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Dexmedetomidine is a highly selective, potent α₂-adrenoceptor agonist which was approved in 2011 by the European Medicines Agency for sedation of patients in intensive care units (ICU). Dexmedetomidine exhibits sedative as well as analgesic and anxiolytic effects. Recent studies suggest that dexmedetomidine may be an alternative to midazolam in long-term ICU sedation. This review summarizes the pharmacokinetics and pharmacodynamics of dexmedetomidine particularly in ICU patients and with special regard to covariate effects. Although dexmedetomidine is currently approved only for use in adults the pharmacokinetics and pharmacodynamics in children will also be addressed as there are numerous studies on this off-label use. [ABSTRACT FROM AUTHOR]

BACKGROUND: Chronic pain is associated with depression. Self-treatment of depression with herbal over-the-counter medicine St John's wort makes pain patients prone to drug interactions. AIMS: The aim of this study was to assess the potential of St John's wort to alter the CYP3A-mediated metabolism of a mu-opioid receptor agonist, oxycodone. METHODS: The study design was placebo-controlled, randomized, cross-over with two phases at intervals of 4 weeks and was conducted with 12 healthy participants. St John's wort (Jarsin) or placebo was administered t.i.d. for 15 days and oral oxycodone hydrochloride 15 mg on day 14. Oxycodone pharmacokinetics and pharmacodynamics were compared after St John's wort or placebo. Behavioural and analgesic effects were assessed with subjective visual analogue scales and cold pressor test. Plasma drug concentrations were measured from 0 to 48 h, behavioural and analgesic effects from 0 to 12 h. RESULTS: Following St John's wort administration the oxycodone AUC decreased 50% (p<0.001). Oxycodone elimination half-life shortened from a mean+/-SD 3.8+/-0.7 to 3.0+/-0.4h (p<0.001). The self-reported drug effect of oxycodone as measured by AUEC(0-12) decreased significantly (p=0.004). Differences between St John's wort and placebo phases in cold pain threshold and intensity AUEC(0-12) were not observed. CONCLUSIONS: St John's wort greatly reduced the plasma concentrations of oral oxycodone. The self-reported drug effect of oxycodone decreased significantly. This interaction may potentially be of some clinical significance when treating patients with chronic pain. [ABSTRACT FROM AUTHOR]

Background: The use of intranasal dexmedetomidine is hampered by a limited understanding of its absorption pharmacokinetics., Methods: We examined the pharmacokinetics and feasibility of intranasal dexmedetomidine administered in the supine position to adult patients undergoing general anaesthesia. Twenty-eight patients between 35 and 80 years of age, ASA 1-3 and weight between 50 and 100 kg, who underwent elective unilateral total hip or knee arthroplasty under general anaesthesia were recruited. All patients received 100 μg of intranasal dexmedetomidine after anaesthesia induction. Six venous blood samples (at 0, 5, 15, 45, 60, 240 min timepoints from dexmedetomidine administration) were collected from each patient and dexmedetomidine plasma concentrations were measured. Concentration-time profiles after nasal administration were pooled with earlier data from a population analysis of intravenous dexmedetomidine (n = 202) in order to estimate absorption parameters using nonlinear mixed effects. Peak concentration (C MAX ) and time (T MAX ) were estimated using simulation (n = 1000) with parameter estimates and their associated variability., Results: There were 28 adult patients with a mean (SD) age of 66 (8) years and weight of 83 (10) kg. The mean weight-adjusted dose of dexmedetomidine was 1.22 (0.15) μg kg -1 . C MAX 0.273 μg L -1 was achieved at 98 min after intranasal administration (T MAX ). The relative bioavailability of dexmedetomidine was 80% (95% CI 75-91%). The absorption half-time (T ABS  = 120 min; 95% CI 90-147 min) was slower than that in previous pharmacokinetic studies on adult patients. Perioperative haemodynamics of all patients remained stable., Conclusions: Administration of intranasal dexmedetomidine in the supine position during general anaesthesia is feasible with good bioavailability. This administration method has slower absorption when compared to awake patients in upright position, with consequent concentrations attained after T MAX for several hours., (© 2024 The Author(s). Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Naloxone is a World Health Organization (WHO)-listed essential medicine and is the first choice for treating the respiratory depression of opioids, also by lay-people witnessing an opioid overdose. Naloxone acts by competitive displacement of opioid agonists at the μ-opioid receptor (MOR). Its effect depends on pharmacological characteristics of the opioid agonist, such as dissociation rate from the MOR receptor and constitution of the victim. Aim of treatment is a balancing act between restoration of respiration (not consciousness) and avoidance of withdrawal, achieved by titration to response after initial doses of 0.4-2 mg. Naloxone is rapidly eliminated [half-life (t 1/2 ) 60-120 min] due to high clearance. Metabolites are inactive. Major routes for administration are intravenous, intramuscular, and intranasal, the latter primarily for take-home naloxone. Nasal bioavailability is about 50%. Nasal uptake [mean time to maximum concentration (T max ) 15-30 min] is likely slower than intramuscular, as reversal of respiration lag behind intramuscular naloxone in overdose victims. The intraindividual, interindividual and between-study variability in pharmacokinetics in volunteers are large. Variability in the target population is unknown. The duration of action of 1 mg intravenous (IV) is 2 h, possibly longer by intramuscular and intranasal administration. Initial parenteral doses of 0.4-0.8 mg are usually sufficient to restore breathing after heroin overdose. Fentanyl overdoses likely require higher doses of naloxone. Controlled clinical trials are feasible in opioid overdose but are absent in cohorts with synthetic opioids. Modeling studies provide valuable insight in pharmacotherapy but cannot replace clinical trials. Laypeople should always have access to at least two dose kits for their interim intervention., (© 2024. The Author(s).)

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is a neurological emergency, affecting a younger population than individuals experiencing an ischemic stroke; aSAH is associated with a high risk of mortality and permanent disability. The noble gas xenon has been shown to possess neuroprotective properties as demonstrated in numerous preclinical animal studies. In addition, a recent study demonstrated that xenon could attenuate a white matter injury after out-of-hospital cardiac arrest., Methods: The study is a prospective, multicenter phase II clinical drug trial. The study design is a single-blind, prospective superiority randomized two-armed parallel follow-up study. The primary objective of the study is to explore the potential neuroprotective effects of inhaled xenon, when administered within 6 h after the onset of symptoms of aSAH. The primary endpoint is the extent of the global white matter injury assessed with magnetic resonance diffusion tensor imaging of the brain., Discussion: Despite improvements in medical technology and advancements in medical science, aSAH mortality and disability rates have remained nearly unchanged for the past 10 years. Therefore, new neuroprotective strategies to attenuate the early and delayed brain injuries after aSAH are needed to reduce morbidity and mortality., Trial Registration: ClinicalTrials.gov NCT04696523. Registered on 6 January 2021. EudraCT, EudraCT Number: 2019-001542-17. Registered on 8 July 2020., (© 2023. The Author(s).)

Background: Spinal fusion surgery causes severe pain. Strong opioids, commonly used as postoperative analgesics, may have unwanted side effects. S-ketamine may be an effective analgesic adjuvant in opioid patient-controlled analgesia (PCA). However, the optimal adjunct S-ketamine dose to reduce postoperative opioid consumption is still unknown., Methods: We randomized 107 patients at two tertiary hospitals in a double-blinded, placebo-controlled clinical trial of adults undergoing major lumbar spinal fusion surgery. Patients were randomly allocated to four groups in order to compare the effects of three different doses of adjunct S-ketamine (0.25, 0.5, and 0.75 mg ml-1) or placebo on postoperative analgesia in oxycodone PCA. Study drugs were administered for 24 hours postoperative after which oxycodone-PCA was continued for further 48 hours. Our primary outcome was cumulative oxycodone consumption at 24 hours after surgery., Results: Of the 100 patients analyzed, patients receiving 0.75 mg ml-1 S-ketamine in oxycodone PCA needed 25% less oxycodone at 24 h postoperatively (61.2 mg) compared with patients receiving 0.5 mg ml-1 (74.7 mg) or 0.25 mg ml-1 (74.1 mg) S-ketamine in oxycodone or oxycodone alone (81.9 mg) (mean difference: -20.6 mg; 95% confidence interval [CI]: -41 to -0.20; P = 0.048). A beneficial effect in mean change of pain intensity at rest was seen in the group receiving 0.75 mg ml-1 S-ketamine in oxycodone PCA compared with patients receiving lower ketamine doses or oxycodone alone (standardized effect size: 0.17, 95% CI: 0.013-0.32, P = 0.033). The occurrence of adverse events was similar among the groups., Conclusions: Oxycodone PCA containing S-ketamine as an adjunct at a ratio of 1: 0.75 decreased cumulative oxycodone consumption at 24 h after major lumbar spinal fusion surgery without additional adverse effects., Competing Interests: The authors have declared that no competing interests exist.

The capability of viscoelastic measurement parameters to screen anticoagulation activity of edoxaban in relation to its plasma concentrations was evaluated in 15 healthy male volunteers. Blood samples were drawn before the oral administration of edoxaban 60 mg and 2, 4, 6, 8, and 24 hours after administration. At each time, standard coagulation tests were performed, blood viscoelastic properties were measured with a thromboelastometry device ROTEM delta analyzer (Instrumentation Laboratory, Werfen, Barcelona, Spain), and edoxaban plasma concentrations were measured. Our primary interest was the possible correlation between edoxaban plasma concentrations and values for ROTEM ExTEM, and FibTEM. We also studied the correlation of edoxaban plasma concentrations with the results of standard coagulation tests. We saw the effect of a single dose of edoxaban most clearly in clotting time (CT) of ROTEM ExTEM and FibTEM. Changes in these parameters correlated significantly with edoxaban plasma concentrations up to 6 hours from the ingestion of the drug. Activated partial thromboplastin time, prothrombin time, and anti-factor Xa were also affected. Peak changes were observed 2 and 4 hours after administration of edoxaban. The changes were mostly reversed after 8 hours. In conclusion, ROTEM CT correlates significantly with edoxaban plasma concentrations and can be used to estimate the effect of edoxaban. ROTEM should be considered as part of the assessment of coagulation, with the big advantage of being readily available on site., (© 2020, The American College of Clinical Pharmacology.)

Background: Total knee arthroplasty (TKA) causes severe pain, and strong opioids are commonly used in postoperative analgesia. Dexmedetomidine is a novel alpha-2-adrenoceptor-activating drug indicated for procedural sedation, but previous studies have shown clinically relevant analgesic and antiemetic effects. We evaluated retrospectively the effect of intranasal dexmedetomidine on the postoperative opioid requirement in patients undergoing TKA., Methods: One hundred and fifty patients with ASA status 1-2, age between 35 and 80 years, and scheduled for unilateral primary TKA under total intravenous anesthesia were included in the study. Half of the patients received 100 μg of intranasal dexmedetomidine after anesthesia induction, while the rest were treated conventionally. The postoperative opioid requirement was calculated as morphine equivalent doses for both groups. The effect of dexmedetomidine on postoperative hemodynamics, length of stay (LOS), and incidence of postoperative nausea and vomiting (PONV), was evaluated., Results: The cumulative postoperative opioid consumption was significantly reduced in the dexmedetomidine group compared to the control group (-28.5 mg, 95% CI 12-47 mg P < .001). The reduction in cumulative opioid dose was significantly different between the groups already at 2, 12, 24, and 36 h postoperatively (P < .001). LOS was shorter in the dexmedetomidine group (P < .001), and the dexmedetomidine group had lower postoperative mean arterial pressure and heart rates were lower compared to the control group (P < .001). The incidence of PONV did not differ between the groups (P = .64)., Conclusion: Intraoperatively administered intranasal dexmedetomidine reduces postoperative opioid consumption and may be associated with a shorter hospital stay in patients undergoing TKA under general anesthesia., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Previous findings indicate that pre-emptive pregabalin as part of multimodal anesthesia reduces opioid requirements compared to conventional anesthesia in patients undergoing robot-assisted laparoscopic prostatectomy (RALP). However, recent studies show contradictory evidence suggesting that pregabalin does not reduce postoperative pain or opioid consumption after surgeries. We conducted a register-based analysis on RALP patients treated over a 5-year period to evaluate postoperative opioid consumption between two multimodal anesthesia protocols., Methods: We retrospectively evaluated patients undergoing RALP between years 2015 and 2019. Patients with American Society of Anesthesiologists status 1-3, age between 30 and 80 years and treated with standard multimodal anesthesia were included in the study. Pregabalin (PG) group received 150 mg of oral pregabalin as premedication before anesthesia induction, while the control (CTRL) group was treated conventionally. Postoperative opioid requirements were calculated as intravenous morphine equivalent doses for both groups. The impact of pregabalin on postoperative nausea and vomiting (PONV), and length of stay (LOS) was evaluated., Results: We included 245 patients in the PG group and 103 in the CTRL group. Median (IQR) opioid consumption over 24 postoperative hours was 15 (8-24) and 17 (8-25) mg in PG and CTRL groups (p = 0.44). We found no difference in postoperative opioid requirement between the two groups in post anesthesia care unit, or within 12 h postoperatively (p = 0.16; p = 0.09). The length of post anesthesia care unit stay was same in each group and there was no difference in PONV Similarly, median postoperative LOS was 31 h in both groups., Conclusion: Patients undergoing RALP and receiving multimodal analgesia do not need significant amount of opioids postoperatively and can be discharged soon after the procedure. Pre-emptive administration of oral pregabalin does not reduce postoperative opioid consumption, PONV or LOS in these patients.

Since patients often experience pain and unpleasantness during a colonoscopy, the present study aimed to evaluate the efficacy and safety of sublingually administered fentanyl tablets for pain treatment. Furthermore, since the use of intravenous drugs significantly increases colonoscopy costs, sublingual tablets could be a cost-effective alternative to intravenous sedation. We conducted a prospective placebo-controlled randomized study of 158 patients to evaluate the analgesic effect of a 100 µg dose of sublingual fentanyl administered before a colonoscopy. Pain, sedation, nausea, and satisfaction were assessed during the colonoscopy by the patients as well as the endoscopists and nurses. Respiratory rate and peripheral arteriolar oxygen saturation were monitored throughout the procedure. There were no differences between the fentanyl and placebo groups in any of the measured variables. The median pain intensity values, as measured using a numerical rating scale, were 4.5 in the fentanyl group and 5 in the placebo group. The sedation and oxygen saturation levels and the respiratory rate did not differ between the groups. The majority of the colonoscopies were completed.Our results indicate that a 100 µg dose of sublingual fentanyl is not beneficial compared to the placebo in the treatment of procedural pain during a colonoscopy.

Background and Objective: Dexmedetomidine is a potent agonist of α 2 -adrenoceptors causing dose-dependent sedation in humans. Intravenous dexmedetomidine is commonly used perioperatively, but an extravascular route of administration would be favoured in palliative care. Subcutaneous infusions provide desired therapeutic plasma concentrations with fewer unwanted effects as compared with intravenous dosing. We aimed to develop semi-mechanistic population models for predicting pharmacokinetic and pharmacodynamic profiles of dexmedetomidine after intravenous and subcutaneous dosing., Methods: Non-linear mixed-effects modelling was performed using previously collected concentration and haemodynamic effects data from ten (eight in the intravenous phase) healthy human subjects, aged 19-27 years, receiving 1 µg/kg of intravenous or subcutaneous dexmedetomidine during a 10-min infusion., Results: The absorption of dexmedetomidine from the subcutaneous injection site, and distribution to local subcutaneous fat tissue was modelled using a semi-physiological approach consisting of a depot and fat compartment, while a two-compartment mammillary model explained further disposition. Dexmedetomidine-induced reductions in plasma norepinephrine concentrations were accurately described by an indirect response model. For blood pressure models, the net effect was specified as hyper- and hypotensive effects of dexmedetomidine due to vasoconstriction on peripheral arteries and sympatholysis mediated via the central nervous system, respectively. A heart rate model combined the dexmedetomidine-induced sympatholytic effect, and input from the central nervous system, predicted from arterial blood pressure levels. Internal evaluation confirmed the predictive performance of the final models, as well as the accuracy of the parameter estimates with narrow confidence intervals., Conclusions: Our final model precisely describes dexmedetomidine pharmacokinetics and accurately predicts dexmedetomidine-induced sympatholysis and other pharmacodynamic effects. After subcutaneous dosing, dexmedetomidine is taken up into subcutaneous fat tissue, but our simulations indicate that accumulation of dexmedetomidine in this compartment is insignificant. CLINICALTRIALS.ORG: NCT02724098 and EudraCT 2015-004698-34.

Background: Cerebral autoregulation is often impaired after aneurysmal subarachnoid haemorrhage (aSAH). Dexmedetomidine is being increasingly used, but its effects on cerebral autoregulation in patients with aSAH have not been studied before. Dexmedetomidine could be a useful sedative in patients with aSAH as it enables neurological assessment during the infusion. The aim of this preliminary study was to compare the effects of dexmedetomidine on dynamic and static cerebral autoregulation with propofol and/or midazolam in patients with aSAH., Methods: Ten patients were recruited. Dynamic and static cerebral autoregulation were assessed using transcranial Doppler ultrasound during propofol and/or midazolam infusion and then during three increasing doses of dexmedetomidine infusion (0.7, 1.0 and 1.4 μg/kg/h). Transient hyperaemic response ratio (THRR) and strength of autoregulation (SA) were calculated to assess dynamic cerebral autoregulation. Static rate of autoregulation (sRoR)% was calculated by using noradrenaline infusion to increase the mean arterial pressure 20 mm Hg above the baseline., Results: Data from nine patients were analysed. Compared to baseline, we found no statistically significant changes in THRR or sROR%. THRR was (mean ± SD) 1.20 ± 0.14, 1.17 ± 0.13 (P = .93), 1.14 ± 0.09 (P = .72) and 1.19 ± 0.18 (P = 1.0) and sROR% was 150.89 ± 84.37, 75.22 ± 27.75 (P = .08), 128.25 ± 58.35 (P = .84) and 104.82 ± 36.92 (P = .42) at baseline and during 0.7, 1.0 and 1.4 μg/kg/h dexmedetomidine infusion, respectively. Dynamic SA was significantly reduced after 1.0 μg/kg/h dexmedetomidine (P = .02)., Conclusions: Compared to propofol and/or midazolam, dexmedetomidine did not alter static cerebral autoregulation in aSAH patients, whereas a significant change was observed in dynamic SA. Further and larger studies with dexmedetomidine in aSAH patients are warranted., (© 2020 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Background: Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates., Objective: This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and time-dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug-drug interactions (DDIs) with CYP3A4 substrates in more detail., Methods: In vitro assays were carried out to explore time-dependent inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration-time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim ® . The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration-time curve (AUC), maximum concentration (C max ), and trough concentrations for multiple dosings (C trough ), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration-time datasets over the full range of recommended intravenous and oral dosing regimens., Results: The result of the half maximal inhibitory concentration (IC 50 ) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregate C max ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregate C max ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1-2 mg/L to < 5-6 mg/L for C trough , while 400 mg twice daily might be more suitable for rapid metabolizers (RMs; *1/*17, *17/*17) and normal metabolizers (NMs; *1/*1). When the model was integrated with independently developed CYP3A4 substrate models (midazolam and alfentanil), the observed AUC change of substrates by voriconazole was inside the 90% confidence interval of the predicted AUC change, indicating that CYP3A4 inhibition was appropriately incorporated into the voriconazole model., Conclusions: Both the in vitro assay and model-based simulations support TDI of CYP3A4 by voriconazole as a pivotal characteristic of this drug's PK. The PBPK model developed here could support individual dose adjustment of voriconazole according to genetic polymorphisms of CYP2C19, and DDI risk management. The applicability of modeling results for patients remains to be confirmed in future studies.

Background: Our aim was to characterize the pharmacokinetics and sedative effects of intranasally (IN) administered dexmedetomidine used as an adjuvant in pediatric patients scheduled for magnetic resonance imaging (MRI) requiring sedation., Methods: This was an open-label, single-period study without randomization. Pediatric patients from 5 months to 11 years of age scheduled for MRI and receiving IN dexmedetomidine for premedication as part of their care were included in this clinical trial. Single doses of 2-3 µg·kg of dexmedetomidine were applied IN approximately 1 hour before MRI. Five or 6 venous blood samples were collected over 4 hours for dexmedetomidine concentration analysis. Sedation was monitored with Comfort-B scores, and vital signs were recorded. Pharmacokinetic variables were calculated with noncompartmental methods and compared between 3 age groups (between 1 and 24 months, from 24 months to 6 years, and over 6-11 years)., Results: We evaluated 187 consecutive patients for suitability, of which 132 were excluded. Remaining 55 patients were recruited, of which 5 were excluded before the analysis. Data from 50 patients were analyzed. The average (standard deviation [SD]) dose-corrected peak plasma concentration (Cmax) was 0.011 liter (0.0051), and the median (interquartile range [IQR]) time to reach peak concentration (tmax) was 37 minutes (30-45 minutes). There was negative correlation with Cmax versus age (r = -0.58; 95% confidence interval [CI], -0.74 to -0.37; P < .001), but not with tmax (r = -0.14; 95% CI, 0.14-0.39; P = .35). Dose-corrected areas under the concentration-time curve were negatively correlated with age (r = -0.53; 95% CI, 0.70 to -0.29; P < .001). Median (IQR) maximal reduction in Comfort-B sedation scores was 8 (6-9), which was achieved 45 minutes (40-48 minutes) after dosing. Median (IQR) decrease in heart rate was 15% (9%-23%) from the baseline., Conclusions: Dexmedetomidine is relatively rapidly absorbed after IN administration and provides clinically meaningful but short-lasting sedation in pediatric patients.

Background: Patients undergoing total hip arthroplasty (THA) need substantial amount of opioids for postoperative pain management, which necessitates opioid-sparing modalities. Dexmedetomidine is a novel alpha-2-adrenoceptor-activating drug for procedural sedation. In addition to its sedative effect, dexmedetomidine has analgesic and antiemetic effects. We evaluated retrospectively the effect of intraoperatively administered intranasal low-dose dexmedetomidine on postoperative opioid requirement in patients undergoing THA., Methods: We included 120 patients with American Society of Anesthesiologists status 1-2, age between 35 and 80 years, and scheduled for unilateral primary THA under general anesthesia with total intravenous anesthesia. Half of the patients received 50 μg of intranasal dexmedetomidine after anesthesia induction, while the rest were treated conventionally. Postoperative opioid requirements were calculated as morphine equivalent doses for both groups. The impact of intranasal dexmedetomidine on postoperative hemodynamics and length of stay was evaluated., Results: The cumulative postoperative opioid requirement was significantly reduced in the dexmedetomidine group compared with the control group (26.3 mg, 95% confidence interval 15.6-36.4, P < .001). The cumulative dose was significantly different between the groups already at 12, 24, and 36 h postoperatively (P = .01; P = .001; P < .001, respectively). Dexmedetomidine group had lower mean arterial pressure in the postanesthesia care unit compared with the control group (P = .01). There was no difference in the postanesthesia care unit stay or postoperative length of stay between the two groups (P = .47; P = .10, respectively)., Conclusion: Compared with the control group, intraoperative use of intranasal low-dose dexmedetomidine decreases opioid consumption and sympathetic response during acute postoperative period in patients undergoing THA., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Barbiturates are commonly used in ambulatory sedation of pediatric patients. However, use of barbiturates involve risks of respiratory complications. Dexmedetomidine, a highly selective α 2 -adrenoceptor agonist, is increasingly used for pediatric sedation. Premedication with intranasal (IN) dexmedetomidine offers a non-invasive and efficient possibility to sedate pediatric patients undergoing magnetic resonance imaging (MRI). Our hypothesis was that dexmedetomidine would reduce barbiturate requirements in procedural sedation., Methods: We included 200 consecutive pediatric patients undergoing MRI, and analyzed their hospital records retrospectively. Half of the patients received 3 μg/kg of IN dexmedetomidine (DEX group) 45-60 min before MRI while the rest received only thiopental (THIO group) for procedural sedation. Sedation was maintained with further intravenous thiopental dosing as needed. Thiopental consumption, heart rate (HR) and peripheral oxygen saturation were recorded., Results: The cumulative thiopental requirement during MRI was (median and interquartile range [IQR]) 4.4 (2.7-6.0) mg/kg/h in the DEX group and 12.4 (9.8-14.8) mg/kg/h in the THIO group (difference 7.9 mg/kg/h, 95% CI 6.8-8.8, P <  0.001). Lowest measured peripheral oxygen saturation remained slightly higher in the DEX group compared to the THIO group (median nadirs and IQR: 97 (95-97) % and 96 (94-97) %, P <  0.001). Supplemental oxygen was delivered to 33% of the patients in the THIO group compared to 2% in the DEX group (P <  0.001). The lowest measured HR (mean and SD) was lower (78 (16) bpm) in the DEX group compared to the THIO group (92 (12) bpm) (P <  0.001)., Conclusion: Premedication with IN dexmedetomidine (3 μg/kg) was associated with markedly reduced thiopental dosage needed for efficient procedural sedation for pediatric MRI.

Purpose: Buprenorphine has low oral bioavailability. Regardless of sublingual administration, a notable part of buprenorphine is exposed to extensive first-pass metabolism by the cytochrome P450 (CYP) 3A4. As drug interaction studies with buprenorphine are limited, we wanted to investigate the effect of voriconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics and pharmacodynamics of oral buprenorphine., Methods: Twelve healthy volunteers were given either placebo or voriconazole (orally, 400 mg twice on day 1 and 200 mg twice on days 2-5) for 5 days in a randomized, cross-over study. On day 5, they ingested 0.2 mg (3.6 mg during placebo phase) oral buprenorphine. We measured plasma and urine concentrations of buprenorphine and norbuprenorphine and monitored their pharmacological effects. Pharmacokinetic parameters were normalized for a buprenorphine dose of 1.0 mg., Results: Voriconazole greatly increased the mean area under the plasma concentration-time curve (AUC 0-18 ) of buprenorphine (4.3-fold, P < 0.001), its peak concentration (C max ) (3.9-fold), half-life (P < 0.05), and excretion into urine (A e ; P < 0.001). Voriconazole also markedly enhanced the C max (P < 0.001), AUC 0-18 (P < 0.001), and A e (P < 0.05) of unconjugated norbuprenorphine but decreased its renal clearance (P < 0.001). Mild dizziness and nausea occurred during both study phases., Conclusions: Voriconazole greatly increases exposure to oral buprenorphine, mainly by inhibiting intestinal and liver CYP3A4. Effect on some transporters may explain elevated norbuprenorphine concentrations. Although oral buprenorphine is not commonly used, this interaction may become relevant in patients receiving sublingual buprenorphine together with voriconazole or other CYP3A4 or transporter inhibitors.

Pressure ulcer (PU) risk assessment practices in adult intensive care unit (ICU) patients remain varied., Purpose: The authors assessed the performance of the Sequential Organ Failure Assessment (SOFA) scale and its subcategories in predicting the development of PUs., Methods: A retrospective cohort study was conducted of all adult patients admitted to the mixed medical-surgical ICU of a Finnish tertiary referral hospital between January 2010 and December 2012. Data (diagnoses, demographics, clinical information, treatments, and instrument scores) were retrieved from the ICU database. Wilcoxon and chi-squared tests were used to examine patient subgroup (medical or surgical ICU and intensive care or high-dependency care patients), length of ICU stay (LOS), modified Jackson/Cubbin (mJ/C) scores and SOFA subcategory variables, and first-day SOFA scores. PU association was determined by logistical regression., Results: Among the 4899 patients in the study population, the overall PU incidence of acquired PUs was 8.1%. Medical patients had significantly more PUs (145/1281; 11.3%) than surgical patients (212/3468; 6.1%) (P <.0001). In all subgroups, significantly more patients with PUs had higher SOFA scores (mean 8.24) than patients without PUs (mean 6.74) (P =.001). The difference persisted when patients with LOS ≥3 days in the ICU were considered. Among the SOFA subcategories, the Glasgow Coma score, renal and respiratory disorders, and hypotension were significantly (P <.0001) linked to PU development. First-day total SOFA score and its cardiovascular and respiratory subcategory scores were the most important predictors of PUs., Conclusion: The total SOFA score provides an additional tool to assess PU risk in ICUs and should be used together with the Braden or the mJ/C Scale.

Low-dose oral S-ketamine is increasingly used in chronic pain therapy, but extensive cytochrome P450 (CYP) mediated metabolism makes it prone to pharmacokinetic drug-drug interactions (DDIs). In our study, concentration-time data from five studies were used to develop a semimechanistic model that describes the ticlopidine-mediated inhibition of S-ketamine biotransformation. A mechanistic model was implemented to account for reversible and time-dependent hepatic CYP2B6 inactivation by ticlopidine, which causes elevated S-ketamine exposure in vivo. A pharmacokinetic model was developed with gut wall and hepatic clearances for S-ketamine, its primary metabolite norketamine, and ticlopidine. Nonlinear mixed effects modeling approach was used (NONMEM version 7.3.0), and the final model was evaluated with visual predictive checks and the sampling-importance-resampling procedure. Our final model produces biologically plausible output and demonstrates that ticlopidine is a strong inhibitor of CYP2B6 mediated S-ketamine metabolism. Simulations from our model may be used to evaluate chronic pain therapy with S-ketamine., (© 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc.on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Palliative care patients often need sedation to alleviate intractable anxiety, stress, and pain. Dexmedetomidine is used for sedation of intensive care patients, but there is no prior information on its subcutaneous (SC) administration, a route that would be favored in palliative care. We compared the pharmacokinetics and cardiovascular, sympatholytic, and sedative effects of SC and intravenously (IV) administered dexmedetomidine in healthy volunteers., Methods: An open two-period, cross-over design with balanced randomization was used. Ten male subjects were randomized to receive 1 μg/kg dexmedetomidine both IV and SC. Concentrations of dexmedetomidine and catecholamines in plasma were measured. Pharmacokinetic variables were calculated with non-compartmental methods. In addition, cardiovascular and sedative drug effects were monitored., Results: Eight subjects completed both treatment periods. Peak concentrations of dexmedetomidine were observed 15 min after SC administration (median; range 15-240). The mean bioavailability of SC dexmedetomidine was 81% (AUC 0-∞ ratio × 100%, range 49-97%). The mean (SD) peak concentration of dexmedetomidine in plasma was 0.3 (0.1) ng/ml, and plasma concentrations associated with sedative effects (i.e., > 0.2 ng/ml) were maintained for 4 h after SC dosing. Plasma noradrenaline concentrations were significantly lower (P < 0.001) within 3 h after IV than after SC administration. Subjective scores for vigilance and performance were significantly lower 0-60 min after IV than SC dosing (P < 0.001 for both). The onset of the cardiovascular, sympatholytic, and sedative effects of dexmedetomidine was clearly less abrupt after SC than IV administration., Conclusions: Dexmedetomidine is relatively rapidly and efficiently absorbed after SC administration. Subcutaneous dexmedetomidine may be a feasible alternative in palliative sedation, and causes attenuated cardiovascular effects compared to IV administration. CLINICALTRIALS., Gov Identifier: NCT02724098 . EUDRA CT number 2015-004698-34 .

Buprenorphine is mainly metabolized by the cytochrome P450 (CYP) 3A4 enzyme. The aim of this study was to evaluate the role of first-pass metabolism in the interaction of rifampicin and analgesic doses of buprenorphine. A four-session paired cross-over study design was used. Twelve subjects ingested either 600 mg oral rifampicin or placebo once daily in a randomized order for 7 days. In the first part of the study, subjects were given 0.6-mg (placebo phase) or 0.8-mg (rifampicin phase) buprenorphine sublingually on day 7. In the second part of the study, subjects received 0.4-mg buprenorphine intravenously. Plasma concentrations of buprenorphine and urine concentrations of buprenorphine and its primary metabolite norbuprenorphine were measured over 18 h. Adverse effects were recorded. Rifampicin decreased the mean area under the dose-corrected plasma concentration-time curve (AUC 0-18 ) of sublingual buprenorphine by 25% (geometric mean ratio (GMR): 0.75; 90% confidence interval (CI) of GMR: 0.60, 0.93) and tended to decrease the bioavailability of sublingual buprenorphine, from 22% to 16% ( P  = 0.31). Plasma concentrations of intravenously administered buprenorphine were not influenced by rifampicin. The amount of norbuprenorphine excreted in the urine was decreased by 65% ( P  < 0.001) and 52% ( P  < 0.001) after sublingual and intravenous administration, respectively, by rifampicin. Adverse effects were frequent. Rifampicin decreases the exposure to sublingual but not intravenous buprenorphine. This can be mainly explained by an enhancement of CYP3A-mediated first-pass metabolism, which sublingual buprenorphine only partially bypasses. Concomitant use of rifampicin and low-dose sublingual buprenorphine may compromise the analgesic effect of buprenorphine.

Purpose: This study aimed to determine possible effects of voriconazole and posaconazole on the pharmacokinetics and pharmacological effects of sublingual buprenorphine., Methods: We used a randomized, placebo-controlled crossover study design with 12 healthy male volunteers. Subjects were given a dose of 0.4 mg (0.6 mg during placebo phase) sublingual buprenorphine after a 5-day oral pretreatment with either (i) placebo, (ii) voriconazole 400 mg twice daily on the first day and 200 mg twice daily thereafter or (iii) posaconazole 400 mg twice daily. Plasma and urine concentrations of buprenorphine and its primary active metabolite norbuprenorphine were monitored over 18 h and pharmacological effects were measured., Results: Compared to placebo, voriconazole increased the mean area under the plasma concentration-time curve (AUC 0-∞ ) of buprenorphine 1.80-fold (90 % confidence interval 1.45-2.24; P < 0.001), its peak concentration (C max ) 1.37-fold (P < 0.013) and half-life (t ½ ) 1.37-fold (P < 0.001). Posaconazole increased the AUC0 0-∞ of buprenorphine 1.25-fold (P < 0.001). Most of the plasma norbuprenorphine concentrations were below the limit of quantification (0.05 ng/ml). Voriconazole, unlike posaconazole, increased the urinary excretion of norbuprenorphine 1.58-fold (90 % confidence interval 1.18-2.12; P < 0.001) but there was no quantifiable parent buprenorphine in urine. Plasma buprenorphine concentrations correlated with the pharmacological effects, but the effects did not differ significantly between the phases., Conclusions: Voriconazole, and to a minor extent posaconazole, increase plasma exposure to sublingual buprenorphine, probably via inhibition of cytochrome P450 3 A and/or P-glycoprotein. Care should be exercised in the combined use of buprenorphine with triazole antimycotics, particularly with voriconazole, because their interaction can be of clinical importance.

Ketamine is a phencyclidine derivative, which functions primarily as an antagonist of the N-methyl-D-aspartate receptor. It has no affinity for gamma-aminobutyric acid receptors in the central nervous system. Ketamine shows a chiral structure consisting of two optical isomers. It undergoes oxidative metabolism, mainly to norketamine by cytochrome P450 (CYP) 3A and CYP2B6 enzymes. The use of S-ketamine is increasing worldwide, since the S(+)-enantiomer has been postulated to be a four times more potent anesthetic and analgesic than the R(-)-enantiomer and approximately two times more effective than the racemic mixture of ketamine. Because of extensive first-pass metabolism, oral bioavailability is poor and ketamine is vulnerable to pharmacokinetic drug interactions. Sublingual and nasal formulations of ketamine are being developed, and especially nasal administration produces rapid maximum plasma ketamine concentrations with relatively high bioavailability. Ketamine produces hemodynamically stable anesthesia via central sympathetic stimulation without affecting respiratory function. Animal studies have shown that ketamine has neuroprotective properties, and there is no evidence of elevated intracranial pressure after ketamine dosing in humans. Low-dose perioperative ketamine may reduce opioid consumption and chronic postsurgical pain after specific surgical procedures. However, long-term analgesic effects of ketamine in chronic pain patients have not been demonstrated. Besides analgesic properties, ketamine has rapid-acting antidepressant effects, which may be useful in treating therapy-resistant depressive patients. Well-known psychotomimetic and cognitive adverse effects restrict the clinical usefulness of ketamine, even though fewer psychomimetic adverse effects have been reported with S-ketamine in comparison with the racemate. Safety issues in long-term use are yet to be resolved.

Background: Patient-controlled analgesia (PCA) is a common method for postoperative pain therapy, but it is characterized by large variation of plasma concentrations. PCA with target-controlled infusion (TCI-PCA) may be an alternative. In a previous analysis, the authors developed a pharmacokinetic model for hydromorphone. In this secondary analysis, the authors investigated the feasibility and efficacy of TCI-PCA for postoperative pain therapy with hydromorphone., Methods: Fifty adult patients undergoing cardiac surgery were enrolled in this study. Postoperatively, hydromorphone was applied intravenously during three sequential periods: (1) as TCI with plasma target concentrations of 1 to 2 ng/ml until extubation; (2) as TCI-PCA with plasma target concentrations between 0.8 and 10 ng/ml during the following 6 to 8 h; and (3) thereafter as PCA with a bolus dose of 0.2 mg until the next morning. During TCI-PCA, pain was regularly assessed using the 11-point numerical rating scale (NRS). A pharmacokinetic/pharmacodynamic model was developed using ordinal logistic regression based on measured plasma concentrations., Results: Data of 43 patients aged 40 to 81 yr were analyzed. The hydromorphone dose during TCI-PCA was 0.26 mg/h (0.07 to 0.93 mg/h). The maximum plasma target concentration during TCI-PCA was 2.3 ng/ml (0.9 to 7.0 ng/ml). The NRS score under deep inspiration was less than 5 in 83% of the ratings. Nausea was present in 30%, vomiting in 9%, and respiratory insufficiency in 5% of the patients. The EC50 of hydromorphone for NRS of 4 or less was 4.1 ng/ml (0.6 to 12.8 ng/ml)., Conclusion: TCI-PCA with hydromorphone offered satisfactory postoperative pain therapy with moderate side effects.

Background: Tramadol is widely used for acute, chronic, and neuropathic pain. Its primary active metabolite is O-desmethyltramadol (M1), which is mainly accountable for the μ-opioid receptor-related analgesic effect. Tramadol is metabolized to M1 mainly by cytochrome P450 (CYP)2D6 enzyme and to other metabolites by CYP3A4 and CYP2B6. We investigated the possible interaction of tramadol with the antifungal agents terbinafine (CYP2D6 inhibitor) and itraconazole (CYP3A4 inhibitor)., Methods: We used a randomized placebo-controlled crossover study design with 12 healthy subjects, of which 8 were extensive and 4 were ultrarapid CYP2D6 metabolizers. On the pretreatment day 4 with terbinafine (250 mg once daily), itraconazole (200 mg once daily) or placebo, subjects were given tramadol 50 mg orally. Plasma concentrations of tramadol and M1 were determined over 48 h and some pharmacodynamic effects over 12 h. Pharmacokinetic variables were calculated using standard non-compartmental methods., Results: Terbinafine increased the area under plasma concentration-time curve (AUC0-∞) of tramadol by 115 % and decreased the AUC0-∞ of M1 by 64 % (P < 0.001). Terbinafine increased the peak concentration (C max) of tramadol by 53 % (P < 0.001) and decreased the C max of M1 by 79 % (P < 0.001). After terbinafine pretreatment the elimination half-life of tramadol and M1 were increased by 48 and 50 %, respectively (P < 0.001). Terbinafine reduced subjective drug effect of tramadol (P < 0.001). Itraconazole had minor effects on tramadol pharmacokinetics., Conclusions: Terbinafine may reduce the opioid effect of tramadol and increase the risk of its monoaminergic adverse effects. Itraconazole has no meaningful interaction with tramadol in subjects who have functional CYP2D6 enzyme.

Background: Our objective was to evaluate the effect of intensive care treatment on the protein binding of sufentanil and hydromorphone in cardiac surgery patients during postoperative analgesia using a target-controlled infusion (TCI) and patient-controlled analgesia (PCA)., Methods: Fifty adult patients were enrolled in this prospective randomized study; of which, 49 completed the study (age range 40-81 yr). Sufentanil was administered as an analgesic intraoperatively, and hydromorphone was dosed after operation with TCI and PCA until 8 a.m. on the first postoperative day. Arterial plasma samples were collected for drug and protein concentration measurements up to 24 h after cardiac surgery. Corresponding patient data were collected from the electronic patient data system. After explorative data analysis with principal component analysis, multivariate regression analysis and non-linear mixed effects modelling was used to study the effect of treatment on protein binding., Results: Data of 35 patients were analysed. The median protein binding of sufentanil and hydromorphone was 88.4% (IQ range 85.7-90.5%) and 11.6% (IQ range 9.5-14.3%), respectively. Free fraction of sufentanil increased towards the end of the study period, whereas hydromorphone free fraction remained nearly constant. The total sufentanil concentration and volume balance were identified as significant covariates for the protein binding of sufentanil. For the protein binding of hydromorphone, no significant covariate effects were found., Conclusions: Sufentanil protein binding was significantly dependent on changes in the total drug concentration and volume balance addressing the importance of adequate dosing and fluid-guided therapy. Hydromorphone protein binding was nearly constant throughout the study period., Clinical Trial Registration: EudraCT 2011-003648-31 and ClinicalTrials.gov: NCT01490268., (© The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Hydromorphone is a µ-selective opioid agonist used in postoperative pain therapy. This study aimed to evaluate the pharmacokinetics of hydromorphone in cardiac surgery patients during postoperative analgesia with target-controlled infusion and patient-controlled analgesia., Methods: In this study, 50 adult patients were enrolled to receive intravenous hydromorphone during postoperative pain therapy. Arterial plasma samples were collected for measurements of drug concentration. Population pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Results were validated and simulations were carried out to evaluate results., Results: Data from 49 patients (age range, 40-81 yr) were analyzed. The pharmacokinetics of hydromorphone were best described by a three-compartment model. Age was incorporated as a significant covariate for elimination clearance and central volume of distribution. Scaling all parameters with body weight improved the model significantly. The final estimates of the model parameters for the typical adult patient (67 yr old, weighing 70 kg) undergoing cardiac surgery were as follows: CL1 = 1.01 l/min, V1 = 3.35 l, CL2 = 1.47 l/min, V2 = 13.9 l, CL3 = 1.41 l/min, and V3 = 145 l. The elimination clearance decreased by 43% between the age of 40 and 80 yr, and simulations demonstrated that context-sensitive half-time increased from 26 to 84 min in 40- and 80-yr-old subjects, respectively., Conclusions: The final pharmacokinetic model gave a robust representation of hydromorphone pharmacokinetics. Inclusion of age and body weight to the model demonstrated a significant influence of these covariates on hydromorphone pharmacokinetics. The application of this patient-derived population model in individualized pain therapy should improve the dosing of hydromorphone in patients undergoing cardiac surgery.

Background: Accurate predictions of cytochrome P450 (CYP) 3A-mediated drug-drug interactions (DDIs) account for dynamic changes of CYP3A activity at both major expression sites (liver and gut wall) by considering the full pharmacokinetic profile of the perpetrator and the substrate. Physiological-based in vitro-in vivo extrapolation models have become of increasing interest. However, due to discrepancies between the predicted and observed magnitude of DDIs, the role of models fully based on in vivo data is still essential., Objective: The primary objective of this study was to develop a coupled dynamic model for the interaction of the CYP3A inhibitor voriconazole and the prototypical CYP3A substrate midazolam., Methods: Raw concentration data were obtained from a DDI study. Ten subjects were given either no pretreatment (control) or voriconazole twice daily orally. Midazolam was given either intravenously or orally after the last voriconazole dose and during control phases. Data analysis was performed by the population pharmacokinetic approach using non-linear mixed effects modelling (NONMEM 7.2.0). Model evaluation was performed using visual predictive checks and bootstrap analysis., Results: A semiphysiological model was able to describe the pharmacokinetics of midazolam, its major metabolite and voriconazole simultaneously. By considering the temporal disposition of all three substances in the liver and gut wall, a time-varying CYP3A inhibition process was implemented. Only the incorporation of hypothetical enzyme site compartments resulted in an adequate fit, suggesting a sustained inhibitory effect through accumulation. Novel key features of this analysis are the identification of (1) an apparent sustained inhibitory effect by voriconazole due to a proposed quasi accumulation at the enzyme site, (2) a significantly reduced inhibitory potency of intravenous voriconazole for oral substrates, (3) voriconazole as a likely uridine diphosphate glucuronosyltransferase (UGT) 2B inhibitor and (4) considerable sources of interindividual variability., Conclusion: The proposed semiphysiological modelling approach generated a mechanistic description of the complex DDI occurring at major CYP3A expression sites and thus may serve as a powerful tool to maximise information acquired from clinical DDI studies. The model has been shown to draw precise and accurate predictions. Therefore, simulations based on this kind of models may be used for various clinical scenarios to improve pharmacotherapy.

Purpose: Tramadol is mainly metabolized by the cytochrome P450 (CYP) 2D6, CYP2B6 and CYP3A4 enzymes. The aim of this study was to evaluate the effect of enzyme induction with rifampicin on the pharmacokinetics and pharmacodynamics of oral and intravenous tramadol., Methods: This was a randomized placebo-controlled crossover study design with 12 healthy subjects. After pretreatment for 5 days with rifampicin (600 mg once daily) or placebo, subjects were given tramadol either 50 mg intravenously or 100 mg orally. Plasma concentrations of tramadol and its active main metabolite O-desmethyltramadol (M1) were determined over 48 h. Analgesic and behavioral effects and whole blood 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were measured., Results: Rifampicin reduced the mean area under the time-concentration curve (AUC0-∞) of intravenously administered tramadol by 43 % and that of M1 by 58 % (P < 0.001); it reduced the AUC0-∞ of oral tramadol by 59 % and that of M1 by 54 % (P < 0.001). Rifampicin increased the clearance of intravenous tramadol by 67 % (P < 0.001). Bioavailability of oral tramadol was reduced by rifampicin from 66 to 49 % (P = 0.002). The pharmacological effects of tramadol or whole blood serotonin concentrations were not influenced by pretreatment with rifampicin., Conclusions: Rifampicin markedly decreased the exposure to tramadol and M1 after both oral and intravenous administration. Therefore, rifampicin and other potent enzyme inducers may have a clinically important interaction with tramadol regardless of the route of its administration.

Oxycodone is a semisynthetic opioid analgesic that is increasingly used for the treatment of acute, cancer, and chronic non-malignant pain. Oxycodone was synthesized in 1917 but its pharmacological properties were not thoroughly studied until recently. Oxycodone is a fairly selective μ-opioid receptor agonist, but there is a striking discrepancy between the relatively low binding potential and G protein activation by oxycodone and its analgesic efficacy. It has been claimed that this is because of active metabolites and enhanced passage to the central nervous system by active transport. We critically review studies on the basic pharmacology of oxycodone and on its pharmacokinetics and pharmacodynamics in humans. In particular, the role of pharmacogenomics and population pharmacokinetics in understanding the properties of oxycodone is discussed in detail. We compare oxycodone with morphine, the standard opioid in clinical use., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: We assessed possible drug interactions of tramadol given concomitantly with the potent CYP2B6 inhibitor ticlopidine, alone or together with the potent CYP3A4 and P-glycoprotein inhibitor itraconazole., Methods: In a randomized, placebo-controlled cross-over study, 12 healthy subjects ingested 50 mg of tramadol after 4 days of pretreatment with either placebo, ticlopidine (250 mg twice daily) or ticlopidine plus itraconazole (200 mg once daily). Plasma and urine concentrations of tramadol and its active metabolite O-desmethyltramadol (M1) were monitored over 48 h and 24 h, respectively., Results: Ticlopidine increased the mean area under the plasma concentration-time curve (AUC0-∞) of tramadol by 2.0-fold (90 % confidence interval (CI) 1.6-2.4; p < 0.001) and Cmax by 1.4-fold (p < 0.001), and reduced its oral and renal clearance (p < 0.01). Ticlopidine reduced the AUC0-3 of M1 (p < 0.001) and the ratio of the AUC0-∞ of M1 to that of tramadol, but did not influence the AUC0-∞ of M1. Tramadol or M1 pharmacokinetics did not differ between the ticlopidine alone and ticlopidine plus itraconazole phases., Conclusions: Ticlopidine increased exposure to tramadol, reduced its renal clearance and inhibited the formation of M1, most likely via inhibition of CYP2B6 and/or CYP2D6. The addition of itraconazole to ticlopidine did not modify the outcome of the drug interaction. Concomitant clinical use of ticlopidine and tramadol may enhance the risk of serotonergic effects, especially when higher doses of tramadol are used.

A method for a sensitive and specific analysis of hydromorphone total and unbound drug concentrations in human plasma was developed and validated. Sample preparation was preceded with an ultrafiltration step to separate the unbound drug from the protein bound fraction of hydromorphone. Both the ultrafiltrate and plasma samples were extracted with solid-phase extraction and substituted with stable isotope-labeled hydromorphone that was used as internal standard. Chromatographic separation was performed by gradient elution with UPLC-like system and eluates were analyzed by tandem mass spectrometry equipped with an electrospray ionization source. Sample preparation was optimized for good recovery of hydromorphone and the results were consistent. Calibration curves demonstrated linearity in the concentration range of 78-5000pg/ml for analysis of both total and unbound concentrations of hydromorphone. The limit of detection was 1pg and the lower limit of quantification was 78pg/ml for both total and unbound hydromorphone plasma drug concentrations. Intra- and interassay reproducibility and inaccuracy did not exceed 10%. Hydromorphone was on the average 14% bound to plasma proteins, supporting the previously published unreferenced statements that the protein binding of hydromorphone is low. Method was applied to a clinical trial in patients undergoing open heart surgery to generate a target controlled infusion model for the postoperative patient controlled analgesia with hydromorphone., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Ketamine is an intravenous anaesthetic and analgesic agent but it can also be used orally as an adjuvant in the treatment of chronic pain. This study investigated the effect of the herbal antidepressant St John's wort, an inducer of cytochrome P450 3A4 (CYP3A4), on the pharmacokinetics and pharmacodynamics of oral S-ketamine. In a randomized cross-over study with two phases, 12 healthy subjects were pretreated with oral St John's wort or placebo for 14 days. On day 14, they were given an oral dose of 0.3 mg/kg of S-ketamine. Plasma concentrations of ketamine and norketamine were measured for 24 h and pharmacodynamic variables for 12 h. St John's wort decreased the mean area under the plasma concentration-time curve (AUC(0-∞)) of ketamine by 58% (P < 0.001) and decreased the peak plasma concentration (C(max)) of ketamine by 66% (P < 0.001) when compared with placebo. Mean C(max) of norketamine (the major metabolite of ketamine) was decreased by 23% (P = 0.002) and mean AUC(0-∞) of norketamine by 18% (P < 0.001) by St John's wort. There was a statistically significant linear correlation between the self-reported drug effect and C(max) of ketamine (r = 0.55; P < 0.01). St John's wort greatly decreased the exposure to oral S-ketamine in healthy volunteers. Although this decrease was not associated with significant changes in the analgesic or behavioural effects of ketamine in the present study, usual doses of S-ketamine may become ineffective if used concomitantly with St John's wort., (© 2011 The Authors Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique.)

Background: Target controlled infusion (TCI) with sufentanil is usually performed using the Gepts model, which was derived from patients undergoing general surgery. It is, however, known that pharmacokinetics of sufentanil can be changed during cardiopulmonary bypass (CPB). We tested whether TCI during coronary artery bypass surgery with CPB produces constant total, unbound sufentanil concentration-time course or both., Methods: After IRB approval, written informed consent was obtained from 38 male patients (48-74 yr) undergoing coronary artery bypass surgery. Anaesthesia was managed with propofol and TCI of sufentanil, using the Gepts model, targeting plasma concentrations of 0.4 (n=18) or 0.8 ng ml(-1) (n=20). Arterial blood samples were taken before, during, and after CPB. Total and unbound sufentanil concentrations were measured by HPLC with tandem mass spectrometry. The accuracy of the TCI model was assessed by the prediction error, and a pharmacokinetic model was determined by population analysis., Results: The median prediction error of the TCI with the Gepts model before, during, and after CPB was 59.6, 3.9, and -10.4%, respectively. The unbound sufentanil concentrations increased significantly during CPB. Pharmacokinetic modelling showed an increase in elimination and intercompartmental clearance after initiation of CPB., Conclusions: Neither total nor unbound sufentanil concentrations remained constant when performing a TCI with the Gepts model in coronary artery bypass surgery with CPB. A pharmacokinetic model derived from patients undergoing cardiac surgery with CPB might improve the performance of TCI in this population.

Low-dose ketamine is currently used in several acute and chronic pain conditions as an analgesic. Ketamine undergoes extensive metabolism and is thus susceptible to drug-drug interactions. We examined the effect rifampicin, a well-known inducer of many cytochrome P450 (CYP) enzymes and transporters, on the pharmacokinetics of intravenous and oral S-ketamine in healthy volunteers. Eleven healthy volunteers were administered in randomized order 600 mg rifampicin or placebo orally for 6 days in a four-session paired cross-over study. On day 6, S-ketamine was administered intravenously (0.1 mg/kg) in the first part of the study and orally (0.3 mg/kg) in the second part. Plasma concentrations of ketamine and norketamine were measured up to 24 hr and behavioural and analgesic effects up to 12 hr. Rifampicin treatment decreased the mean area under the plasma ketamine concentration-time curve extrapolated to infinity (AUC (0-∞)) of intravenous and oral S-ketamine by 14% (p = 0.005) and 86% (p < 0.001), respectively. Rifampicin decreased greatly the peak plasma concentration of oral S-ketamine by 81% (p < 0.001), but shortened only moderately the elimination half-life of intravenous and oral S-ketamine. Rifampicin decreased the ratio of norketamine AUC (0-∞) to ketamine AUC (0-∞) after intravenous S-ketamine by 66%, (p < 0.001) but increased the ratio by 147% (p < 0.001) after the oral administration of S-ketamine. Rifampicin profoundly reduces the plasma concentrations of ketamine and norketamine after oral administration of S-ketamine, by inducing mainly its first-pass metabolism., (© 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.)

A sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of sufentanil total and unbound drug concentrations. Unbound drug was separated by an ultrafiltration step before sample preparation. Both the ultrafiltrate and plasma samples were extracted with solid-phase extraction and substituted with deuterated sufentanil used as an internal standard. Separation was performed by gradient elution using UPLC-like system and analysed by MS/MS consisting of an electrospray ionization source. Calibration curves showed linearity in the concentration range of 5-2500 pg/ml for analysis of both total and unbound concentrations of sufentanil. The lower limit of quantification was 5 pg/ml for both total and unbound sufentanil plasma drug concentrations. Intra- and interassay precision and accuracy did not exceed 15%. Method was applied to pharmacokinetic study in patients undergoing coronary artery bypass grafting., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Purpose: We examined the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral S-ketamine., Methods: A randomized crossover open-label study design with two phases at an interval of 4 weeks was conducted in 12 healthy volunteers. Grapefruit juice or water was ingested 200 ml t.i.d. for 5 days. An oral dose of 0.2 mg/kg of S-ketamine was ingested on day 5 with 150 ml grapefruit juice or water. Plasma concentrations of ketamine and norketamine were determined for 24 h, and pharmacodynamic variables were recorded for 12 h. Noncompartmental methods were used to calculate pharmacokinetic parameters., Results: Grapefruit juice increased the geometric mean value of the area under the plasma ketamine concentration-time curve(AUC0-∞) by 3.0-fold (range 2.4- to 3.6-fold; P<0.001), the peak plasma concentration (Cmax) by 2.1-fold (range 1.8- to 2.6-fold; P<0.001), and the elimination half-life by 24% (P<0.05) as compared to the water phase. The ratio of main metabolite norketamine to ketamine (AUCm/AUCp) was decreased by 57% (P<0.001) during the grapefruit phase.Self-rated relaxation was decreased (P<0.05) and the performance in the digit symbol substitution test was increased (P<0.05) after grapefruit juice, but other behavioral or analgesic effects were not affected., Conclusions: Grapefruit juice significantly increased the plasma concentrations of oral ketamine in healthy volunteers.Dose reductions of ketamine should be considered when using oral ketamine concomitantly with grapefruit juice.

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.

This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0-∞)) of oral ketamine by 2.4-fold (P < 0.001), whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0-∞) to ketamine AUC(0-∞) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine.

GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). The type A GABA receptor (GABA(A)R) system is the primary pharmacological target for many drugs used in clinical anesthesia. The α1, β2, and γ2 subunit-containing GABA(A)Rs located in the various parts of CNS are thought to be involved in versatile effects caused by inhaled anesthetics and classic benzodiazepines (BZD), both of which are widely used in clinical anesthesiology. During the past decade, the emergence of tonic inhibitory conductance in extrasynaptic GABA(A)Rs has coincided with evidence showing that these receptors are highly sensitive to the sedatives and hypnotics used in anesthesia. Anesthetic enhancement of tonic GABAergic inhibition seems to be preferentially increased in regions shown to be important in controlling memory, awareness, and sleep. This review focuses on the physiology of the GABA(A)Rs and the pharmacological properties of clinically used BZDs. Although classic BZDs are widely used in anesthesiological practice, there is a constant need for new drugs with more favorable pharmacokinetic and pharmacodynamic effects and fewer side effects. New hypnotics are currently developed, and promising results for one of these, the GABA(A)R agonist remimazolam, have recently been published.

Our aim was to assess the effect of miconazole oral gel on the pharmacokinetics of oral oxycodone. In an open crossover study with two phases, 12 healthy volunteers took a single oral dose of 10 mg of immediate-release oxycodone with or without thrice-daily 85-mg miconazole oral gel treatment. The plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h. Pharmacological effects of oxycodone were recorded for 12 h. Pharmacokinetic parameters were compared by use of the geometric mean ratios (GMRs) and their 90% confidence interval (CIs). Pretreatment with miconazole oral gel caused a strong inhibition of the CYP2D6-dependent metabolism and moderate inhibition of the CYP3A4-dependent metabolism of oxycodone. The mean area under the concentration-time curve (AUC) from time zero to infinity (AUC(0-∞); GMR, 1.63; 90% CI, 1.48 to 1.79) and the peak concentration of oxycodone (GMR, 1.31; 90% CI, 1.19 to 1.44) were increased. The AUC of the CYP2D6-dependent metabolite oxymorphone was greatly decreased (GMR, 0.17; 90% CI, 0.09 to 0.31) by miconazole gel, whereas that of the CYP3A4-dependent metabolite noroxycodone was increased (GMR, 1.30; 90% CI, 1.15 to 1.47) by miconazole gel. Differences in the pharmacological response to oxycodone between phases were insignificant. Miconazole oral gel increases the exposure to oral oxycodone, but the clinical relevance of the interaction is moderate. Miconazole oral gel produces a rather strong inhibitory effect on CYP2D6, which deserves further study.

Background and Objective: Oxycodone is a μ-opioid receptor agonist that is mainly metabolized by hepatic cytochrome P450 (CYP) enzymes. Because CYP enzymes can be inhibited by other drugs, the pharmacokinetics of oxycodone are prone to drug interactions. The aim of this study was to determine whether inhibition of CYP2D6 alone by paroxetine or inhibition of both CYP2D6 and CYP3A4 by a combination of paroxetine and itraconazole alters the pharmacokinetics of and pharmacological response to intravenous oxycodone., Methods: We used a randomized, three-phase, crossover, placebo-controlled study design in 12 healthy subjects. The subjects were given 0.1  mg/kg of intravenous oxycodone after pre-treatments with placebo, paroxetine or a combination of paroxetine and itraconazole for 4 days. Plasma concentrations of oxycodone and its oxidative metabolites were measured over 48 hours, and pharmacokinetic and pharmacodynamic parameters subsequently evaluated., Results: The effect of paroxetine on the plasma concentrations of oxycodone was negligible. The combination of paroxetine and itraconazole prolonged the mean elimination half-life of oxycodone from 3.8 to 6.6 hours (p < 0.001), and increased the exposure to oxycodone 2-fold (p < 0.001). However, these changes were not reflected in pharmacological response., Conclusion: The results of this study indicate that there are no clinically relevant drug interactions with intravenous oxycodone and inhibitors of CYP2D6. If both oxidative metabolic pathways via CYP3A4 and 2D6 are inhibited the exposure to intravenous oxycodone increases substantially.

Grapefruit juice alters the concentrations of many CYP3A substrates. The objective of this study was to examine the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral oxycodone in a randomized cross-over study with two phases at an interval of 4 weeks. Twelve healthy volunteers ingested 200 ml of grapefruit juice or water t.i.d. for 5 days. An oral dose of oxycodone hydrochloride 10 mg was administered on day 4. Oxycodone, noroxycodone, oxymorphone and noroxymorphone concentrations were analysed from the plasma samples for 48 hr and behavioural and analgesic effects were recorded for 12 hr. Grapefruit juice increased the mean area under the oxycodone concentration-time curve (AUC(0-∞) ) by 1.7-fold (p<0.001), the peak plasma concentration by 1.5-fold (p<0.001) and the half-life of oxycodone by 1.2-fold (p<0.001) as compared to the water. The metabolite-to-parent AUC(0-∞) ratios (AUC(m)/AUC(p) ) of noroxycodone and noroxymorphone decreased by 44% (p<0.001) and 45% (p<0.001), respectively. Oxymorphone AUC(0-∞) increased by 1.6-fold (p<0.01) after grapefruit juice, but the AUC(m)/AUC(p) remained unchanged. Pharmacodynamic changes were modest and only self-reported performance significantly impaired after grapefruit juice. Analgesic effects were not influenced. Grapefruit juice inhibited the CYP3A4-mediated first-pass metabolism of oxycodone, decreased the formation of noroxycodone and noroxymorphone and increased that of oxymorphone. We conclude that dietary consumption of grapefruit products may increase the concentrations and effects of oxycodone in clinical use., (© 2010 The Authors. © 2010 Nordic Pharmacological Society.)

Purpose: this study aimed to investigate the effect of antivirals ritonavir and lopinavir/ritonavir on the pharmacokinetics and pharmacodynamics of oral oxycodone, a widely used opioid receptor agonist used in the treatment of moderate to severe pain., Methods: a randomized crossover study design with three phases at intervals of 4 weeks was conducted in 12 healthy volunteers. Ritonavir 300 mg, lopinavir/ritonavir 400/100 mg, or placebo b.i.d. for 4 days was given to the subjects. On day 3, 10 mg oxycodone hydrochloride was administered orally. Plasma concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were determined for 48 h. Pharmacokinetic parameters were calculated with standard noncompartmental methods. Behavioral effects and experimental cold pain analgesia were assessed for 12 h. ANOVA for repeated measures was used for statistical analysis., Results: ritonavir and lopinavir/ritonavir increased the area under the plasma concentration-time curve of oral oxycodone by 3.0-fold (range 1.9- to 4.3-fold; P <0.001) and 2.6-fold (range 1.9- to 3.3-fold; P <0.001). The mean (± SD) elimination half-life increased after ritonavir and lopinavir/ritonavir from 3.6 ± 0.6 to 5.6 ± 0.9 h (P <0.001) and 5.7 ± 0.9 h (P <0.001), respectively. Both ritonavir (P <0.001) and lopinavir/ritonavir (P <0.05) increased the self-reported drug effect of oxycodone., Conclusions: ritonavir and lopinavir/ritonavir greatly increase the plasma concentrations of oral oxycodone in healthy volunteers and enhance its effect. When oxycodone is used clinically in patients during ritonavir and lopinavir/ritonavir treatment, reductions in oxycodone dose may be needed to avoid opioid-related adverse effects.

What Is Already Known About This Subject: Oxycodone is an opioid analgesic that is metabolized mainly in the liver by cytochrome P450 (CYP) 2D6 and 3A4 enzymes. So far, the effects of CYP2D6 or CYP3A4 inhibitors on the pharmacokinetics of oxycodone in humans have not been systematically studied., What This Study Adds: Drug interactions arising from CYP2D6 inhibition most likely have minor clinical importance for oral oxycodone. When both of CYP2D6 and CYP3A4 pathways are inhibited, the exposure to oral oxycodone is increased substantially., Aim: The aim of this study was to find out whether the inhibition of cytochrome P450 2D6 (CYP2D6) with paroxetine or concomitant inhibition of CYP2D6 and CYP3A4 with paroxetine and itraconazole, altered the pharmacokinetics and pharmacological response of orally administered oxycodone., Methods: A randomized placebo-controlled cross-over study design with three phases was used. Eleven healthy subjects ingested 10 mg of oral immediate release oxycodone on the fourth day of pre-treatment with either placebo, paroxetine (20 mg once daily) or paroxetine (20 mg once daily) and itraconazole (200 mg once daily) for 5 days. The plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h, and pharmacological (analgesic and behavioural) effects were evaluated., Results: Paroxetine alone reduced the area under concentration-time curve (AUC(0,0-48 h)) of the CYP2D6 dependent metabolite oxymorphone by 44% (P < 0.05), but had no significant effects on the plasma concentrations of oxycodone or its pharmacological effects when compared with the placebo phase. When both oxidative pathways of the metabolism of oxycodone were inhibited with paroxetine and itraconazole, the mean AUC(0,infinity) of oxycodone increased by 2.9-fold (P < 0.001), and its C(max) by 1.8-fold (P < 0.001). Visual analogue scores for subjective drug effects, drowsiness and deterioration of performance were slightly increased (P < 0.05) after paroxetine + itraconazole pre-treatment when compared with placebo., Conclusions: Drug interactions arising from CYP2D6 inhibition most likely have minor clinical importance for oral oxycodone if the function of the CYP3A4 pathway is normal. When both CYP2D6 and CYP3A4 pathways are inhibited, the exposure to oral oxycodone is increased substantially.

Background: Oral ketamine is used as an adjuvant in the treatment of refractory neuropathic and cancer-related pain. Drug interactions may alter the analgesic or other effects of ketamine., Aim and Methods: The aim of the study was to investigate the effect of cytochrome P450 3A enzyme inhibition with clarithromycin on the pharmacokinetics and pharmacodynamics of oral S-ketamine in a randomized controlled cross-over study with two phases. Ten healthy subjects were pre-treated with oral clarithromycin or placebo for 4 days. On day 4, they ingested an oral dose of 0.2mg/kg of S-ketamine syrup. Plasma concentrations of ketamine and norketamine were measured for 24h. Analgesic effects were evaluated in a cold pressor test and psychomotor effects were followed for 12h., Results: Clarithromycin increased the mean C(max) of ketamine by 3.6-fold (p<0.001) and the mean AUC(0-infinity) of ketamine by 2.6-fold (p=0.001). The relative amount of the CYP3A dependent metabolite norketamine was decreased by 54% by clarithromycin (p=0.004). Self-rated drug effect of S-ketamine was enhanced by clarithromycin (p<0.05) but other behavioral effects or cold pain scores were not affected., Conclusions: Clarithromycin strongly increases plasma concentrations of oral S-ketamine probably by inhibiting its CYP3A-mediated N-demethylation. This increase is reflected as modest changes in behavioral effects of oral S-ketamine., (Copyright (c) 2009 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to investigate the effects of the cytochrome P450 3A4 (CYP34A) inhibitor itraconazole on the pharmacokinetics and pharmacodynamics of orally and intravenously administered oxycodone., Methods: Twelve healthy subjects were administered 200 mg itraconazole or placebo orally for 5 days in a four-session paired cross-over study. On day 4, oxycodone was administered intravenously (0.1 mg/kg) in the first part of the study and orally (10 mg) in the second part. Plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h, and pharmacodynamic effects were evaluated., Results: Itraconazole decreased plasma clearance (Cl) and increased the area under the plasma concentration-time curve (AUC0-infinity) of intravenous oxycodone by 32 and 51%, respectively (P<0.001) and increased the AUC(0-infinity) of orally administrated oxycodone by 144% (P<0.001). Most of the pharmacokinetic changes in oral oxycodone were seen in the elimination phase, with modest effects by itraconazole on its peak concentration, which was increased by 45% (P=0.009). The AUC(0-48) of noroxycodone was decreased by 49% (P<0.001) and that of oxymorphone was increased by 359% (P<0.001) after the administration of oral oxycodone. The pharmacologic effects of oxycodone were enhanced by itraconazole only modestly., Conclusions: Itraconazole increased the exposure to oxycodone by inhibiting its CYP3A4-mediated N-demethylation. The clinical use of itraconazole in patients receiving multiple doses of oxycodone for pain relief may increase the risk of opioid-associated adverse effects.