Plasma Fentanyl Research Articles

Antinociceptive and respiratory effects following application of transdermal fentanyl patches and assessment of brain μ-opioid receptor mRNA expression in ball pythons.

OBJECTIVE To quantify plasma fentanyl concentrations (PFCs) and evaluate antinociceptive and respiratory effects following application of transdermal fentanyl patches (TFPs) and assess cerebrospinal μ-opioid receptor mRNA expression in ball pythons (compared with findings in turtles). ANIMALS 44 ball pythons (Python regius) and 10 turtles (Trachemys scripta elegans). PROCEDURES To administer 3 or 12 μg of fentanyl/h, a quarter or whole TFP (TFP-3 and TFP-12, respectively) was used. At intervals after TFP-12 application in snakes, PFCs were measured by reverse-phase high-pressure liquid chromatography. Infrared heat stimuli were applied to the rostroventral surface of snakes to determine thermal withdrawal latencies after treatments with no TFP (control [n = 16]) and TFP-3 (8) or TFP-12 (9). Breathing frequency was measured in unrestrained controls and TFP-12-treated snakes. μ-Opioid receptor mRNA expression in brain and spinal cord tissue samples from snakes and turtles (which are responsive to μ-opioid receptor agonist drugs) were quantified with a reverse transcription PCR assay. RESULTS Mean PFCs were 79, 238, and 111 ng/mL at 6, 24, and 48 hours after TFP-12 application, respectively. At 3 to 48 hours after TFP-3 or TFP-12 application, thermal withdrawal latencies did not differ from pretreatment values or control treatment findings. For TFP-12-treated snakes, mean breathing frequency significantly decreased from the pretreatment value by 23% and 41% at the 24- and 48-hour time points, respectively. Brain and spinal cord tissue μ-opioid receptor mRNA expressions in snakes and turtles did not differ. CONCLUSIONS AND CLINICAL RELEVANCE In ball pythons, TFP-12 application resulted in high PFCs, but there was no change in thermal antinociception, indicating resistance to μ-opioid-dependent antinociception in this species.

Pharmacokinetics of intravenous and transdermal fentanyl in alpacas.

The purpose of the study was to determine pharmacokinetics of fentanyl after intravenous (i.v.) and transdermal (t.d.) administration to six adult alpacas. Fentanyl was administered i.v. (2μg/kg) or t.d. (nominal dose: 2μgkg-1 hr-1 ). Plasma concentrations were determined using liquid chromatography-mass spectrometry. Heart rate and respiratory rate were assessed. Extrapolated, zero-time plasma fentanyl concentrations were 6.0ng/ml (1.7-14.6ng/ml) after i.v. administration, total plasma clearance was 1.10Lhr-1 kg-1 (0.75-1.40Lhr-1 kg-1 ), volumes of distribution were 0.30L/kg (0.10-0.99L/kg), 1.10L/kg (0.70-2.96L/kg) and 1.5L/kg (0.8-3.5L/kg) for V1 , V2 , and Vss , respectively. Elimination half-life was 1.2hr (0.5-4.3hr). Mean residence time (range) after i.v. dosing was 1.30hr (0.65-4.00hr). After t.d. fentanyl administration, maximum plasma fentanyl concentration was 1.20ng/ml (0.72-3.00ng/ml), which occurred at 25hr (8-48hr) after patch placement. The area under the plasma fentanyl concentration-vs-time curve (extrapolated to infinity) after t.d. fentanyl was 61ng*hr/ml (49-93ng*hr/ml). The dose-normalized bioavailability of fentanyl from t.d. fentanyl in alpacas was 35.5% (27-64%). Fentanyl absorption from the t.d. fentanyl patch into the central compartment occurred at a rate of approximately 50μg/hr (29-81μg/hr) between 8 and 72hr after patch placement.

Isoflurane minimum alveolar concentration sparing effects of fentanyl in the dog

ObjectiveTo characterize the isoflurane-sparing effects of a high and a low dose of fentanyl in dogs, and its effects on mean arterial pressure (MAP) and heart rate (HR). Study designProspective, randomized crossover trial. AnimalsEight healthy male Beagle dogs weighing 12.1 ± 1.6 kg [mean ± standard deviation (SD)] and approximate age 1 year. MethodsDogs were anesthetized using isoflurane and minimum alveolar concentration (MAC) was determined in duplicate by the bracketing method using an electrical stimulus on the tarsus. Animals were administered fentanyl: low dose (33 μg kg−1 loading dose, 0.2 μg kg−1 minute−1) or high dose (102 μg kg−1 loading dose, 0.8 μg kg−1 minute−1) and MAC was re-determined (MACISO-F). Blood was collected for analysis of plasma fentanyl concentrations before administration and after MACISO-F determination. All values are presented as mean ± SD. ResultsIsoflurane MAC (MACISO) was 1.30 ± 0.23% in the low dose treatment, which significantly decreased to 0.75 ± 0.22% (average MAC reduction 42.3 ± 9.4%). MACISO was 1.30 ± 0.18% in the high dose treatment, which significantly decreased to 0.30 ± 0.11% (average MAC reduction 76.9 ± 7.4%). Mean fentanyl plasma concentrations were 6.2 and 29.5 ng mL−1 for low and high dose treatments, respectively. MAP increased significantly only in the high dose treatment (from 81 ± 8 to 92 ± 9 mmHg). HR decreased significantly in both treatments from 108 ± 25 to 61 ± 14 beats minute−1 with the low dose and from 95 ± 14 to 42 ± 4 beats minute−1 with the high dose. Conclusions and clinical relevanceFentanyl administration resulted in a dose-dependent isoflurane MAC-sparing effect with bradycardia at both doses and an increase in MAP only at high dose. Further evaluation is needed to determine the effects of fentanyl on the overall cardiovascular function.

Effect of fentanyl and lidocaine on the end-tidal sevoflurane concentration preventing motor movement in dogs.

OBJECTIVE To determine effects of fentanyl, lidocaine, and a fentanyl-lidocaine combination on the minimum alveolar concentration of sevoflurane preventing motor movement (MACNM) in dogs. ANIMALS 6 adult Beagles. PROCEDURES Dogs were anesthetized with sevoflurane in oxygen 3 times (1-week intervals). Baseline MACNM (MACNM-B) was determined starting 45 minutes after induction of anesthesia. Dogs then received 1 of 3 treatments IV: fentanyl (loading dose, 15 μg/kg; constant rate infusion [CRI], 6 μg/kg/h), lidocaine (loading dose, 2 mg/kg; CRI, 6 mg/kg/h), and the fentanyl-lidocaine combination at the same doses. Determination of treatment MACNM (MACNM-T) was initiated 90 minutes after start of the CRI. Venous blood samples were collected at the time of each treatment MACNM measurement for determination of plasma concentrations of fentanyl and lidocaine. RESULTS Mean ± SEM overall MACNM-B for the 3 treatments was 2.70 ± 0.27 vol%. The MACNM decreased from MACNM-B to MACNM-T by 39%, 21%, and 55% for fentanyl, lidocaine, and the fentanyl-lidocaine combination, respectively. This decrease differed significantly among treatments. Plasma fentanyl concentration was 3.25 and 2.94 ng/mL for fentanyl and the fentanyl-lidocaine combination, respectively. Plasma lidocaine concentration was 2,570 and 2,417 ng/mL for lidocaine and the fentanyl-lidocaine combination, respectively. Plasma fentanyl and lidocaine concentrations did not differ significantly between fentanyl and the fentanyl-lidocaine combination or between lidocaine and the fentanyl-lidocaine combination. CONCLUSIONS AND CLINICAL RELEVANCE CRIs of fentanyl, lidocaine, and the fentanyl-lidocaine combination at the doses used were associated with clinically important and significant decreases in the MACNM of sevoflurane in dogs.

Foetal Fentanyl Exposure and Ion Trapping after Intravenous and Transdermal Administration to the Ewe

Opioids given to pregnant and parturient women are relatively freely transferred across the placenta. Spinal, epidural and intravenous fentanyl has been studied in pregnant women and neonates, but foetal safety of fentanyl dosing with transdermal patch during pregnancy and labour is not sufficiently studied. Foetal pH is physiologically lower than maternal pH, and thus, opioids, which are weak bases, are ionized and may cumulate to foetus. Foetal asphyxia may further worsen acidosis, and ion trapping induced by low pH is assumed to increase the foetal exposure to opioids. Here, we show that no correlation between foetal acidosis and ion trapping of fentanyl could be found. In three experiments, 29 pregnant sheep were administered fentanyl with 2 μg/kg/h patch supplemented with IV boluses/infusion. Foetal exposure to fentanyl was extensive, median 0.34 ng/ml (quartiles 0.21, 0.42), yet drug accumulation to foetus was not observed, and median of foetal/maternal concentration (F/M) ratio was 0.63 (0.43, 0.75) during the first hours after the fentanyl administration. Low foetal pH and pH difference between ewe and the foetus did not correlate with fentanyl concentration in the foetus or F/M ratio. At steady-state during the second patch worn, foetal plasma fentanyl was low, 0.13 ng/ml, and the median of F/M ratio was 0.69. Our results demonstrate that drug accumulation to foetus caused by ion trapping seen with some weak base opioids may not be that significant with fentanyl. These results have a clinical relevance when fentanyl is dosed to pregnant woman and the foetus is acidemic.

Fentanyl Transdermal Therapeutic System Provides Rapid Systemic Fentanyl Absorption in Two Ball Pythons (Python regius)

Abstract Although our understanding of reptile analgesia continues to develop, μ-opioid receptor agonists are currently the most effective analgesics in a variety of reptile species. Fentanyl, a potent, short-acting, μ- and δ-opioid receptor agonist, is formulated for use as a transdermal therapeutic system (TTS) and was shown to be absorbed across the skin of prehensile-tailed skinks (Corucia zebrata). Snakes, which possess highly permeable skin, seem to be ideal candidates for effective transdermal analgesia. Fentanyl TTS (12 μg/h) was applied to the midbody, dorsal surface of two ball pythons (Python regius). Specimen mean body weight was 2.60 kg (2.20–2.99 kg). Cardiac blood samples were collected for 7 days, and plasma fentanyl concentrations were determined using high-performance liquid chromatography–mass spectroscopy. Therapeutic concentrations, as defined in mammals (1 ng/ml), were reached within 4 h of patch application, and they were sustained throughout the study. Plasma fentanyl steady-state ...

Relationship between the plasma fentanyl and serum 4β-hydroxycholesterol based on CYP3A5 genotype and gender in patients with cancer pain

This study aimed to evaluate the relationship between the concentrations of plasma fentanyl and serum 4β-hydroxycholesterol based on CYP3A5 genotype and gender in cancer patients. Thirty-three Japanese cancer patients treated with transdermal fentanyl were enrolled. The concentrations of plasma fentanyl and norfentanyl, and serum 4β-hydroxycholesterol and total cholesterol were determined at day 8 or later after starting the medication. The plasma fentanyl concentration was significantly higher in the CYP3A5*3/*3 group than in the *1 allele carrier group. The *3/*3 group had a lower metabolic ratio of fentanyl. The serum 4β-hydroxycholesterol concentration and its ratio to total cholesterol were significantly lower in the CYP3A5*3/*3 group than in the *1 allele carrier group. The concentrations of plasma fentanyl and serum 4β-hydroxycholesterol were significantly higher in women than in men. Gender did not affect the metabolic ratio of fentanyl or the concentration ratio of 4β-hydroxycholesterol. The plasma fentanyl concentration was not correlated with the serum 4β-hydroxycholesterol concentration, while the metabolic ratio of fentanyl was slightly correlated with the serum concentration ratio of 4β-hydroxycholesterol. In conclusion, CYP3A5*3 and gender affected the plasma fentanyl and serum 4β-hydroxycholesterol concentrations in cancer patients. However, the plasma disposition of fentanyl was not determined using the serum 4β-hydroxycholesterol concentration.

A rapid, simple and sensitive method for the determination and bioequivalence study of transdermal fentanyl in human plasma using liquid chromatography-electrospray ionization tandem mass spectrometry.

Since the 1960s, fentanyl has been used to replace morphine nd other opioids due to its higher potency in the treatment of acute pain; since the 1990s, it has also been administrated to control chronic pain by using transdermal fentanyl device system. It is crucial and of utmost importance and crucial to validate a sensitive method for the quantification of transdermal fentanyl in human plasma. A rapid, simple and sensitive high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method has been established and validated for the determination of transdermal fentanyl in human plasma using fentanyl-D5 as an internal standard (IS). Following liquid-liquid extraction (LLE) with n-hexane, the extracts were separated on a Thermo Hypersil ODS(C18) column (2.1 × 150 mm i.d., 5 μm) interfaced with a triple-quadrupole tandem mass spectrometer using positive electrospray ionization. Quantification of fentanyl was carried out by multiple reaction monitoring (MRM) of the transitions at m/z 337.1→188.0 for fentanyl and 341.9→187.9 for IS. The lower limit of quantification was 9.75 pg×mL-1, and the test showed a linear range of 9.75 - 10,000 pg×mL-1. The validated method was subsequently applied to a bioequivalence (BE) study in 24 healthy Chinese volunteers by using transdermal fentanyl patches.

Determination of the minimum alveolar concentration of isoflurane that blunts adrenergic responses in sheep and evaluation of the effects of fentanyl.

To determine the minimum alveolar concentration that blunts adrenergic responses (MACBAR) for isoflurane and evaluate effects of fentanyl on isoflurane MACBAR in sheep. ANIMALS 13 healthy adult Dorset-cross adult ewes. In a crossover design, each ewe was anesthetized 2 times for determination of isoflurane MACBAR. Anesthesia was induced with propofol administered IV. Sheep initially received fentanyl (5 μg/kg, IV, followed by a constant rate infusion of 5 μg/kg/h) or an equivalent volume of saline (0.9% NaCl) solution (control treatment). After a washout period of at least 8 days, the other treatment was administered. For MACBAR determination, a mechanical nociceptive stimulus (ie, sponge forceps) was applied at the coronary band for 1 minute. The MACBAR values of the 2 treatments were compared by means of a paired t test. During MACBAR determination, blood samples were collected for measurement of plasma fentanyl concentration. Mean ± SD isoflurane MACBAR of the fentanyl and control treatments was 1.70 ± 0.28% and 1.79 ± 0.35%, respectively; no significant difference was found between the 2 treatments. Plasma concentration of fentanyl reached a median steady-state concentration of 1.69 ng/mL (interquartile range [25th to 75th percentile], 1.47 to 1.79 ng/mL), which was maintained throughout the study. Administration of fentanyl at 5 μg/kg, IV, followed by a constant rate infusion of the drug at 5 μg/kg/h did not decrease isoflurane MACBAR. Further studies to determine the effect of higher doses of fentanyl on inhalation anesthetic agents and their potential adverse effects are warranted.

Treatment with subcutaneous and transdermal fentanyl: results from a population pharmacokinetic study in cancer patients.

PurposeTransdermal fentanyl is effective for the treatment of moderate to severe cancer-related pain but is unsuitable for fast titration. In this setting, continuous subcutaneous fentanyl may be used. As data on the pharmacokinetics of continuous subcutaneous fentanyl are lacking, we studied the pharmacokinetics of subcutaneous and transdermal fentanyl. Furthermore, we evaluated rotations from the subcutaneous to the transdermal route.MethodsFifty-two patients treated with subcutaneous and/or transdermal fentanyl for moderate to severe cancer-related pain participated. A population pharmacokinetic model was developed and evaluated using non-linear mixed-effects modelling. For rotations from subcutaneous to transdermal fentanyl, a 1:1 dose conversion ratio was used while the subcutaneous infusion was continued for 12 h (with a 50 % tapering after 6 h). A 6-h scheme with 50 % tapering after 3 h was simulated using the final model.ResultsA one-compartment model with first-order elimination and separate first-order absorption processes for each route adequately described the data. The estimated apparent clearance of fentanyl was 49.6 L/h; the absorption rate constant for subcutaneous and transdermal fentanyl was 0.0358 and 0.0135 h−1, respectively. Moderate to large inter-individual and inter-occasion variability was found. Around rotation from subcutaneous to transdermal fentanyl, measured and simulated plasma fentanyl concentrations rose and increasing side effects were observed.ConclusionsWe describe the pharmacokinetics of subcutaneous and transdermal fentanyl in one patient cohort and report several findings that are relevant for clinical practice. Further research is warranted to study the optimal scheme for rotations from the subcutaneous to the transdermal route.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-015-2005-x) contains supplementary material, which is available to authorized users.

Comparison of a triple-quadrupole and a quadrupole time-of-flight mass analyzer to quantify 16 opioids in human plasma

The aim of this work is to study whether a quadrupole time-of-flight (QToF) mass analyzer, coupled to an ultra high performance liquid chromatography (UHPLC) system, can be a valuable alternative for a triple-quadrupole (QqQ) mass analyzer, for quantitative toxicological purposes. The case study considered was the quantification of 16 opioids (6-monoacetylmorphine, buprenorphine, codeine, dihydrocodeine, ethylmorphine, fentanyl, hydrocodone, hydromorphone, morphine, norbuprenorphine, norcodeine, norfentanyl, oxycodone, oxymorphone, pholcodine and tilidine) in human plasma. Both methods were validated in parallel in terms of selectivity, matrix effects, extraction recovery, carry-over, bias, precision and sensitivity. Accuracy-profile methodology was used to determine the optimal calibration model, and to estimate bias, repeatability, intermediate precision and total error. Selectivity was demonstrated for all opioids and deuterated analogues, except for codeine-d3 on the UHPLC-QTOF. For most compounds, extraction recoveries were in the range 60 to 80% on both systems, except for the synthetic analogues, buprenorphine, fentanyl and tilidine, where large variability is observed. Carry-over was negligible on both systems. For different opioids, the optimal calibration model was different between the systems. The accuracy profiles of the majority of the opioids indicated that, over the entire tested concentration range, for more than 5% of the future measurements, total errors are expected to exceed the a priori defined 15% acceptance limit. For some exceptions, however, the measurements even suffer from total errors above 30%, which can be attributed to the solid phase extraction procedure that was applied as sample pretreatment technique. Sensitivity was generally tenfold better on the LC-QToF system, probably due to the difference in ion choice for quantification between both systems. In conclusion, the best performing system seemed to depend on the compound, on the parameter and even on the concentration. Accuracy profiles clearly provided valuable information complementary to that obtained in classical validation tests, and therefore preferably are taken into account when deciding on a method's performance.

Exposure to Fentanyl After Transdermal Patch Administration for Cancer Pain Management.

This study aimed to describe exposure after fentanyl transdermal patch administration in patients with advanced cancer to quantify variability around the exposure. Patients (n = 56) with advanced cancer who received transdermal fentanyl (Durogesic®; median dose, 50 μg/h; range, 12-200 μg/h) provided venous blood samples (n = 163) at various times (0.5-72 hours) during several patch application intervals. Plasma fentanyl concentration was determined (median, 0.9 μg/L; range, 0.04-9.7 μg/L) by high-performance liquid chromatography coupled to tandem mass spectrometry. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling with NONMEM. A 1-compartment distribution model with first-order absorption and elimination described fentanyl exposure after transdermal patch administration. Fentanyl apparent clearance (between-subject variability [BSV], %) was estimated at 122 L/h/70 kg and 38.5%, respectively. The absorption rate constant was 0.013 h(-1) . Between-occasion variability on apparent clearance was 22.0%, which was lower than BSV, suggesting predictable exposure within the same patient and justifying therapeutic drug monitoring. Except for weight-based dosing, no other patient characteristic could be identified to guide initial fentanyl dose selection in patients with advanced cancer.

Saliva versus Plasma for Pharmacokinetic and Pharmacodynamic Studies of Fentanyl in Patients with Cancer

PurposeFentanyl is widely used to relieve cancer pain. However there is great interpatient variation in the dose required to relieve pain and little knowledge about the pharmacokinetic and pharmacodynamic (PK/PD) relationship of fentanyl and pain control. Patients with cancer are fragile and there is reluctance on the part of health professionals to take multiple plasma samples for PK/PD studies. The relationship between plasma and saliva fentanyl concentrations was investigated to determine whether saliva could be a valid substitute for plasma in PK/PD studies. MethodsOne hundred sixty-three paired plasma and saliva samples were collected from 56 patients prescribed transdermal fentanyl (Durogesic, Janssen-Cilag Pty Limited, NSW, Australia) at varying doses (12–200 µg/h). Pain scores were recorded at the time of sampling. Fentanyl and norfentanyl concentrations in plasma and saliva were quantified using HPLC-MS/MS. FindingsSaliva concentrations of fentanyl (mean = 4.84 μg/L) were much higher than paired plasma concentrations of fentanyl (mean = 0.877 μg/L). Both plasma and saliva mean concentrations of fentanyl were well correlated with dose with considerable interpatient variation at each dose. The relationship between fentanyl and norfentanyl concentrations was poor in both plasma and saliva. No correlation was observed between fentanyl concentration in plasma and saliva (r2 = 0.3743) or free fentanyl in plasma and total saliva concentrations (r2 = 0.1374). Pain scores and fentanyl concentration in either of the matrices were also not correlated. ImplicationsNo predictive correlation was observed between plasma and saliva fentanyl concentration. However the detection of higher fentanyl concentrations in saliva than plasma, with a good correlation to dose, may allow saliva to be used as an alternative to plasma in PK/PD studies of fentanyl in patients with cancer.

Cardiovascular effects of equipotent doses of isoflurane alone and isoflurane plus fentanyl in New Zealand White rabbits (Oryctolagus cuniculus)

OBJECTIVE To determine effects of equipotent concentrations of fentanyl and isoflurane, compared with isoflurane alone, on cardiovascular variables in New Zealand White rabbits (Oryctolagus cuniculus). ANIMALS 6 adult female New Zealand White rabbits. PROCEDURES Rabbits were anesthetized with isoflurane, and lungs were mechanically ventilated. The minimum alveolar concentration (MAC) of isoflurane alone (baseline) and with fentanyl administered IV to achieve 3 targeted plasma concentrations was determined for each rabbit by means of an electrical stimulus. Cardiovascular variables were measured in a separate experiment at 1.3X isoflurane MAC and equipotent doses of isoflurane plus fentanyl at the same 3 targeted plasma concentrations. Blood samples were collected for measurement of blood gas variables and plasma fentanyl concentrations. Treatment effects were evaluated by repeated-measures ANOVA followed by 2-tailed paired t tests with sequentially rejective Bonferroni correction. RESULTS Mean ± SD MAC of isoflurane was 1.95 ± 0.27%. Mean measured plasma fentanyl concentrations of 4.97, 8.93, and 17.19 ng/mL reduced isoflurane MAC by 17%, 37%, and 56%, respectively. Mean measured plasma fentanyl concentrations during cardiovascular measurements were 5.49, 10.26, and 18.40 ng/mL. Compared with baseline measurements, heart rate was significantly lower at all 3 plasma fentanyl concentrations, mean arterial blood pressure and systemic vascular resistance were significantly higher at mean fentanyl concentrations of 10.26 and 18.40 ng/mL, and cardiac output was significantly higher at 18.40 ng of fentanyl/mL. CONCLUSIONS AND CLINICAL RELEVANCE Administration of fentanyl in isoflurane-anesthetized rabbits resulted in improved mean arterial blood pressure and cardiac output, compared with isoflurane alone. This balanced anesthesia technique may prove useful in the management of clinical cases in this species.

Refractory cachexia is associated with increased plasma concentrations of fentanyl in cancer patients.

BackgroundAn appropriate plasma concentration of fentanyl is the key to achieving good pain control in cancer patients. Cachexia, a multifactorial syndrome, is known to affect drug-metabolizing enzymes. However, the fentanyl concentrations in the blood of patients with cachexia have not been analyzed. The aim of this study was to evaluate the influence of cancer cachexia on dose-adjusted plasma fentanyl concentrations in cancer patients.MethodsBlood was collected from 21 Japanese cancer patients treated with a 24-hour trans-dermal fentanyl patch during the steady state of fentanyl plasma concentration. Plasma fentanyl concentrations were analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS), and the levels were adjusted with the dose of fentanyl. Laboratory data were collected, and the cachexia stage was determined, based on study by Fearon et al. Multiple regression analysis was performed to identify the factors that affected fentanyl plasma concentrations.ResultsEight patients were classified as precachexia, nine as cachexia, and four as refractory cachexia, and the median dose-adjusted fentanyl concentrations (ng/mL per mg/kg/day) were 27.5, 34.4, and 44.5, respectively. The dose-adjusted fentanyl concentration in patients with refractory cachexia was higher than that in patients with precachexia (Kruskal–Wallis test and post hoc Mann–Whitney U-test, P<0.01). The factors that were found to possibly affect the dose-adjusted concentration of fentanyl included aspartate aminotransferase, C-reactive protein, and estimated glomerular filtration rate, when analyzed as six independent variables (multiple regression analysis, P<0.05).ConclusionThe dose-adjusted plasma concentrations of fentanyl increased with progression of cancer cachexia. Such an increase is associated with a multifactorial and systemic syndrome in cancer cachexia patients, including lower albumin, higher C-reactive protein, and impaired kidney function. In patients with cancer cachexia, we suggest that evaluation of cancer cachexia might help pain management when using a transdermal fentanyl patch in palliative care.

Quantitative determination of fentanyl in newborn pig plasma and cerebrospinal fluid samples by HPLC-MS/MS.

In this study, a selective and sensitive high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method requiring low sample volume (≤100 μL) was developed and validated for the quantitative determination of the opioid drug fentanyl in plasma and cerebrospinal fluid (CSF). A protein precipitation extraction with acetonitrile was used for plasma samples whereas CSF samples were injected directly on the HPLC column. Fentanyl and (13) C6 -fentanyl (Internal Standard) were analyzed in an electrospray ionization source in positive mode, with multiple reaction monitoring (MRM) of the transitions m/z 337.0/188.0 and m/z 337.0/105.0 for quantification and confirmation of fentanyl, and m/z 343.0/188.0 for (13) C6 -fentanyl. The respective lowest limits of quantification for plasma and CSF were 0.2 and 0.25 ng/mL. Intra- and inter-assay precision and accuracy did not exceed 15%, in accordance with bioanalytical validation guidelines. The described analytical method was proven to be robust and was successfully applied to the determination of fentanyl in plasma and CSF samples from a pharmacokinetic and pharmacodynamic study in newborn piglets receiving intravenous fentanyl (5 µg/kg bolus immediately followed by a 90-min infusion of 3 µg/kg/h).

Effect of dosing interval on pharmacokinetics of fentanyl pectin nasal spray from a crossover study.

To evaluate the effects of different dosing intervals on multiple-dose pharmacokinetics, and safety and tolerability of fentanyl pectin nasal spray (FPNS). This was an open-label study in healthy volunteers. Five FPNS treatments (1 × 100 μg; 2 × 100 μg at 4-, 2-, and 1-hour intervals, and 8 × 100 μg consecutively) were administered to the right nostril, with a ≥ 3-day washout period. Blood samples were collected at predose and up to 1,440 minutes postdose. Plasma fentanyl concentrations were determined. Pharmacokinetic parameters-peak concentration (C(max)), time to C(max) (t(max)), and area under the concentration-time curve (AUC)-were derived using noncompartmental method. For the two-dose regimens, pharmacokinetic parameters were compared between doses using a paired t-test with p < 0.05 as statistically significant. Thirteen subjects were enrolled and 10 completed the study. Median tmax was 10-15 minutes across five regimens. Cmax post the second dose significantly increased for 1-hour (p < 0.0001) and 2-hour (p < 0.001) but not 4-hour intervals (p = 0.462). C(max) and AUC(0-24) following 8 × 100 μg were approximately fivefold of those following 1 × 100 μg. Dizziness (11.9 percent) and somnolence (4.9 percent) were most common adverse events (AEs). 12.9 percent of patients discontinued due to AEs. FPNS exhibited consistently rapid t(max). When intervals between two doses were shorter, the difference in C(max) between the first and second dose was larger. All regimens of FPNS were well tolerated. Exposure reached a plateau after eight consecutive doses, suggesting potential limited absorption through the nasal mucosa.

Effects of fentanyl on isoflurane minimum alveolar concentration in New Zealand White rabbits (Oryctolagus cuniculus).

To determine effects of increasing plasma fentanyl concentrations on the minimum alveolar concentration (MAC) of isoflurane in rabbits. 6 adult female New Zealand White rabbits (Oryctolagus cuniculus). Rabbits were anesthetized with isoflurane in oxygen; ventilation was controlled and body temperature maintained between 38.5° and 39.5°C. Fentanyl was administered IV by use of a computer-controlled infusion system to achieve 6 target plasma concentrations. Isoflurane MAC was determined in duplicate by use of the bracketing technique with a supramaximal electrical stimulus. Blood samples were collected for measurement of plasma fentanyl concentration at each MAC determination. The MAC values were analyzed with a repeated-measures ANOVA followed by Holm-Sidak pairwise comparisons. Mean ± SD plasma fentanyl concentrations were 0 ± 0 ng/mL (baseline), 1.2 ± 0.1 ng/mL, 2.2 ± 0.3 ng/mL, 4.4 ± 0.4 ng/mL, 9.2 ± 0.4 ng/mL, 17.5 ± 2.6 ng/mL, and 36.8 ± 2.4 ng/mL. Corresponding mean values for isoflurane MAC were 1.92 ± 0.16%, 1.80 ± 0.16%, 1.60 ± 0.23%, 1.46 ± 0.22%, 1.12 ± 0.19%, 0.89 ± 0.14%, and 0.70 ± 0.15%, respectively. Isoflurane MAC for plasma fentanyl concentrations ≥ 2.2 ng/mL differed significantly from the baseline value. In 3 rabbits, excessive spontaneous movement prevented MAC determination at the highest plasma fentanyl concentration. Fentanyl reduced isoflurane MAC by approximately 60% in New Zealand White rabbits. Further studies will be needed to investigate the cardiorespiratory effects of isoflurane and fentanyl combinations in rabbits; however, fentanyl may prove to be a useful adjunct to inhalation anesthesia in this species.

Effect of dosing interval on pharmacokinetics and safety of fentanyl pectin nasal spray.

148 Background: Fentanyl pectin nasal spray(FPNS) contains fentanyl citrate and is approved for treatment of breakthrough cancer pain. Nasal delivery allows direct nasal epithelium-to-blood absorption of fentanyl, and thus rapid and effective pain relief. This study evaluated the effect of dosing interval on pharmacokinetics (PK) and safety/tolerability of FPNS. Methods: This was an open-label randomized study in healthy volunteers. Five treatments were administered under naltrexone block to the right nostril, with a ≥3-day washout period: 1 x 100 μg (A); 2 x 100 μg, 4-hr (B), 2-hr (C), and 1-hr apart (D); and 8 x 100 μg consecutively (E). Blood samples were collected and analyzed for plasma fentanyl concentrations. PK data were derived using a non-compartmental model method. Results: 13 subjects were enrolled, 10 (77%) completed the study. For the two-dose regimens, Cmax was higher after the second dose than the first; the increase was statistically significant for the 1- and 2-hr intervals, but not the 4-hr. There were no significant differences in AUC among them. Eight consecutive 100-µg doses resulted in an ~5-fold in Cmax and AUC of those of a single 100-µg dose, suggesting a less than dose proportional increase in rate (peak) and extent (AUC). No new adverse events (AEs) were observed. 53% of subjects reported ≥1 AE, with dizziness (11.9%) and somnolence (4.9%) most common. 12.9% of subjects discontinued due to AEs. All AEs rapidly decreased to sustained low levels after 4–5 weeks. Conclusions: FPNS at 100-800 µg was well tolerated. The shorter the dosing interval, the higher the second Cmax. Dosing interval had no effect on AUC. Exposure plateaued after 8 consecutive 100 µg doses to the same nostril, suggesting an additional safety feature of FPNS. [Table: see text]

Protein binding of fentanyl and its metabolite nor-fentanyl in human plasma, albumin and α-1 acid glycoprotein

1. Fentanyl is a highly lipophilic opioid commonly used to treat cancer pain. Plasma protein binding (PPB) of fentanyl in human plasma is reported as 80–85%, however it is unclear whether fentanyl binds primarily to albumin (ALB) or α-1 acid glycoprotein (AAG) and no studies have been conducted on the metabolite, nor-fentanyl. Fentanyl is also known to bind to plasticware and ultrafiltration (UF) devices which impacts adversely on binding experiments.2. PPB of fentanyl and nor-fentanyl to ALB and AAG in isotonic phosphate buffer solution and seeded human plasma was quantified. PPB was also performed in plasma samples obtained from cancer patients receiving transdermal fentanyl. The adsorption of fentanyl and nor-fentanyl to UF devices and plasticware commonly used in PPB studies was also assessed.3. Fentanyl was shown to bind primarily to ALB as opposed to AAG, with nor-fentanyl exhibiting negligible binding to plasma proteins. Total PPB of fentanyl was 86–89% in seeded human plasma. PPB in 56 cancer patient samples was 95.1 ± 3.52% for fentanyl and 32.4 ± 21.9% for nor-fentanyl.4. UF was shown to be a reliable and convenient method for PPB studies, thereby removing the need for complex testing for adsorption of the drug to plasticware during UF.