

doi:10.1016/s0885-3924(98)00094-3

Cited by 104 publications

(59 citation statements)

References 18 publications

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“…single and multiple dosing and populations (40). The concentrations of MNTX in our in vitro study were similar to those achieved in clinical trials of the drug.…”

Section: Discussionsupporting

confidence: 78%

Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor–induced angiogenesis

Singleton

Garcia

Moss

2008

Molecular Cancer Therapeutics

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Many patients with cancer receive combinations of drug treatments that include 5-fluorouracil (5-FU) and bevacizumab. Therapeutic doses of 5-FU are often associated with unwanted side effects, and bevacizumab is costly. Therefore, we explored potential agents that can reduce the therapeutic concentration of these drugs. Our data indicate that methylnaltrexone (MNTX), a peripheral antagonist of the M-opioid receptor, exerts a synergistic effect with 5-FU and bevacizumab on inhibition of vascular endothelial growth factor (VEGF) -induced human pulmonary microvascular endothelial cell (EC) proliferation and migration, two key components in cancer-associated angiogenesis. MNTX inhibited EC proliferation with an IC 50 of f100 nmol/L. Adding 100 nmol/L MNTX to EC shifted the IC 50 of 5-FU from f5 Mmol/L to f7 nmol/L. Further, adding 50 ng/mL MNTX shifted the IC 50 of bevacizumab on inhibition of EC migration from f25 to f6 ng/mL. These synergistic effects were not observed with naltrexone, a tertiary M-opioid receptor antagonist. On a mechanistic level, we observed that treatment of human EC with MNTX, but not naltrexone, increased receptor protein tyrosine phosphatase M activity, which was independent of M-opioid receptor expression. Silencing receptor protein tyrosine phosphatase M expression (small interfering RNA) in human EC inhibited both synergy between MNTX and bevacizumab or 5-FU and increased VEGF-induced tyrosine phosphorylation of Src and p190 RhoGAP with enhanced activation of Akt and the actin cytoskeletal regulatory protein, RhoA, whereas silencing Src, Akt, or RhoA blocked VEGF-induced angiogenic events. Therefore, addition of MNTX could potentially lower the therapeutic doses of 5-FU and bevacizumab, which could improve index.

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“…single and multiple dosing and populations (40). The concentrations of MNTX in our in vitro study were similar to those achieved in clinical trials of the drug.…”

Section: Discussionsupporting

confidence: 78%

Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor–induced angiogenesis

Singleton

Garcia

Moss

2008

Molecular Cancer Therapeutics

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“…Although in principle it is unwise to change between preparations when using modified release products because of possible variations in release profiles and oral bioavailability there is no consistent evidence that the various oral formulations of morphine designed for administration every 12 hours have a different pharmacokinetic or pharmacodynamic profile in patients (Collins et al, 1998). Several once-a-day formulations of morphine have also been developed.…”

Section: Several Modified Release Formulations Are Available There Imentioning

confidence: 99%

Morphine and alternative opioids in cancer pain: the EAPC recommendations

et al. 2001

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Summary An expert working group of the European Association for Palliative Care has revised and updated its guidelines on the use of morphine in the management of cancer pain. The revised recommendations presented here give guidance on the use of morphine and the alternative strong opioid analgesics which have been introduced in many parts of the world in recent years. Practical strategies for dealing with difficult situations are described presenting a consensus view where supporting evidence is lacking. The strength of the evidence on which each recommendation is based is indicated. http://www.bjcancer.com Daytime drowsiness, dizziness or mental clouding commonly occur at the start of treatment but resolve when patients are stabilized (usually within a few days). For most patients receiving stable doses of morphine effects on cognitive and psychomotor function are minimal. In particular, there are data indicating that patients' driving ability is not significantly impaired, in alert patients receiving a stable dose (Vainio et al, 1995). Similarly, nausea and vomiting, which occur in up to two-thirds of patients when morphine is started, usually resolve. The main continuing adverse effect from morphine is constipation, and the prophylactic use of a laxative is almost always required. Morphine: limitationsThe systemic availability of morphine by the oral route is poor (20-30%) and this contributes to a sometimes unpredictable onset of action and great interindividual variability in dose requirements and response (Glare and Walsh, 1991). Active metabolites may contribute to toxicity, particularly in patients with renal impairment (McQuay and Moore, 1997). And some types of pain do not always respond well or completely to morphine, notably neuropathic pain. However, none of the alternatives to morphine has so far demonstrated advantages which would make it preferable as the first line oral opioid for cancer pain. Morphine remains our first choice but for reasons of familiarity, availability and cost rather than proven superiority.2. The optimal route of administration of morphine is by mouth. Ideally, two types of formulation are required: normal release (for dose titration) and modified release (for maintenance treatment) CThe oral route is the simplest and most acceptable to patients.There is large interindividual variation in kinetics (Säwe, 1986) and dynamics in cancer patients whose pain will also vary in severity so that the dose must be titrated against effect for each patient, and the starting dose will be determined by previous analgesic treatment. Patients changing from regular administration of a step 2 opioid (in combination with a non-opioid) will usually start with 10 mg every 4 hours. If step 2 of the analgesic ladder is omitted 5 mg every 4 hours may suffice, whereas patients converted from another step 3 opioid will require more. During dose titration it is preferable to use a formulation of morphine that has a rapid onset and a short duration of action to allow steady state to be achieved as quic...

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“…C max is 1 hour for the oral route, 30 minutes for the subcutaneous route, and 6 minutes for the intravenous route. 127,128 Once C max is reached, another dose should be given if pain is not adequately controlled.…”

Section: Dose Titrationmentioning

confidence: 99%

Pharmacological Management of Cancer-Related Pain

Prommer

2015

Cancer Control

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Peak Plasma Concentrations After Oral Morphine

Cited by 104 publications

References 18 publications

Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor–induced angiogenesis

Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor–induced angiogenesis

Morphine and alternative opioids in cancer pain: the EAPC recommendations

Pharmacological Management of Cancer-Related Pain

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