A rapid and sensitive LC-MS/MS method for quantifying oxycodone, noroxycodone, oxymorphone and noroxymorphone in human plasma to support pharmacokinetic drug interaction studies of oxycodone.

A sensitive and reliable LC-MS/MS method was developed and validated for the quantification of oxycodone and metabolites in human plasma. The method has a runtime of 6 min and a sensitivity of 0.1 µg/L for all analytes. Sample preparation consisted of protein precipitation. Separation was performed on a Kinetix biphenyl column (2.1 × 100 mm, 1.7 µm), using ammonium formate 5 mm in 0.1% aqueous formic acid and methanol LC-MS grade 100% in gradient elution at a flow rate of 0.4 ml/min. Detection was performed in multiple reaction monitoring mode using positive electrospray ionization. The method was linear over the calibration range of 0.1-25.0 µg/L for oxycodone, noroxycodone and noroxymorphone and 0.1-5.0 µg/L for oxymorphone. The method demonstrated good performance in terms of intra- and interday accuracy (86.5-110.3%) and precision (CV 1.7-9.3%). The criteria for the matrix effect were met (CV < 15%) except for noroxymorphone, for which an additional method was applied to compensate for the matrix effect. Whole blood samples were stable for 4 h at room temperature. Plasma samples were stable for 24 h at room temperature and 3 months at -20°C. Furthermore, the method was successfully applied in a pharmacokinetic drug interaction study of oxycodone and enzalutamide in patients with prostate cancer.

Electrochemical sensor based on glassy carbon electrode modified by polymelamine formaldehyde/graphene oxide nanocomposite for ultrasensitive detection of oxycodone.

Polymelamine formaldehyde/graphene oxide (PMF/GO) nanocomposite was used, for the first time, to study the ultrasensitive and selective electrochemical detection of oxycodone (OXC). The successful characterization of PMF/GO was verified based on scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR), X-ray diffraction (XRD), energy-dispersive spectroscopy (EDS), and Raman spectroscopy. The modified GCE (PMF/GO-GCE) proved its electrocatalytic effect on OXC determination according to cyclic, linear sweep, and differential pulse voltammetry (CV, LSV, and DPV) and electrochemical impedance spectroscopy (EIS) studies. The developed sensor under optimal conditions offered a linear relationship in a limited range of  0.01 to 45 µmol L-1 with the limit of detection (LOD) of 2.0 nmol L-1. The proposed PMF/GO-GCE sensor was effectively employed for the OXC detection in human urine and serum samples. Graphical abstract.

Oral prescription opioid-seeking behavior in male and female mice.

A significant portion of prescription opioid users self-administer orally rather than intravenously. Animal models of opioid addiction have demonstrated that intravenous cues are sufficient to cause drug seeking. However, intravenous models may not characterize oral users, and the preference to self-administer orally appears to be partially influenced by the user's sex. Our objectives were to determine whether oral opioid-associated cues are sufficient for relapse and whether sex differences exist in relapse susceptibility. Mice orally self-administered escalating doses of oxycodone under postprandial (prefed) or non-postprandial (no prefeeding) conditions. Both sexes demonstrated cue-induced reinstatement following abstinence. In separate mice, we found that oral oxycodone cues were sufficient to reinstate extinguished oral oxycodone-seeking behavior following abstinence without prior postprandial or water self-administration training. During self-administration, we incidentally found that female mice earned significantly more mg/kg oxycodone than male mice. Follow-up studies indicated sex differences in psychomotor stimulation and plasma oxycodone/oxymorphone following oral oxycodone administration. In addition, gonadal studies were performed in which we found divergent responses where ovariectomy-enhanced and orchiectomy-suppressed oral self-administration. While the suppressive effects of orchiectomy were identified across doses and postprandial conditions, the enhancing effects of ovariectomy were selective to non-postprandial conditions. These studies establish that (a) oral drug cues are sufficient to cause reinstatement that is independent of prandial conditions and water-seeking behavior, (b) earned oral oxycodone is larger in female mice compared with male mice potentially through differences in psychomotor stimulation and drug metabolism, and (c) gonadectomy produces divergent effects on oral oxycodone self-administration between sexes.

Sex differences in oral oxycodone self-administration and stress-primed reinstatement in rats.

The opioid epidemic has become a severe public health problem, with approximately 130 opioid-induced deaths occurring each day in the United States. Prescription opioids are responsible for approximately 40% of these deaths. Oxycodone is one of the most commonly abused prescription opioids, but despite its prevalent misuse, the number of preclinical studies investigating oxycodone-seeking behaviors is relatively limited. Furthermore, preclinical oxycodone studies that include female subjects are even more scarce, and it is critical that future work includes both sexes. Additionally, the oral route of administration is one of the most common routes for recreational users, especially in the early stages of drug experimentation. However, currently, only two studies have been published investigating operant oral oxycodone self-administration in rodents. Therefore, the primary goal of the present study was to establish an oral oxycodone operant self-administration model in adult male and female rats, as well as to examine a potential mechanism of stress-primed reinstatement. We found that females consumed significantly more oral oxycodone than males in operant self-administration sessions. We also found that active oxycodone self-administration was reduced by mu opioid receptor antagonism and by substitution of water for oxycodone solution. Lastly, we induced stress-primed reinstatement and found that this behavior was significantly attenuated by antagonism of the neurokinin-1 receptor, consistent with our prior work examining stress-induced reinstatement of alcohol- and cocaine-seeking.

Oxycodone for pain management in the latent phase of labour - A pragmatic trial.

BACKGROUND: Parenteral opioids are used for pain relief in labour but there are little data for oxycodone in this context. The aim of this study was to evaluate the efficacy, foetal exposure and safety of subcutaneous oxycodone in the latent phase of labour. METHODS: This pragmatic trial included 76 parturients, who received subcutaneous oxycodone for pain relief in the latent phase of labour according to the hospital protocol: an initial dose 0.1 mg/kg, and a second dose, 0.05 mg/kg, could be administered four hours later. Pain intensity and pain relief were assessed using a numerical rating scale of 0-10. After delivery, blood samples from the maternal and umbilical veins were collected, and plasma concentrations of oxycodone and its main metabolites were quantified using UPLC-MS/MS. The Apgar scores and maternal and neonatal adverse effects were recorded. RESULTS: The foetal exposure at birth was low, the median oxycodone and oxymorphone umbilical vein plasma concentrations were 1.2 ng/mL (range 0.21-7.8) and 0.14 ng/mL (0-0.26), respectively. Pain scores decreased substantially, from a median pain score of 7/10 before oxycodone to median scores of 5/10 at 30 minutes after administration, 5/10 at 60 minutes and 6/10 at 120 minutes. The median Apgar score was 9 (range 2-10) at 1 minute and 9 (6-10) at 5 minutes. Maternal adverse effects were mild, and there were no oxycodone-related neonatal adverse effects. CONCLUSION: Subcutaneous oxycodone provided effective analgesia during the latent phase of labour. Newborn exposure at birth was low, and oxycodone was well-tolerated.

Effectiveness and Safety of Once-Daily Extended-Release Hydrocodone in Individuals Previously Receiving Immediate-Release Oxycodone for Chronic Pain.

Objectives: This study evaluated the safety and effectiveness of a once-daily, single-entity, extended-release hydrocodone bitartrate (HYD) among patients with chronic noncancer and non-neuropathic pain who required opioid rotation from a previous analgesic regimen that primarily consisted of immediate-release (IR) oxycodone. Methods: Post hoc analyses of a primary study that assessed HYD 20 to 120 mg over a 52-week period are presented. The primary study included a dose titration period (up to 45 days), a 52-week maintenance period, and an optional taper period (up to 14 days). Results: Relative to baseline, mean "average pain over the last 24 hours" declined by 1.9 points at the end of the titration period and by 2.6 points at the end of the maintenance period. Additionally, interference and severity of pain as measured by the Brief Pain Inventory-Short Form decreased by 2.3 and 1.9 points, respectively, during the maintenance period. The use of supplemental opioid analgesics decreased. Most patients remained on a stable HYD dose throughout the maintenance period. Most patients indicated satisfaction with HYD and considered it convenient and easy to use. HYD demonstrated a safety profile typical of µ opioids; nausea, constipation, vomiting, and dizziness were the most frequently reported opioid-related adverse events during the study. Conclusions: In patients with chronic pain who received HYD over a 52-week period, treatment was generally well tolerated and provided effective analgesia among those who rotated from a pain regimen primarily consisting of IR oxycodone.

Determination of oxycodone and its major metabolites noroxycodone and oxymorphone by ultra-high-performance liquid chromatography tandem mass spectrometry in plasma and urine: application to real cases.

BACKGROUND: Oxycodone is a narcotic drug widely used to alleviate moderate and severe acute and chronic pain. Variability in analgesic efficacy could be explained by inter-subject variations in plasma concentrations of parent drug and its active metabolite, oxymorphone. To evaluate patient compliance and to set up therapeutic drug monitoring (TDM), an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) assay was developed and validated for the parent drug and its major metabolites noroxycodone and oxymorphone. METHODS: Extraction of analytes from plasma and urine samples was obtained by simple liquid-liquid extraction. The chromatographic separation was achieved with a reversed phase column using a linear gradient elution with two solvents: acetic acid 1% in water and methanol. The separated analytes were detected with a triple quadrupole mass spectrometer operated in multiple reaction monitoring (MRM) mode via positive electrospray ionization (ESI). RESULTS: Separation of analytes was obtained in less than 5 min. Linear calibration curves for all the analytes under investigation in urine and plasma samples showed determination coefficients (r2) equal or higher than 0.990. Mean absolute analytical recoveries were always above 86%. Intra- and inter-assay precision (measured as coefficient of variation, CV%) and accuracy (measured as % error) values were always better than 13%. Limit of detection at 0.06 and 0.15 ng/mL and limit of quantification at 0.2 and 0.5 ng/mL for plasma and urine samples, respectively, were adequate for the purpose of the present study. CONCLUSIONS: Rapid extraction, identification and quantification of oxycodone and its metabolites both in urine and plasma by UHPLC-MS/MS assay was tested for its feasibility in clinical samples and provided excellent results for rapid and effective drug testing in patients under oxycodone treatment.

Abuse Potential Study of ALO-02 (Extended-Release Oxycodone Surrounding Sequestered Naltrexone) Compared with Immediate-Release Oxycodone Administered Orally to Nondependent Recreational Opioid Users.

Objective: To evaluate the abuse potential of ALO-02, an abuse-deterrent formulation comprising pellets of extended-release oxycodone hydrochloride surrounding sequestered naltrexone hydrochloride. Design: Randomized, double-blind, placebo-/active-controlled, 6-way crossover study, with naloxone challenge, drug discrimination, and treatment phases. Subjects: Nondependent, recreational opioid users. Methods: Oral administration of crushed and intact ALO-02, crushed immediate-release (IR) oxycodone, and placebo. Primary endpoints were Drug Liking and High measured on visual analog scales and reported as maximum effect (E max ) and area-under-the-effect-curve from 0 to 2 hours (AUE 0-2h ). Other pharmacodynamic, pharmacokinetic and safety assessments were included. Results: Drug Liking and High (E max ) for crushed oxycodone IR 40 mg were significantly higher compared with placebo, confirming study validity ( P < 0.0001). Drug Liking and High (E max, AUE 0-2h ) for crushed ALO-02 (40 mg/4.8 mg and 60 mg/7.2 mg) were significantly lower compared to corresponding doses of crushed oxycodone IR (40 and 60 mg; P < 0.0001). Likewise, Drug Liking and High (E max and AUE 0-2h ) for intact ALO-02 60 mg/7.2 mg were significantly lower compared with crushed oxycodone IR 60 mg ( P < 0.0001). Secondary pharmacodynamic endpoints and plasma concentrations of oxycodone and naltrexone were consistent with these results. Fewer participants experienced adverse events (AEs) after ALO-02 (crushed or intact: 71.1-91.9%) compared with crushed oxycodone IR (100%). Most common AEs following crushed ALO-02 and oxycodone IR were euphoric mood, pruritus, somnolence, and dizziness. Conclusions: The results suggest that ALO-02 (crushed or intact) has lower abuse potential than crushed oxycodone IR when administered orally in nondependent, recreational opioid users.

Oxycodone in Palliative Care-Art and Empathy Still Have a Place.

A 47-year-old woman who was receiving palliative care for metastatic breast cancer, which included oxycodone, was found dead in bed. The femoral blood level of oxycodone at autopsy was 1200 µg/L, which is a value within the lethal range. Could the cause of death be attributed to misadventure or suicide? Would the coroner consider a recommendation of therapeutic drug monitoring in palliative care which could have a serious negative impact on pain relief practice? A narrative verdict was the outcome linking the primary cause of death with the drug cocktail found at autopsy.

Dialyzability of Oxycodone and Its Metabolites in Chronic Noncancer Pain Patients with End-Stage Renal Disease.

OBJECTIVES: Opioids are the preferred analgesic drugs to treat severe chronic pain conditions among dialysis patients; however, knowledge about their dialyzability features is limited. Oxycodone is increasingly used for the treatment of chronic pain conditions as oral controlled release (CR) tablets; however, evidence about this drug and its metabolites' dialyzability is lacking. METHODS: We assessed, during 4-hour dialysis sessions, the effect of standard hemodialysis (HD) and online hemodiafiltration (HDF) methods on the plasma concentration of oxycodone and its metabolites in n = 20 chronic pain patients with end-stage renal disease who were stably treated with oral CR oxycodone. Chromatographic techniques were used to evaluate the studied compounds' plasma concentrations at three different time points during dialysis. RESULTS: Mean plasma concentrations of oxycodone and noroxycodone in the sample showed an overall reduction trend over time, but it was less enhanced for noroxycodone. Mean reduction in oxycodone and noroxycodone arterial concentrations was significant and higher with HDF (54% and 27%, respectively) than with HD (22% and 17%, respectively). Analysis of the regression of these compounds' clearance on their increasing arterial concentration showed a more stable and linear clearance prediction with HDF (roughly 85 mL/min); with HD, for increasing arterial concentration, clearance of oxycodone decreased while noroxycodone clearance increased. DISCUSSION: While no oxymorphone or noroxymorphone metabolites were detected, limited dialyzability of oxycodone and noroxycodone was documented along with insignificant postdialysis pain increment. This evidence will contribute toward considerations as to the safety of the use of oxycodone in dialysis patients in the future.

Relationships between oxycodone pharmacokinetics, central symptoms, and serum interleukin-6 in cachectic cancer patients.

PURPOSE: Elevated serum proinflammatory cytokines are associated with the reduction of cytochrome P450 enzyme (CYP) activity. This study aimed to evaluate the oxycodone pharmacokinetics, central symptoms, and serum proinflammatory cytokines based on cachexia stage in cancer patients. METHODS: Forty-seven cancer patients receiving extended-release oxycodone were enrolled. Predose plasma concentrations of oxycodone and its metabolites were normalized with the daily dose and body weight. The central symptoms and serum level of proinflammatory cytokines were investigated at each cachexia stage. RESULTS: The plasma concentrations of oxycodone in patients with cachexia and refractory cachexia were significantly higher than that in patients with precachexia. The metabolic ratio to noroxycodone in patients with cachexia was significantly lower than that in patients with precachexia. The patients with a higher cachexia stage had a higher serum level of interleukin-6 (IL-6), but not tumor necrosis factor-α and interleukin-1ß. The serum IL-6 level was correlated with the plasma concentration of oxycodone and inversely with the metabolic ratio to noroxycodone. The incidence of somnolence was not associated with the plasma oxycodone concentration. In contrast, the cachexia stage and its associated serum IL-6 level were correlated with the incidence of somnolence. CONCLUSIONS: Cancer cachexia raised the plasma exposure of oxycodone through the reduction of CYP3A metabolic pathway. The reduction of CYP3A in cachectic cancer patients was associated with an elevation of serum IL-6. Although cachectic cancer patients with higher serum IL-6 levels had the symptom of somnolence, the alterations in oxycodone pharmacokinetics were not related to the incidence of symptom.

Correlation of Subjective Effects with Systemic Opioid Exposure from Fixed-Dose Combinations of Oxycodone/Acetaminophen in Recreational Users of Prescription Drugs.

OBJECTIVE: To correlate abuse-related pharmacodynamic measures and pharmacokinetic measures after administering immediate-release/extended-release and immediate-release oxycodone/acetaminophen fixed-dose combination analgesicsDesign. Randomized, double-blind, active- and placebo-controlled, 7-way crossover studySetting. Contract research organizationSubjects. Nondependent recreational users of prescription opioids. METHODS: Participants received single doses of intact immediate-release/extended-release and immediate-release oxycodone/acetaminophen 15/650 mg, intact immediate-release/extended-release and immediate-release oxycodone/acetaminophen 30/1,300 mg, crushed immediate-release/extended-release and immediate-release oxycodone/acetaminophen 30/1,300 mg, and placebo. Measures of pharmacodynamics (pupillometry, drug liking, drug high, good drug effects) and pharmacokinetics were assessed predose and up to 24 hours postdose, and correlations between pharmacokinetic parameters and pharmacodynamic data were explored. RESULTS: Of 61 participants, 55 completed all 7 treatments. Intact immediate-release/extended-release oxycodone/acetaminophen produced 50% lower oxycodone peak plasma concentration (Cmax) than immediate-release oxycodone/acetaminophen. Median oxycodone time to Cmax (tmax) was significantly longer (P<0.001) for intact immediate-release/extended-release oxycodone/acetaminophen than immediate-release oxycodone/acetaminophen. The pharmacokinetics of crushed immediate-release/extended-release and immediate-release oxycodone/acetaminophen (30/1,300 mg) followed a similar pattern. Crushing did not shorten the median oxycodone tmax for immediate-release/extended-release oxycodone/acetaminophen (30/1,300 mg). Strong correlations were observed between oxycodone Cmax and area under the curve from time 0 to time x peak effects and area under the subjective effect curve from time 0 to time x for all subjective effects (R2=0.711-0.997). CONCLUSION: Immediate-release/extended-release oxycodone/acetaminophen produced lower oxycodone Cmax and longer tmax than immediate-release oxycodone/acetaminophen. Lower oxycodone concentrations, particularly at earlier time points, were strongly correlated with lesser positive subjective drug effects.

Intravenous abuse potential study of oxycodone alone or in combination with naltrexone in nondependent recreational opioid users.

BACKGROUND: ALO-02, comprising pellets of extended-release oxycodone surrounding sequestered naltrexone, is intended to deter abuse. OBJECTIVE: Determine the abuse potential of intravenous oxycodone combined with naltrexone, which represents simulated crushed ALO-02 in solution, compared with intravenous oxycodone in nondependent, recreational opioid users. METHODS: A randomized, double-blind, placebo-controlled, three-way crossover study with naloxone challenge, drug discrimination, and treatment phases. Intravenous treatments included oxycodone hydrochloride 20 mg, oxycodone hydrochloride 20 mg plus naltrexone hydrochloride 2.4 mg (simulated crushed ALO-02 20 mg/2.4 mg), or placebo (0.9% sodium chloride for injection). Primary end points were peak effects (Emax) and area under the effects curve within 2 h postdose (AUE0-2h) on drug liking and high visual analog scales. RESULTS: Thirty-three participants were randomized into treatment phase, and 29 completed all treatments. Study validity was confirmed with statistically significant differences in Emax for drug liking and high (p < 0.0001) between intravenous oxycodone and placebo. Intravenous simulated crushed ALO-02 resulted in significantly lower scores than oxycodone on drug liking (Emax: 58.2 vs. 92.4; AUE0-2h: 104.3 vs. 152.4) and high (Emax: 17.2 vs. 93.1; AUE0-2h: 12.0 vs. 133.6), respectively (p < 0.0001, all comparisons). More participants experienced adverse events after intravenous oxycodone (n = 27 [90%]) versus intravenous simulated crushed ALO-02 (n = 4 [12.5%]) or placebo (n = 2 [6.5%]). CONCLUSION: Intravenous administration of simulated crushed ALO-02 resulted in significantly lower abuse potential, as assessed by subjective ratings of drug liking and high, than intravenous oxycodone in nondependent, recreational opioid users. This suggests that injection of ALO-02 may not be as desirable to recreational opioid users compared with oxycodone taken for nonmedical reasons.

Should the dosage of controlled-release oxycodone in advanced cancer be modified on the basis of patient characteristics?

PURPOSE: This study aimed to investigate whether the characteristics of patients with advanced cancer explain the variability in oxycodone clearance, with the potential for this information to determine maintenance dosing. METHODS: Patients (n = 36) with advanced cancer who were receiving delayed-release oxycodone (Oxycontin®) (mean dose, 31.4 mg; range, 5-120 mg) mostly twice daily (mean duration = 80 days; range, 5-651 days) provided venous blood samples (n = 139, median = 3 per patient) drawn from 0.25 to 23.4 h post-dose. Plasma was assayed for oxycodone (mean = 39.4 ng/mL; range, 1-256 ng/mL) by high-performance liquid chromatography with tandem mass spectrometry detection. Pharmacokinetic modeling was performed using nonlinear mixed-effects modeling (NONMEM). RESULTS: A one-compartment model with first-order absorption and elimination best described the data. Typical population values and between-subject variability (coefficient of variation, percent) for oxycodone clearance and the oral absorption rate constant were 73 L/h (31.9 %) and 0.0735 h (133 %), respectively. The volume of distribution was estimated based on literature values for intravenous oxycodone in cancer patients. The inclusion of weight, sex, age, creatinine clearance, and serum albumin concentration did not significantly explain pharmacokinetic variability in clearance or absorption rate constant. The subject with the most elevated liver function test values also had the lowest clearance per kilogram. CONCLUSIONS: Oxycodone clearance was similar to that reported previously for healthy adults. Despite reports that patient characteristics significantly affect oxycodone pharmacokinetics, our results do not support alteration of current prescribing practices for maintenance dosing of Oxycontin® in most patients with advanced cancer. The influence of marked liver dysfunction on oxycodone clearance requires further investigation.

Electrochemical sensor based on mesoporous g-C3N4/N-CNO/gold nanoparticles for measuring oxycodone.

Oxycodone, often used as an analgesic, is a potent opioid. While its effectiveness has been proven in the control of moderate to acute pain, excessive use of oxycodone imposes heart failure, heart palpitations, reduction of red blood cells, bone pain, and even death. Therefore, monitoring the oxycodone concentration in blood is vital for emergency care. For this purpose, a novel electrochemical sensor was designed based on a glassy carbon electrode modified with mesoporous g-C3N4 (M-C3N4), carbon nano-onions doped with nitrogen (N-CNO), and gold nanoparticles. At first, the SEM and XRD techniques were employed to characterize prepared M-C3N4 and N-CNO samples. The electro-oxidation behavior of the oxycodone was evaluated by cyclic and differential pulse voltammetric methods. Based on the influence of the potential scanning rate and solution pH on the voltammetric response of oxycodone oxidation, a redox mechanism was proposed. A 16 nM detection limit was acquired for the oxycodone analysis with a linear response in the 0.05-150 µM range. This sensor showed a remarkable ability for oxycodone detection in plasma samples. The long-term stability, superior selectivity, and reproducibility of this sensor prove its ability to measure oxycodone accurately and precisely in authentic spices.

Serum concentrations of opioids when comparing two switching strategies to methadone for cancer pain.

PURPOSE: Our aim was to compare pharmacological aspects of two switching strategies from morphine/oxycodone to methadone; the stop and go (SAG) strategy in which methadone is started directly after the initial opioid has been stopped, and the 3-days switch (3DS), in which morphine/oxycodone is gradually changed to methadone by cross-tapering over 3 days. METHODS: Forty-two cancer patients with pain and/or opioid side effects were assessed in this randomised trial. Trough serum concentrations of methadone, morphine, morphine-6-glucuronide (M6G), and oxycodone were measured on days 1, 2, 3, 4, 7, and 14. Primary outcome was number of patients with methadone concentrations in apparent C(SS) on day 4. Secondary outcomes were exposure to opioids during the first 3 days, interindividual variation of opioid concentrations, and correlation between methadone concentrations and pain intensity (PI) day 3. RESULTS: Thirty-five patients received methadone (16 in the SAG group, 19 in the 3DS group). The median preswitch morphine equivalent doses were 620 (range 350-2000) mg/day in the SAG group and 800 (range 90-3600) mg/day in the 3DS group (p = 0.43);42% reached C(SS) for methadone in the SAG group on day 4 compared with 22% in the 3DS group (p = 0.42). The SAG group was significantly less exposed to morphine/M6G/oxycodone and significantly more exposed to methadone in the first 3 days. Methadone showed a low correlation with PI. More patients dropped out after intervention in the SAG group than in the 3DS group (38% vs. 5%; p = 0.032). One SAG patient suffered from respiratory depression on day 5. CONCLUSION: The SAG group was initially more exposed to methadone and less to the replaced opioids but without observed clinical benefit and with a higher dropout rate. Patients switched to methadone should be followed closely for the first 5 days, regardless of switching strategy.

Oxycodone clearance is markedly reduced with advancing age: a population pharmacokinetic study.

BACKGROUND: Oxycodone is a µ-opioid receptor agonist, the global use of which has increased vigorously during the past decade. The pharmacokinetic data of oxycodone available for elderly are limited, and there appear to be only little data on the population pharmacokinetics of oxycodone. METHODS: We analysed 1272 plasma oxycodone samples of 77 individuals (range of age 19-89 yr) with non-linear mixed effect modelling. Inter- and intra-individual variability of the model was estimated for clearances and distribution volumes. The effect of covariates was studied with simulations. RESULTS: Data were best described with a two-compartment linear model. Lean body mass and age were found to be significant covariates for elimination clearance and the volume of the central compartment. The population estimates of elimination clearance, volume of the central compartment, and the volume of distribution at steady state for a reference individual (male 35 yr, 70 kg, 170 cm) were 51.0 litre h(-1), 134, and 258 litres, respectively. The elimination half-life of oxycodone showed an age-dependent increase. The context-sensitive half-time at steady state increased from 3.8 to 4.6 h between the age of 25 and 85 yr, respectively. Simulations of repetitive bolus dosing showed a 20% increase in oxycodone concentration in the elderly. CONCLUSIONS: Age was found to be a significant covariate for oxycodone pharmacokinetics. In elderly patients, dosing should therefore be reduced and carefully titrated to avoid considerable accumulation of oxycodone and potentially hazardous side-effects.

Randomized, double-blind, placebo-controlled study of the abuse potential of different formulations of oral oxycodone.

OBJECTIVE: The objective of this study was to evaluate the pharmacokinetics and abuse potential of different formulations of oxycodone. DESIGN: The participants completed an 8-day, placebo-controlled trial with four phases: naloxone challenge, double-blind drug discrimination, double-blind abuse liability, and discontinuation. SUBJECTS: Nineteen healthy, male, recreational drug abusers participated in this study. INTERVENTIONS: The participants were administered different doses and formulations of oxycodone (40 mg immediate release [IR], 40 mg controlled release [CR], crushed 40 mg CR, and 80 mg CR) to evaluate pharmacokinetic parameters and ratings of drug liking and high. OUTCOME MEASURES: Pharmacokinetic parameters were determined over a 12-hour dosing interval. The primary pharmacodynamic endpoints were two questions from the Drug Effects Questionnaire ("Do you like the drug?" and "How high are you now?"). RESULTS: Maximal plasma concentrations and area under the curve determinations were similar for 40 mg IR, crushed 40 mg CR, and 80 mg CR, which were all greater than 40 mg CR. For drug liking and high, the maximal effect and area under the effect curve were similar for the three formulations, which were all greater than 40 mg CR. The dose required to produce comparable reports of drug liking and high was approximately twofold greater for the CR vs IR formulation. When the 40 mg CR tablet was crushed, the pharmacokinetic and pharmacodynamic profile was similar to the 40 mg IR formulation. Adverse events were consistent with opioid administration. CONCLUSIONS: Intact, orally administered oxycodone CR produced less drug liking and high than IR oxycodone, and required approximately twofold greater doses to produce subjective effects comparable to IR oxycodone.

Ingestion of drugs by "parachuting": a unique drug delivery technique.

"Parachuting" is a technique of drug delivery where medications or illicit drugs are ingested by wrapping the drug of choice in a covering, which then will dissolve or unravel in the gastrointestinal tract, thereby releasing the drug for absorption. Parachuting of drugs can entail crushing of a pill prior to packaging to theoretically increase the surface area for absorption or may involve the packaging of a higher than usual dose of a drug in attempts to attain a sustained-release effect as the "parachute" dissolves or unravels. A case is presented in which a prescription drug abuser known to parachute his medications dies from obstruction of his airway by the inhaled packet. Risks of parachuting any drug would include overdose and fatal toxic effect from the drug itself and adverse effects from the packaging including bowel obstruction or perforation, or airway obstruction.