Plasma Concentrations Of Oxycodone Research Articles

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

This study measured the objective and subjective neurocognitive effects of a single 10-mg dose of immediate-release oxycodone in healthy, older (> 65 years), and middle-aged (35 to 55 years) adults who were not suffering from chronic or significant daily pain. Seventy-one participants completed 2 separate study days and were blind to medication condition (placebo, 10-mg oxycodone). Plasma oxycodone concentration peaked between 60 and 90 minutes postdose (P < .01) and pupil size, an indication of physiological effects of the medication, peaked at approximately 90 to 120 minutes postdose (P < .01). Significant declines in simple and sustained attention, working memory, and verbal memory were observed at 1 hour postdose compared to baseline for both age groups with a trend toward return to baseline by 5 hours postdose. For almost all cognitive measures, there were no medication by age-interaction effects, which indicates that the 2 age groups exhibited 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-aged adults. Study findings indicate that the metabolism, neurocognitive effects, and physical side effects of oral oxycodone are similar for healthy middle-aged 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.

Comparison of effects and plasma concentrations of opioids between elderly and middle‐aged patients after cardiac surgery

In elderly patients, opioids may cause prominent postoperative sedation and respiratory depression. We evaluated the influence of age on the effects of opioids and plasma concentrations of fentanyl and oxycodone in cardiac surgery patients. Thirty (>or=75 years, gender M9/F21) and 20 (<or=60 years, gender M20/F0) patients scheduled to undergo cardiac surgery. A standard anesthesia with fentanyl as an opioid was used. Fentanyl plasma concentrations were measured at the end of surgery and 2 h later. After tracheal extubation, when the pain intensity was at least moderate, blood samples for fentanyl and oxycodone plasma concentration measurements were taken. Thereafter, oxycodone hydrochloride 0.05 mg/kg i.v. was administered. After 15 and 45 min, pain intensity, sedation and oxycodone plasma concentration were determined. This test protocol was repeated twice. The elderly had a higher plasma concentration of fentanyl at the end of surgery than younger patients (5.7+/-2.2 vs. 3.8+/-1.2 ng/ml, P=0.001). The plasma concentrations of oxycodone were comparable between the groups. The interval between the second and the third oxycodone dose was longer in the elderly patients (P=0.036). Pain intensity on the verbal rating scale was lower at the 45-min assessment point after all three oxycodone test doses (P=0.008) and sedation scores were significantly higher after the third dose in the elderly patients (P=0.035). In elderly patients, the plasma concentration of fentanyl was higher but plasma levels of oxycodone were at a similar level compared with middle-aged patients. However, the elderly patients had less pain and were more sedated after doses of oxycodone.

Plasma Concentrations of Oral Oxycodone Are Greatly Increased in the Elderly

We compared the pharmacokinetics of 10 mg oral oxycodone in four groups of 10 patients each, aged 20-40, 60-70, 70-80, and 80-90 years. Patients aged 70-80 and 80-90 years had 50-80% higher mean exposure to oxycodone (P < 0.05) and a twofold higher plasma oxycodone concentration (P < 0.05) than the young adults 12 h after ingestion of the drug. Because oxycodone pharmacokinetics depend to a great extent on the age of the subject, it is important to titrate the analgesic dose individually, particularly in the elderly.

SEX DIFFERENCES IN THE PHARMACOKINETICS, OXIDATIVE METABOLISM AND ORAL BIOAVAILABILITY OF OXYCODONE IN THE SPRAGUE‐DAWLEY RAT

1. The pharmacokinetics and oxidative metabolism of oxycodone were investigated following intravenous and oral administration in male and female Sprague-Dawley (SD) rats. 2. High-performance liquid chromatography (HPLC)-electrospray ionization (ESI)-tandem mass spectrometry (MS-MS) was used to quantify plasma concentrations of oxycodone and its oxidative metabolites noroxycodone and oxymorphone following administration of single bolus intravenous (5 mg/kg) and oral (10 mg/kg) doses of oxycodone. 3. The mean (+/-SEM) clearance of intravenous oxycodone was significantly higher in male than female SD rats (4.9 +/- 0.3 vs 3.1 +/- 0.3 L/h per kg, respectively; P < 0.01). Mean areas under the plasma concentration versus time curves (AUC) for oxycodone were significantly higher in female than male SD rats following intravenous (approximately 1.6-fold; P < 0.01) and oral (approximately sevenfold; P < 0.005) administration. 4. The oral bioavailability of oxycodone was low (at 1.2 and 5.0%, respectively) in male and female SD rats, a finding consistent with high first-pass metabolism. Noroxycodone : oxycodone AUC ratios were significantly higher in male than female SD rats after intravenous (approximately 2.4-fold; P < 0.005) and oral (approximately 12-fold; P < 0.005) administration. 5. Circulating oxymorphone concentrations remained very low following both routes of administration. Noroxycodone : oxymorphone AUC ratios were greater in male than female SD rats after intravenous (approximately 13- and fivefold, respectively) and oral (approximately 90- and sixfold, respectively) administration. 6. Sex differences were apparent in the pharmacokinetics, oxidative metabolism and oral bioavailability of oxycodone. Systemic exposure to oxycodone was greater in female compared with male SD rats, whereas systemic exposure to metabolically derived noroxycodone was higher in male than female SD rats. 7. Oral administration of oxycodone to the SD rat is a poor model of the human for the study of the pharmacodynamic effects of oxycodone.

The Effect of Single-Dose Tramadol on Oxycodone Clearance

We have noticed increased prescribing of tramadol by emergency physicians for breakthrough pain in patients chronically taking oxycodone. Both oxycodone and tramadol undergo oxidative metabolism by CYP2D6 and CYP3A4, suggesting the possibility that tramadol may compete with oxycodone for metabolism. A randomized controlled trial in 10 human volunteers was performed to determine if single-dose tramadol therapy would impair oxycodone clearance. Subjects were randomized whether to enter the control or experimental arm of the study first, with each subject serving as his or her own control. In the control arm, each subject received 10 mg immediate-release oxycodone orally and had serial plasma oxycodone and oxymorphone concentrations measured over 8 h. The experimental arm was identical except that 100 mg tramadol was ingested 1.5 h before oxycodone. Clearance divided by fraction absorbed (CL/f) was calculated using the dose and the area under the 8-h time-plasma oxycodone concentration curve. Peak plasma oxycodone concentrations (C max) and time until peak oxycodone concentrations (T max) were secondary outcome parameters. Group size was chosen to produce a power of 0.8 to detect a 20% difference in CL/f between study arms. Values for CL/f, C max, and T max were compared between study arms using two-tailed, paired t-tests. No statistically significant difference between groups was demonstrated for any parameter. We failed to demonstrate that single doses of tramadol impaired oxycodone clearance.

Premedication with controlled-release oxycodone does not improve management of postoperative pain after day-case gynaecological laparoscopic surgery

Controlled-release (CR) oxycodone provides an option for the prevention of postoperative pain. We designed this randomized double-blinded placebo controlled study to evaluate the control of pain after premedication with CR oxycodone 15 mg in addition to ibuprofen 800 mg orally in day-case gynaecological laparoscopic surgery. Sixty consenting patients were anaesthetized in a standardized fashion. Postoperative analgesia was provided by ibuprofen 800 mg twice a day in combination with fentanyl i.v. in the recovery room and normal-release (NR) oxycodone orally after the recovery room. The visual analogue scale (VAS) scores for pain and side-effects, and the amounts of postoperative analgesics were recorded for 24 h after discharge from the hospital. After a statistical analysis of the original study, we extended the study to investigate another 10 patients, who received CR oxycodone 15 mg orally in an open-labelled fashion 60 min before surgery. The plasma concentrations of oxycodone were measured from samples drawn before and 2, 4, 6 and 8 h after premedication. The amounts of fentanyl [100 microg (0-330) in the CR oxycodone group; 125 microg (0-330) in the placebo group], NR oxycodone, or the VAS scores for pain during the first 24 h after the discharge from the hospital did not differ after the premedication with CR oxycodone or placebo. In the extension study group, the peak plasma concentration (C(max)) of oxycodone was 10.0 (4.6-14.7) ng ml(-1), indicating possibly a sub-therapeutic level. Oral premedication with CR oxycodone did not improve management of postoperative pain after day-case gynaecological laparoscopic surgery.

Effect of pH on sublingual absorption of oxycodone hydrochloride.

The purpose of this study was to develop a sublingual spray drug delivery formulation of oxycodone and evaluate the effect of formulation pH on sublingual absorption of oxycodone for acute pain management using rabbit as the animal model. Using a new, sensitive, and specific liquid chromatography/mass spectrometry (LC/MS) with electrospray ionization detector assay, the absorption bioavailability of sublingual oxycodone was determined in rabbits by comparing plasma concentration after sublingual spray delivery with equivalent intravenous dose. The effect of formulation pH on sublingual absorption of oxycodone was also tested on rabbits that had received oxycodone sublingually at a dose of 0.1 mg/0.1 mL (pH 4.0 and 9.0). Blood samples were collected at different time points, and plasma oxycodone concentrations were determined by LC/MS. Following administration of a 0.1 mg dose, the average Cmax values were found to be 64.9±12.1 and 95.2±10.1 ng/mL, for pH 4.0 and 9.0, respectively. The area under the curve (AUC) values were found to be 5807.0, and 8965.3 ng.min/mL for formulation pH 4.0 and 9.0, respectively. The mean sublingual bioavailability of oxycodone was 45.4%±20.1% and 70.1%±17.9%, for pH 4.0 and 9.0, respectively. the formulation pH had no significant influence on oxycodone bioavailability (P<.05). A sublingual spray dosage form of oxycodone hydrochloride would be a good alternative for fast onset pain management, especially in children.

Comparison of the analgesic effects of intrabursal oxycodone and bupivacaine after acromioplasty

Study Objectives: To compare the peripheral analgesic effect of oxycodone, an opioid agonist, to the effect of bupivacaine infiltration and parenteral oxycodone administration in conjunction with shoulder surgery. Design: Prospective, randomized, double-blind study. Setting: University teaching hospital. Patients: 42 ASA physical status I and II patients scheduled for shoulder surgery with general anesthesia. Interventions: Patients were randomized to three study groups: at the end of the surgery patients received either 10 ml of 0.5% bupivacaine (group BIB) or 5 mg of oxycodone in 10 ml of saline (group OIB) in the subacromial bursa; or 5 mg of oxycodone intramuscularly (group OIM). Postoperative analgesia was provided by patient-controlled analgesia (PCA). Measurements and Main Results: The fentanyl requirements were recorded for the 24-hour postoperative period and the total perioperative period. Postoperative pain was assessed by visual analog scale for pain (VASP). Plasma oxycodone concentrations were measured in groups OIB and OIM. The total perioperative fentanyl consumption was significantly lower in groups BIB (0.97 ± 0.09 mg) and OIB (1.23 ± 0.12 mg) than in group OIM (1.61 ± 0.12 mg) (p = 0.01 and 0.048, respectively). Groups BIB and OIB were similar (p = 0.34). The absorption of oxycodone was significantly lower after subacromial than after intramuscular administration. Conclusion: Intrabursal oxycodone and intrabursal bupivacaine reduced perioperative analgesic requirements similarly. Intrabursal oxycodone may offer an effective, simple, and safe method for postoperative analgesia after shoulder surgery.

Comparison of analgesic efficacy of oxycodone and morphine in postoperative intravenous patient‐controlled analgesia

Morphine has been the standard opioid in patient-controlled analgesia (PCA). Oxycodone, the analgesic potency of which in i.v. administration has been suggested to be slightly greater than that of morphine, has not yet been studied for its efficacy in PCA. Fifty patients, undergoing a plastic reconstruction of the breast or a major operation of the vertebrae, such as lumbar spinal fusion, used PCA for postoperative pain. Patients were randomized to receive either morphine 45 microg/kg or oxycodone 30 microg/kg as i.v. bolus doses. Patients were assessed for pain with a visual analogue scale (VAS) and side effects at 3, 9 and 24 h. Venous blood samples for the measurement of plasma concentration of oxycodone and that of morphine and its metabolites were taken. In this study patients needed, on average, the same amount of oxycodone and morphine in the recovery room and on the ward. There was no difference in the quality of analgesia (VAS) or incidence of side effects, such as nausea, vomiting, pruritus and urinary retention. The plasma concentrations of morphine-6-glucuronide showed that this metabolite might contribute to the analgesia resulting from morphine administration. The same dose of intravenous oxycodone and morphine administered by PCA pump was needed for immediate postoperative analgesia. The two drugs appear to be equipotent.

A pharmacokinetic/pharmacodynamic study of controlled-release oxycodone

A single-dose, analytically blinded, randomized, crossover study was conducted in 22 healthy male volunteers to compare the bioavailability of one 20 mg with two 10 mg controlled-release (CR) oxycodone tablets. In addition, pharmacodynamic effects were assessed using both objective and subjective measures for up to 48 hr after dosing. The two treatments were bioequivalent, with comparable rates (C max of one 20 mg tablet was 109% of two 10 mg tablets; 90% confidence limits: 98.4%–120%) and extents (AUC 0−x; 107%; 100%–114%) of absorption. In addition, no significant differences between tablets were found for mean values of T max T/12abs, or T/12elim. Correlations between plasma oxycodone concentrations and most pharmacodynamic measures were significant. The strongest correlations were observed for pupil size ( r = −0.53) and subjects' assessment of drug effect ( r = 0.53), with changes in plasma concentration accounting for more than 25% of the observed changes in these variables. This study demonstrated bioequivalence of two 10 mg and one 20 mg CR oxycodone tablet, with significant correlation between plasma oxycodone concentrations and pharmacodynamic effects in normal volunteers.

Differential Effects of Food on the Bioavailability of Controlled-Release Oxycodone Tablets and Immediate-Release Oxycodone Solution

AbstractThe effects of a high-fat meal on the bioavailability of oxycodone hydrochloride, administered as a recently developed 40mg controlled-release (CR) tablet or a 20mg immediate-release (IR) solution, were evaluated in a randomized crossover study in 22 normal male and female subjects. Serial blood samples were collected for 36h after dosing and analyzed for oxycodone by a validated method using gas chromatography/mass spectrometry. There was no significant food effect with CR oxycodone as judged by 90% confidence interval (CI) analysis of AUC0−∞and Cmax values under fed and fasted conditions. For the IR solution, both oxycodone bioavailability and peak plasma oxycodone concentration were significantly altered by consumption of the high-fat meal, with the mean value for AUC0−∞ increasing to 120% (CI=109– 132%) and the mean value for Cmax decreasing to 82% (CI=47–91%) of values observed in the fasted condition. Adverse events reported for both formulations were mostly mild to moderate in severity and typical of those observed with opioids.

Steady-state bioavailability of controlled-release oxycodone in normal subjects

The steady-state bioavailability of a controlled-release (CR) oxycodone tablet was compared with that of an immediate-release (IR) oxycodone solution in a randomized, analytically masked, multiple-dose, crossover study in 24 normal subjects. Each subject received either one 10-mg CR oxycodone tablet every 12 hours for 4 days or 5 mL of a 1-mg/1 mL IR oxycodone solution every 6 hours for 4 days. Steady state was achieved after approximately 1 day of dosing. The mean (±SD) maximum plasma oxycodone concentrations for CR oxycodone and IR oxycodone were 15.1 ± 4.7 ng/mL and 15.6 ± 4.4 ng/mL, respectively. The time to maximum concentration (T max) was approximately twice as long for CR oxycodone (3.2 ± 2.2 hours) as for IR oxycodone (1.4 ± 0.7 hours) ( P = 0.005). The area under the plasma concentation—time curve from 0 to 12 hours at steady state was 103.6 ± 40.0 ng • h/mL for CR oxycodone and 99.0 ± 35.8 ng • h/mL for IR oxycodone. Except for T max, there were no significant differences in pharmacokinetic parameters between treatments. Approximately twice as many adverse experiences, several of longer duration than noted with CR oxycodone, were reported with IR oxycodone. The bioavailability of the CR tablet was equal to that of the IR solution; however, the rate of oxycodone absorption from the CR tablet was slower than that from the IR solution, as shown by the T max value. The use of CR oxycodone will allow selection of the most clinically appropriate nonopioid analgesic, as well as independent titration and dosing, thereby enhancing therapeutic flexibility.

Pharmacokinetic-pharmacodynamic relationships of controlled-release oxycodone.

Plasma concentrations of oxycodone, oxymorphone, and noroxycodone were determined after administration of 20 mg oral controlled-release oxycodone tablets to four subject groups: young (aged 21 to 45 years) men, elderly (aged 65 to 79 years) men, young women, and elderly women. Area under the oxycodone and noroxycodone concentration-time curve (AUC) values were comparable among the four groups. Compared with oxycodone, the oxymorphone AUC values were small, with significant differences between subject groups. AUC values were also calculated for the pharmacodynamic variable "drug effect," scored on a 100 mm visual analog scale. The two groups with the highest oxycodone AUC values (young and elderly women) had the lowest oxymorphone AUC values and the greatest drug effect AUC values. The two groups with the lowest oxycodone AUC values (young and elderly men) had the highest oxymorphone AUC values and the lowest drug effect AUC values. These results support oxycodone, and not oxymorphone, as being primarily responsible for pharmacodynamic and analgesic effects.