Pharmacokinetics of morphine-6-glucuronide following oral administration in healthy volunteers

Villesen, Hanne H.; Kristensen, Kim; Hansen, Steen Honoré; Jensen, Niels Rosendal; Skram, Ulrik; Christrup, Lona Louring

doi:10.1007/s00228-007-0306-4

Cited by 23 publications

(23 citation statements)

References 11 publications

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“…Kokobun et al (2007) 42 had previously reported an inverse correlation between clearance of intravenous or subcutaneous oxycodone and age in a group of Japanese cancer patients. On the other hand Villesen et al (2007) 76 reported, that the pharmacokinetics of intravenous oxycodone in a group of older adults patients (>70 years) undergoing hip surgery did not appear to differ remarkably from previous literature data gathered in younger subjects. Kaiko et al (1996) 39 also did not observe any significant difference in the AUC of a single 20 mg oral dose of controlled-release oxycodone between young (<45 years) and older (>65 years) subjects.…”

Section: Discussionmentioning

confidence: 78%

Comparative Cognitive and Subjective Side Effects of Immediate-Release Oxycodone in Healthy Middle-Aged and Older Adults

Cherrier¹,

Amory²,

Ersek³

et al. 2009

The Journal of Pain

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This study measured the objective and subjective neurocognitive effects of a single 10mg dose of immediate-release oxycodone in healthy, older (>65 years) and middle age (35 -55 years) adults who were not suffering from chronic or significant daily pain. Seventy-one participants completed two separate study days and were blind to medication condition (placebo, 10 mg oxycodone). Plasma oxycodone concentration peaked between 60 and 90 min post dose (p<0.01) and pupil size, an indication of physiological effects of the medication peaked at approximately 90 to 120 min post dose (p<0.01). Significant declines in simple and sustained attention, working memory and verbal memory were observed at one hour post dose compared to baseline for both age groups with a trend toward return to baseline by five hours post dose. For almost all cognitive measures there were no medication by age interaction effects, which indicates that the two age groups exhibited a similar responses to the medication challenge. This study suggests that for healthy older adults who are not suffering from chronic pain, neurocognitive and pharmacodynamic changes in response to a 10 mg dose of immediate release oxycodone are similar to those observed for middle age adults.Perspective-Study findings indicate that the metabolism, neurocognitive effects, and physical side effects of oral oxycodone are similar for healthy middle-age and older adults. Therefore, clinicians should not avoid prescribing oral opioids to older adults based on the belief that older adults are at higher risk for side effects than younger adults.

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Section: Discussionmentioning

confidence: 78%

Comparative Cognitive and Subjective Side Effects of Immediate-Release Oxycodone in Healthy Middle-Aged and Older Adults

Cherrier¹,

Amory²,

Ersek³

et al. 2009

The Journal of Pain

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“…The concentrations are normalized to a 40 mg dose for furosemide and to a 10 mg dose for morphine. Observed data are superimposed ( black open symbols represent values for the elderly [130, 134, 137]; grey open symbols represent values for younger adults [129, 130, 133, 136–138, 141, 142]). Lower panel : goodness-of-fit plots for furosemide and morphine model predictions in the adult population ( black dots ) and the elderly population ( grey dots ).…”

Section: Resultsmentioning

confidence: 99%

Development of a Whole-Body Physiologically Based Pharmacokinetic Approach to Assess the Pharmacokinetics of Drugs in Elderly Individuals

et al. 2016

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BackgroundBecause of the vulnerability and frailty of elderly adults, clinical drug development has traditionally been biased towards young and middle-aged adults. Recent efforts have begun to incorporate data from paediatric investigations. Nevertheless, the elderly often remain underrepresented in clinical trials, even though persons aged 65 years and older receive the majority of drug prescriptions. Consequently, a knowledge gap exists with regard to pharmacokinetic (PK) and pharmacodynamic (PD) responses in elderly subjects, leaving the safety and efficacy of medicines for this population unclear.ObjectivesThe goal of this study was to extend a physiologically based pharmacokinetic (PBPK) model for adults to encompass the full course of healthy aging through to the age of 100 years, to support dose selection and improve pharmacotherapy for the elderly age group.MethodsFor parameterization of the PBPK model for healthy aging individuals, the literature was scanned for anthropometric and physiological data, which were consolidated and incorporated into the PBPK software PK-Sim®. Age-related changes that occur from 65 to 100 years of age were the main focus of this work. For a sound and continuous description of an aging human, data on anatomical and physiological changes ranging from early adulthood to old age were included. The capability of the PBPK approach to predict distribution and elimination of drugs was verified using the test compounds morphine and furosemide, administered intravenously. Both are cleared by a single elimination pathway. PK parameters for the two compounds in younger adults and elderly individuals were obtained from the literature. Matching virtual populations—with regard to age, sex, anthropometric measures and dosage—were generated. Profiles of plasma drug concentrations over time, volume of distribution at steady state (V ss) values and elimination half-life (t ½) values from the literature were compared with those predicted by PBPK simulations for both younger adults and the elderly.ResultsFor most organs, the age-dependent information gathered in the extensive literature analysis was dense. In contrast, with respect to blood flow, the literature study produced only sparse data for several tissues, and in these cases, linear regression was required to capture the entire elderly age range. On the basis of age-informed physiology, the predicted PK profiles described age-associated trends well. The root mean squared prediction error for the prediction of plasma concentrations of furosemide and morphine in the elderly were improved by 32 and 49 %, respectively, by use of age-informed physiology. The majority of the individual V ss and t ½ values for the two model compounds, furosemide and morphine, were well predicted in the elderly population, except for long furosemide half-lifes.ConclusionThe results of this study support the feasibility of using a knowledge-driven PBPK aging model that includes the elderly to predict PK alterations throughout the entire course of aging, and thus to...

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“…Increased and prolonged duration of pain relief following IV morphine has been reported in geriatric patients, but the reasons behind this have never been clearly elucidated, nor is it clear if similar results would occur with IV oxycodone in the elderly. The pharmacokinetics of IV oxycodone were compared to IV morphine in a nonblinded study of hip replacement patients over age 70 ( n = 16, mean age 76.1 ± 4.5 years) . The drug elimination half‐life was 2.7 ± 3.6 hours (range 0.8 to 11.6) for morphine and 3.1 ± 1.3 hours (range 1.1 to 4.8) for oxycodone.…”

Section: Oxycodone and Special Populationsmentioning

confidence: 99%

“…The drug elimination half‐life was 2.7 ± 3.6 hours (range 0.8 to 11.6) for morphine and 3.1 ± 1.3 hours (range 1.1 to 4.8) for oxycodone. However, pharmacokinetic variations can be substantial among individuals and become more diffuse in groups; in fact, in this study, an age‐related drug effect could not be ascribed to drug pharmacokinetics alone . In contrast, a study of 41 knee surgery patients divided into four age groups (ages 20 to 40, 60 to 70, 70 to 80, and 80 to 90 years) and administered a single dose of IV oxycodone for postoperative pain control demonstrated clear age‐dependent pharmacokinetic differences .…”

Section: Oxycodone and Special Populationsmentioning

confidence: 99%

Perspectives on Intravenous Oxycodone for Control of Postoperative Pain

et al. 2015

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Intravenous (IV) analgesia has particular advantages in the immediate postoperative period. For example, IV administration results in a faster onset of pain relief and results in more predictable pharmacokinetics than does administration by other routes. It also allows for convenient dosing before or during surgery, permitting the initiation of effective analgesia in the early phase of the postoperative period. In addition, when patients are able to tolerate oral intake, they can be switched from IV to oral dosing based on maintaining the predictable analgesia established by the IV route. IV morphine is widely used for the control of postoperative pain, but there is a trend toward the use of oxycodone. Oxycodone (which may be mediated partly through kappa- as well as mu-opioid receptors) offers several potential advantages. Published studies comparing IV oxycodone to other IV opioids for postsurgical pain report that oxycodone is a safe and effective analgesic. Some studies show that IV oxycodone may be associated with greater pain control, fewer or less severe adverse events, and faster onset of action, although the results are not consistent across all studies. Oxycodone has been reported to be safe in the geriatric and other special populations when adequate clinical adjustments are made. Thus, the clinical reports and oxycodone's pharmacologic profile make intravenous oxycodone a potentially important "new" old drug for postoperative pain control.

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Pharmacokinetics of morphine-6-glucuronide following oral administration in healthy volunteers

Cited by 23 publications

References 11 publications

Comparative Cognitive and Subjective Side Effects of Immediate-Release Oxycodone in Healthy Middle-Aged and Older Adults

Comparative Cognitive and Subjective Side Effects of Immediate-Release Oxycodone in Healthy Middle-Aged and Older Adults

Development of a Whole-Body Physiologically Based Pharmacokinetic Approach to Assess the Pharmacokinetics of Drugs in Elderly Individuals

Perspectives on Intravenous Oxycodone for Control of Postoperative Pain

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