Plasma Fentanyl Research Articles

Physiologically based modeling reveals different risk of respiratory depression after fentanyl overdose between adults and children.

Despite a rapid increase in pediatric mortality rate from prescription and illicit opioids, there is limited research on the dose-dependent impact of opioids on respiratory depression in children, the leading cause of opioid-associated death. In this article, we extend a previously developed translational model to cover pediatric populations by incorporating age-dependent pharmacokinetic, pharmacodynamic, and physiological changes compared to adults. Our model reproduced previous perioperative clinical findings that adults and children have similar risk of respiratory depression at the same plasma fentanyl concentration when specific endpoints (minute ventilation, CO2 tension in the blood) were used. However, our model points to a potential caveat that, in a perioperative setting, routine use of mechanical ventilation and supplemental oxygen maintained the blood and tissue oxygen partial pressures in patients and prevented the use of oxygen-related endpoints to evaluate the consequences of respiratory depression. In a community setting when such oxygenation procedures are not immediately available, our model suggests that the higher oxygen demand and reduced cerebrovascular reactivity could make children more susceptible to severe hypoxemia and brain hypoxia, even with the same plasma fentanyl concentration as adults. Our work indicates that when developing intervention strategies to protect children from opioid overdose in a community setting, these pediatric-specific factors may need to be considered.

Developing and Evaluating the Greenness of a Reliable, All-in-One Thin-Film Microextraction Protocol for Determining Fentanyl, Methadone, and Zolpidem in Plasma, Urine, and Oral Fluid.

This paper proposes an all-in-one microextraction-based protocol capable of determining and quantifying fentanyl, methadone, and zolpidem in plasma, urine, and saliva at concentrations below those required by international regulatory organizations. A homemade thin-film microextraction device featuring an octyl-cyanopropyl stationary phase was coupled with LC-MS/MS. The proposed method was developed and validated according to FDA criteria, providing extraction efficiency values ranging from 26.7% to 76.2% with no significant matrix effects (2.6% to 15.5% signal suppression). The developed protocol provided low limits of quantification (mostly equal to 1 ng mL-1) and good reproducibility (intra- and inter-day RSDs of less than 9.6% and 12.0%, respectively) and accuracy (89% to 104% of the test concentration). An assessment of the protocol's environmental impact indicated that attention must be devoted to eliminating the use of toxic reagents and developing its capability for in situ sampling and in-field analysis using portable instruments. The proposed TFME-based protocol provides clinical laboratories with a versatile, one-step tool that enables the simultaneous monitoring of fentanyl, methadone, and zolpidem using the most popular biological matrices.

Population Pharmacokinetics of Single Bolus Dose Fentanyl in Obese Children.

Childhood obesity is a significant problem. Obesity may alter the pharmacokinetics (PKs) of medications. Fentanyl is commonly used for procedural sedation, but there is a paucity of bolus dose fentanyl PK data in obese children. Better understanding of fentanyl PK in obese children would facilitate dosing recommendations. We conducted a study involving children with and without obesity to assess the potential differences in bolus dose fentanyl PK between the 2 groups. We enrolled children 2 to 12 years of age with and without obesity, defined as >95th percentile body mass index (BMI) for age and sex, undergoing elective tonsillectomy ± adenoidectomy. After induction, subjects had 2 intravenous (IV) lines placed in 2 different extremities: 1 for medications and IV fluids and 1 for obtaining blood aliquots for fentanyl concentration analysis. After administration of 1 mcg/kg of fentanyl based on total body weight (TBW), blood sample collections for fentanyl concentration analysis were attempted at 5, 15, 30, 60, 90, and 120 minutes. Five-minute fentanyl concentrations were compared between obese and nonobese cohorts. Population PK analysis to examine the differences between obese and nonobese children was performed and included various body size descriptors, such as TBW, BMI, and fat-free mass (FFM), to examine their influence on model parameters. Half of the 30 subjects were obese. Mean fentanyl concentrations at 5 minutes were 0.53 ng/mL for the nonobese group and 0.88 ng/mL for the obese group, difference 0.35 ng/mL (95% CI, 0.08-0.61 ng/mL; P = .01). Population PK analysis showed that FFM was a significant covariate for the central volume of distribution. The potential clinical effect of an IV bolus dose of fentanyl based on TBW versus FFM in an obese child was assessed in a simulation using our model. 1 mcg/kg fentanyl dose based on TBW resulted in an approximately 60% higher peak fentanyl effect site concentration than dosing based on FFM. Our data demonstrated higher peak plasma fentanyl concentrations in obese compared to nonobese subjects. Population PK analysis found that FFM was a significant covariate for the central volume of distribution. Model simulation showed dosing of fentanyl in obese children based on TBW resulted in significantly higher peak concentrations than dosing based on FFM. Based on this modeling and the known concentration-effect relationship between fentanyl and adverse effects, our results suggest that bolus dosing of fentanyl in obese children should be based on FFM rather than TBW, particularly for procedures of short duration.

Longitudinal evaluation of fentanyl concentrations in equine plasma and synovial fluid following application of transdermal fentanyl patches over one carpal joint.

To determine if transdermally delivered fentanyl can achieve greater concentrations of fentanyl in synovial fluid when applied over a synovial structure. Randomized, experimental study. Six healthy adult horses. Each horse had two 100 μg/h fentanyl matrix patches applied on the dorsal aspect of one, randomly assigned, carpometacarpal joint (CMCJ) for 48 h. Whole blood and bilateral synovial samples from the intercarpal joint were obtained at 0, 2, 6, 12, 24, 36 and 48 h. Fentanyl concentrations were measured with liquid chromatography-mass spectrometry. All subjects achieved detectable concentrations of fentanyl in both plasma and synovial fluid. Time to peak synovial and plasma concentration was 12 h. At 6 h, the synovial concentration in the untreated carpus (0.104 ng/mL ± 0.106) was lower than plasma fentanyl concentrations 0.31 ± 0.27 (p = .036). At 12 h, both treated (0.55 ng/mL ± 0.3) and untreated (0.53 ng/mL ± 0.28) synovial fluid fentanyl concentrations were lower than plasma (0.87 ng/mL ± 0.48) concentrations (p < .001 and p = .001, respectively). Synovial concentrations of fentanyl did not differbetween treated and untreated joints (p > 0.608 for all time points). Application of fentanyl matrix patches directly over the CMCJ did not result in increased fentanyl concentrations in the synovial fluid of the treated intercarpal joint in normal horses. There is likely no analgesic advantage to placing fentanyl patches directly over the affected joint, as it did not result in increased synovial concentrations at the tested site.

An individualized digital twin of a patient for transdermal fentanyl therapy for chronic pain management

Fentanyl transdermal therapy is a suitable treatment for moderate-to-severe cancer-related pain. The inter-individual variability of the patients leads to different therapy responses. This study aims to determine the effect of physiological features on the achieved pain relief. Therefore, a set of virtual patients was developed by using Markov chain Monte Carlo (MCMC) based on actual patient data. The members of this virtual population differ by age, weight, gender, and height. Tailored digital twins were developed using these correlated, individualized parameters to propose a personalized therapy for each patient. It was shown that patients of different ages, weights, and gender have significantly different fentanyl blood uptake, plasma fentanyl concentration, pain relief, and ventilation rate. In the digital twins, we included the virtual patients’ response to the treatment, namely, pain relief. Therefore, the digital twin was able to adjust the therapy in silico to have more efficient pain relief. By implementing digital-twin-assisted therapy, the average pain intensity decreased by 16% compared to conventional therapy. The median time without pain increased by 23 h over 72 h. Therefore, the digital twin can be successfully used in individual control of transdermal therapy to reach higher pain relief and maintain steady pain relief.Graphical (Created with BioRender.com)

Trace level identifications of fentanyl and eutylone in equine plasma, pharmacological significance and probable origins – a case report and analysis

Trace level identifications of fentanyl and eutylone in equine plasma, pharmacological significance and probable origins – a case report and analysis

Effect of fentanyl, with or without treatment of bradycardia, on the minimum alveolar concentration of isoflurane and cardiovascular function in dogs

ObjectiveTo determine the effect of fentanyl on the minimum alveolar concentration of isoflurane (MACISO) and cardiovascular variables in dogs, and how the treatment of bradycardia affects them. Study designProspective, randomized crossover-controlled trial. AnimalsA total of six male Beagle dogs weighing 9.9 ± 0.7 kg (mean ± standard deviation) and aged 13 months. MethodsTo each dog, two treatments were assigned on different days: fentanyl (FENTA) or fentanyl plus glycopyrrolate (FENTAglyco) to maintain heart rate (HR) between 100 and 132 beats minute−1. Determinations of MACISO were performed with 10 plasma fentanyl target concentrations ([Fenta]Target (0, 0.16, 0.32, 0.64, 1.25, 2.5, 5.0, 10.0, 20.0 and 40.0 ng mL−1) for FENTA and 5 [Fenta]Target (0, 1.25, 2.5, 5.0, 10.0 ng mL−1)) for FENTAglyco. During each MACISO determination, cardiovascular variables [mean arterial pressure (MAP), HR and cardiac index (CI)] were measured, and systemic vascular resistance index (SVRI) calculated. Pharmacodynamic models were used to describe the plasma fentanyl concentration [Fenta]–response relationship for the effect on MACISO and cardiovascular variables. A mixed-model analysis of variance followed by Dunnett’s or Tukey’s test, and the Bonferroni adjustment were used for comparisons within and between each treatment, respectively. Significance was set as p < 0.05. ResultsFentanyl decreased MACISO by a maximum of 84%. The [Fenta] producing 50% decrease in MAC, HR and CI were 2.64, 3.65 and 4.30 ng mL−1 (typical values of population model), respectively. The prevention of fentanyl-mediated bradycardia caused no significant effect on MACISO, but increased HR, MAP and CI, and decreased SVRI when compared with isoflurane alone. Conclusions and clinical relevanceFentanyl caused a plasma concentration-dependent decrease in MACISO, HR and CI and an increase in SVRI. Cardiovascular improvements associated with fentanyl in isoflurane-anesthetized dogs only occurred when the fentanyl-mediated bradycardia was prevented.

Long-Term Analgesia following a Single Application of Fentanyl Transdermal Solution in Pigs

Introduction: In animal research, obtaining efficient and constant pain control is regulatory but challenging. The gold standard pain management consists of opioid analgesic administration, such as buprenorphine or fentanyl extended-release patches. However, as in all drugs with a short half-life time, repeated buprenorphine administrations are needed, leading to multiple injections that affect the research protocol. On the other hand, fentanyl patch efficacy is discussed in some species. These elements highlight the need of an optimal formulation of analgesic drugs for laboratory animals. In this study, we investigated how Recuvyra®, a fentanyl transdermal solution (FTS), validated in dog perioperative pain management, could provide sustained analgesia after a single topical administration in pigs in a surgical context. Methods: A total of 11 minipigs were used in this study. As a preliminary experiment, two different doses were tested as a single application on five pigs: two pigs at full dose (2.6 mg/kg) and three pigs at half dose (1.3 mg/kg). Plasma fentanyl dosages were performed during 4 consecutive days, using liquid chromatography with tandem mass spectrometry detection. The efficacy of FTS was then evaluated in a perioperative period. Six minipigs benefited from a surgical intervention comprising a laparotomy. The FTS was blotted on the skin in a single application 20 min before the surgical incision and plasma fentanyl dosages, clinical examination (body weight, food intake, heart rate, and body temperature) and pain assessment were performed for 7 consecutive days. Results: During the preliminary experiment, all fentanyl concentrations reached the minimum effective concentration (MEC) extrapolated in pigs (fentanylemia ≥0.2 ng/mL) throughout the 4 days. The half dose was chosen for the next step of the study. After the surgical intervention, all plasma fentanyl concentrations remained above the MEC up to 7 days post administration. Pig clinical examinations and pain evaluations showed efficient and constant pain control at the half dose, and few adverse events were observed. Discussion and Conclusion: This study confirms the pharmacological and clinical efficacy of FTS at 1.3 mg/kg in pigs throughout at least 7 postoperative days following laparotomy. The clinical analgesic effect of FTS appears more efficient and well-tolerated than the one observed with repeated injections of buprenorphine. This analgesic drug formulation could be universally used in animal research to provide optimal perioperative pain management and long-term analgesia.

Intranasal Fentanyl for Intervention-Associated Breakthrough Pain After Cardiac Surgery.

BackgroundCardiac bypass surgery patients have early postoperative interventions that elicit breakthrough pain. We evaluated the use of intranasal fentanyl for breakthrough pain management in these patients.MethodsMultimodal analgesia (paracetamol 1 g three times a day, oxycodone 2–3 mg boluses with a patient-controlled intravenous pump) was used in 16 patients (age 49–70 years, weight 59–129 kg) after cardiac bypass surgery. Intranasal fentanyl 100 µg or 200 µg was used to manage breakthrough pain on the first and third postoperative mornings in a randomised order. Blood samples were collected for up to 3 h after fentanyl administration, pain was assessed with a numeric rating scale of 0–10. Plasma fentanyl concentration was assayed using liquid chromatography-mass spectrometry. Body composition was measured with a bioelectrical impedance device.ResultsBioavailability of intranasal fentanyl was high (77%), absorption half-time short (< 2 min) and an analgesic plasma concentration ≥ 0.5 ng/mL was achieved in 31 of 32 administrations. Fentanyl exposure correlated inversely with skeletal muscle mass and total body water. Fentanyl analgesia was effective both on the first postoperative morning with chest pleural tube removal and during physiotherapy on the third postoperative morning. The median time of subsequent oxycodone administration was 1.1 h after intranasal fentanyl 100 µg and 2.1 h after intranasal fentanyl 200 µg, despite similar oxycodone concentrations (median 13.8, range 5.2–35 ng/mL) in both fentanyl dose groups.ConclusionsIntranasal fentanyl 100 µg provided rapid-onset analgesia within 10 min and is an appropriate starting dose for incidental breakthrough pain in the first 3 postoperative days after cardiac bypass surgery.Clinical Trial RegistrationEudraCT Number: 2018-001280-22.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01002-4.

Influence of St. John's Wort on Intravenous Fentanyl Pharmacokinetics, Pharmacodynamics, and Clinical Effects: A Randomized Clinical Trial.

Patients often use complementary and alternative herbal medicines, hence, potential exists for adverse herb-drug interactions. Fentanyl is metabolized by hepatic CYP3A4 and considered transported by blood-brain barrier P-glycoprotein. Both disposition processes could be upregulated by the herbal St. John's wort. This investigation evaluated effects of St. John's wort on fixed-dose and apparent steady-state IV fentanyl pharmacokinetics, pharmacodynamics, and clinical effects. Healthy volunteers received a fentanyl fixed-dose infusion and an individually tailored target controlled infusion on separate days, before and after 30-day St. John's wort (300 mg thrice daily; n = 8) or placebo control (n = 8) in a randomized parallel-group design. Fentanyl plasma concentrations, pupil diameter, analgesic response to experimental pain (cold pressor), subjective side effects, and cognitive effects were measured. Plasma fentanyl concentrations and changes in pupil diameter were subjected to pharmacokinetic-pharmacodynamic modeling. St. John's wort did not alter fentanyl pharmacokinetics. Clearance (l/min) before and after St. John's wort (1.13 ± 0.29 and 1.24 ± 0.26, respectively) or placebo (0.96 ± 0.28 and 1.12 ± 0.27, respectively) were not different. St. John's wort also did not affect fentanyl pharmacodynamics as measured by pupil constriction after fixed-dose and tailored fentanyl infusions. EC50 (ng/ml) was 1.1 ± 0.7 and 1.4 ± 0.9 before and after St. John's wort versus 1.2 ± 0.8 and 1.4 ± 1.7 before and after placebo. Effect site equilibration time, T½,ke0 (min), was 12.8 ± 5.3 and 11.3 ± 6.4 before and after St. John's wort versus 11.4 ± 6.4 and 11.1 ± 5.6 before and after placebo. St. John's wort had no influence on analgesia, cognitive performance, or somatic cognitive-affective effects of fentanyl. St. John's wort did not alter fentanyl pharmacokinetics, pharmacodynamics or clinical effects, suggesting no effect on hepatic clearance or blood-brain barrier efflux. Patients taking St. John's wort will likely not respond differently to IV fentanyl for anesthesia or analgesia.

Effect of heart rate on the pharmacokinetics of fentanyl in dogs anesthetized with isoflurane and hydromorphone

ObjectiveTo compare the pharmacokinetics of fentanyl at lower (LHR) or higher heart rate (HHR) in dogs anesthetized with isoflurane. Study designProspective, randomized, crossover controlled trial. AnimalsA group of six healthy 13-month-old male Beagle dogs weighing 9.9 ± 0.7 kg (mean ± standard deviation). MethodsDogs were allocated to two treatments: LHR (HR: 45–75 beats minute−1) and HHR (HR: 100–130 beats minute−1). Anesthesia was maintained with isoflurane and hydromorphone (0.1 mg kg−1 followed by 0.02–0.10 mg kg−1 hour−1) for both treatments. Glycopyrrolate was administered in HHR to maintain HR within the desired range. Afterwards, fentanyl (20 μg kg−1) was intravenously administered over 5 minutes. Arterial blood samples were collected for plasma fentanyl concentration measurement by liquid chromatography/mass spectrometry. The pharmacokinetics of fentanyl were compared between treatments and the differences were considered significant at p < 0.05. ResultsA three-compartment model best fitted the changes in plasma fentanyl concentration. Clearance (CL; mL minute−1 kg−1) was 33.2 (24.0–48.0) and 61.3 (44.5–72.7), maximum concentration (ng mL−1) 33.6 (23.4–36.6) and 20.0 (16.7–28.0), apparent volume of the rapid peripheral compartment (mL kg−1) 436 (352–723) and 925 (499–1887), apparent volume at steady state (mL kg−1) 4064 (3453–6546) and 7195 (5077–8601), cardiac index (CI; mL minute−1 m−2) 2.83 (1.98–3.67) and 4.91 (3.22–6.09) and HR (beats minute−1) 68 (49–72) and 120 (102–129) for LHR and HHR, respectively, with significant differences between treatments. Significant correlations (0.92 and 0.90) were found between CI and CL, and between HR and CL, respectively. Conclusions and clinical relevanceThe increase in HR and the resultant improvement in cardiac output increased fentanyl CL and volume of distribution, which resulted in a decrease in plasma fentanyl concentration in isoflurane-anesthetized dogs.

Effect of fentanyl on thermal and mechanical nociceptive thresholds in horses and estimation of anti-nociceptive plasma concentration

There are few investigations relating anti-nociception to plasma concentrations of fentanyl in horses. The study objective was to evaluate analgesic efficacy and duration in horses and determine the minimum anti-nociceptive plasma concentrations. Eight horses were treated with saline (P) and fentanyl (F2.5=2.5μg/kg; F5=5μg/kg; F10=10μg/kg) given IV over 5min, with a wash-out period of 10 days. To evaluate thermal (°C) and mechanical (N) nociceptive threshold single stimulations were applied prior to (baseline) and 10, 30, 60, 90, 120, 180, 240, 300, 360, 420, 540min and 22.5h after treatment. Plasma fentanyl concentrations were measured at specific time points. Locomotor activity, heart rate, respiratory rate and gastrointestinal sounds were recorded. Two-way repeated measures ANOVA and pairwise comparisons were used for data analysis (P<0.05).With treatment F10, there was a significant increase in thermal threshold above baseline (47.2ö4.1°C) at t10 (53.7ö4.2°C) and t30 (52.1ö5.6°C), whereas mechanical threshold increased considerably above baseline (3.7ö1.3N) only at t10 (6.6ö3.6N). Estimated mean minimum anti-nociceptive plasma concentration determined by thermal stimulation was 6.1–6.8ng/mL. Dose-dependent increased locomotion occurred, but no significant changes in heart rate, respiratory rate and gastrointestinal sounds were observed. Fentanyl IV at 10μg/kg produced anti-nociception for 10–30min and fentanyl plasma concentrations of ≥6.1–6.8ng/mL appear necessary to induce thermal anti-nociception. Dose-dependent increased locomotion was the main side effect observed.

Simple and Sensitive Technique for Fentanyl Quantification in Urine and Plasma by GC-MS

This work reports a sensitive and specific gas chromatography (GC) mass spectrometry (MS) method for the detection of subnanogram concentrations of fentanyl in plasma. Objective- Fentanyl is a high-potency, rapid–onset synthetic opioid prescribed for the treatment of chronic pain and used as a surgical anesthetic. In the past decade its abuse and accidental overdose have steadily been on the rise. Method- This study was planned to develop an analytical procedure for fentanyl detection in biological samples which will help in to distinguish between therapeutic drug use and abuse. For sample preparation Solid phase extraction coupled (SPE) was opted while quantification was done with Gas Chromatograph Mass Spectrometer (GC-MS). GC-MS is among the best known precise and effective techniques for biological samples analysis. Chromatographic separation was achieved on using DB-5MS column on a selected ion monitoring (SIM) mode. Results-Signal to noise ratio was 3:1.The linearity lay between 0.62-40ng/ml correlation coefficient was ≥ 0.9899 and recovery was ≥80%. Limit of Detection was 0.6ng/ml and limit of quantification was 0.24ng/ml. Conclusion- Current analytical procedure for fentanyl quantification had good specificity and sensitivity and showed good recovery. This method will be helpful for quantification of fentanyl in clinical and can be applied to forensic as well .

Detection of codeine and fentanyl in saliva, blood plasma and whole blood in 5-minutes using a SERS flow-separation strip.

A simple-to-use device to measure drugs in saliva, blood plasma, and whole blood for point-of-care analysis and treatment of overdose patients has been investigated. A rudimentary flow strip has been developed to separate opioids from these biofluids for analysis by surface-enhanced Raman spectroscopy (SERS). The strips are based on lateral flow assays, in which the antibodies have been substituted by SERS-active pads for detection. Samples of codeine and fentanyl, artificially added to these biofluids, were measured using the strips by a field-usable Raman spectrometer. We report measurement of these drugs in these biofluids from 0.5 to 5 μg mL-1 in 5 minutes. Calculated limits of detection for the spectra suggest that these drugs could be measured at 5 to 20 ng mL-1 with improvements in the strips' separation capability.

Is the transdermal fentanyl patch an efficient way to achieve acute postoperative pain control?: A randomized controlled trial.

Backgroupd:This study investigated the plasma fentanyl concentration and efficacy of transdermal fentanyl patch (TFP) (25 μg/h) in the management of acute postoperative pain.Methods:Patients undergoing laparoscopic cholecystectomy were randomly allocated to 2 groups. The TFP group (n = 30) received a single TFP 25 μg/ h to the anterior chest wall 14 h before operation. The IV group (n = 30) received a placebo patch. After the operation, intravenous fentanyl infusion (25 μg/h) was begun with loading dose 25 μg in the IV group and only normal saline in the TFP group. Plasma fentanyl levels were measured at admission, 1, 6, 12, 24, and 48 h postoperatively. Pain severity and adverse effects were evaluated too.Results:The fentanyl level peaked 1 h after operation in the TFP group (3.27 ± 0.34 ng/mL) and 24 h postoperatively in the IV group (2.9 ± 0.42 ng/mL). Pain scores and the use of rescue analgesics were not significantly different between 2 groups. Respiratory depression was not happened in both groups.Conclusions:The TFP (25 μg/h) affixed 14 h before surgery reached a higher constant concentration than the same dose setting of a constant IV infusion of fentanyl after surgery. Although the concentration of fentanyl was higher than those of previous researches, there was no respiratory depression. But, there was no advantage of reducing pain score and the use of rescue analgesics. Clinical trial registration: (available at: http://cris.nih.go.kr, KCT0002221).

Identification of Cytochrome P450 Polymorphisms in Burn Patients and Impact on Fentanyl Pharmacokinetics: A Pilot Study.

Pain management is critical for burn care. Unfortunately, interindividual variation in pharmacokinetics (PK) due to burn hypermetabolism and genetic polymorphisms can lead to treatment failures in this at-risk population. Analgesics may be affected by genetic polymorphisms affecting cytochrome P450 (CYP) drug metabolizing enzymes. Fentanyl is a common opiate primarily metabolized by CYP3A4 subtypes. Recent studies demonstrate CYP2D6 variants, affecting fentanyl PK. Functional CYP polymorphisms can significantly alter opiate levels resulting in inadequate analgesia or life-threatening toxicity. The goal of our study was to evaluate fentanyl PK and assess associations with CYP polymorphisms. We obtained samples from the previously banked blood of 13 patients (eight males and five females) with >20% TBSA burns. Mean (SD) patient age was 41.7 (14.5) years, and mean burn size was 25.8 (15.3) %TBSA. Plasma fentanyl was quantified, and CYP genotyping was performed. Pharmacokinetic analysis was performed using Monolix software (Lixsoft, France) with a two-compartment population model best-representing fentanyl profiles. Three CYP slow-metabolizing genotypes were identified, which included CYP2D6*9, CYP2D6*29, and CYP3A4*1B. All three patients with variant polymorphisms had increased serum fentanyl concentrations due to impaired clearance. This pilot study supports the need for further research in this topic, and CYP genotyping of individual patients prior to receiving opiate analgesics to inform precision-guided decisions, improve therapeutic efficacy, and, most importantly, increase patient well-being and safety.

Effects of two fentanyl constant rate infusions on thermal thresholds and plasma fentanyl concentrations in awake cats

ObjectiveTo determine the pharmacokinetics and effects on thermal thresholds (TT) of two fentanyl constant rate infusions in awake cats. Study designA blinded, randomized crossover study. AnimalsA group of six healthy female cats, aged 3 ± 1 years, weighing 4.1 ± 0.7 kg. MethodsSkin temperature (TSKIN) and TT were evaluated using a wireless TT device. TSKIN, TT, sedation score (SS) and blood samples were collected before an intravenous loading dose (LD; over 5 seconds) and at specific time points during (360 minutes) and after infusion. Each cat was administered two treatments: fentanyl (LD 3 μg kg−1, infusion 3 μg kg−1 hour−1; treatment F3) or fentanyl (LD 5 μg kg−1, infusion 5 μg kg−1 hour−1; treatment F5). SS between treatments was analyzed using a Kruskal–Wallis test. Statistical analysis of TT and TSKIN was performed using analysis of variance with appropriate post hoc test (p < 0.05). ResultsTSKIN did not vary over time for each treatment. SS did not differ between treatments. TTs were significantly higher than baseline at 15 minutes after LD for F3 and F5. TT was significantly increased at 30, 90, 120, 180 and 300 minutes in treatment F5 but not in F3. Plasma fentanyl concentrations decreased rapidly in both treatments over the first 30 minutes after infusion. The terminal half-life was 3.31 (2.93–4.41) hours for F3 and 3.67 (3.39–4.32) hours for F5 (median, range). Systemic clearance for treatments F3 and F5 was 1.95 (1.46–2.44) and 2.25 (1.98–2.47) L hour−1 kg−1 (median, range), respectively. Plasma concentrations <1.84 ng mL−1 were not associated with a significant increase in TT. Conclusionsand clinical relevance A fentanyl infusion rate of 5 μg kg−1 hour−1 increased TT during the infusion period. Effects on TT were lost rapidly with cessation of the infusion.

Effects of three fentanyl plasma concentrations on the minimum alveolar concentration of isoflurane in Hispaniolan Amazon parrots (Amazona ventralis).

OBJECTIVE To determine effects of 3 plasma concentrations of fentanyl on the minimum alveolar concentration of isoflurane (MACiso) and cardiovascular variables in Hispaniolan Amazon parrots (Amazona ventralis). ANIMALS 6 adult parrots. PROCEDURES In phase 1, anesthesia was induced and maintained with isoflurane; intermittent positive-pressure ventilation was provided. The MACiso was determined for each bird by use of a bracketing method and supramaximal electrical stimulus. Fentanyl (20 μg/kg) was administered IV, and blood samples were collected over time to measure plasma fentanyl concentrations for pharmacokinetic calculations. In phase 2, pharmacokinetic values for individual birds were used for administration of fentanyl to achieve target plasma concentrations of 8, 16, and 32 ng/mL. At each concentration, MACiso and cardiovascular variables were determined. Data were analyzed with mixed-effects multilevel linear regression analysis. RESULTS Mean ± SD fentanyl plasma concentrations were 0 ng/mL, 5.01 ± 1.53 ng/mL, 12.12 ± 3.58 ng/mL, and 24.93 ± 4.13 ng/mL, and MACiso values were 2.09 ± 0.17%, 1.45 ± 0.32%, 1.34 ± 0.31%, and 0.95 ± 0.14% for fentanyl target concentrations of 0, 8, 16, and 32 ng/mL, respectively. Fentanyl significantly decreased MACiso in a dose-dependent manner. Heart rate and blood pressure significantly decreased at all fentanyl doses, compared with values for MACiso at 0 ng of fentanyl/mL. CONCLUSIONS AND CLINICAL RELEVANCE Fentanyl significantly decreased the MACiso in healthy Hispaniolan Amazon parrots, but this was accompanied by a depressive effect on heart rate and blood pressure that would need to be considered for application of this technique in clinical settings.

Adverse reactions to fentanyl transdermal patches in calves: a preliminary clinical and pharmacokinetic study

ObjectiveTo describe adverse reactions and measure plasma fentanyl concentrations in calves following administration of a fentanyl transdermal patch (FTP). Study designProspective, experimental clinical study. AnimalsSix female Holstein calves and one male Angus calf. Four calves were healthy experimental animals and three calves were clinical patients. MethodsPlasma fentanyl concentrations were measured in blood collected from a jugular vein. FTP 2 μg kg–1 hour–1 and 1 μg kg–1 hour–1 was applied to four and three calves, respectively. Heart rate, respiratory rate, temperature and ataxia were recorded at the same times as blood collection (0, 2, 4, 6, 12, 24, 36, 48, 60, 72, 84 and 96 hours). Substance P concentrations were determined via radioimmunoassay for two calves. ResultsAfter the FTP (2 μg kg–1 hour–1) application, two calves developed tachycardia, hyperthermia, excitement and ataxia within 6 hours; no adverse effect was observed in the other two calves. The three calves administered FTP (1 μg kg–1 hour–1) exhibited tachycardia and excitement, and the FTP were removed at 4 hours. Naloxone was administered to two calves before the adverse clinical signs ceased, while adverse events in the other three calves resolved within 2 hours of FTP removal. Variables returned to previous baseline values by 2–4 hours after FTP removal. Maximum plasma fentanyl concentrations were variable among calves (0.726–6.923 ng mL–1). Substance P concentrations measured in two calves were not consistently depressed during FTP application. Fentanyl concentrations at 4 and 6 hours were significantly associated with the appearance of adverse effects. Conclusions and clinical relevanceFTP (1–2 μg kg–1 hour–1) administered to calves may result in adverse behavioral and cardiovascular effects. Patch removal and treatment with an opioid antagonist may resolve these adverse effects. Additional research is needed to determine optimal FTP dosing for cattle.

Pharmacokinetics of fentanyl citrate and norfentanyl in Holstein calves and effect of analytical performances on fentanyl parameter estimation.

This study describes the pharmacokinetics of intravenously administered (i.v.) fentanyl citrate, and its primary metabolite norfentanyl in Holstein calves. Eight calves (58.6±2.2kg), aged 3-4weeks, were administered fentanyl citrate at a single dose of 5.0μg/kg i.v. Blood samples were collected from 0 to 24hr. Plasma (nor)fentanyl concentrations were determined using liquid chromatography with mass spectrometry and a lower limit of quantification (LLOQ) of 0.03ng/ml. To explore the effect of analytical performance on fentanyl parameter estimation, the noncompartmental pharmacokinetic analysis was then repeated with a hypothetical LLOQ value of 0.05ng/ml. Terminal elimination half-life was estimated at 12.7 and 3.6hr for fentanyl and norfentanyl, respectively. For fentanyl, systemic clearance was estimated at 2.0Lhr-1 kg-1 , volume of distribution at steady-state was 24.8L/kg and extraction ratio was 0.42. At a hypothetical LLOQ of 0.05ng/ml fentanyl half-life, volume of distribution at steady-state and clearance were, respectively, of 3.0hr, 8.8L/kg and 3.4Lkg-1 hr-1 . Fentanyl citrate administered i.v. at 5.0μg/kg can reach levels associated with analgesia in other species. Pharmacokinetic parameters should be interpreted with respect to LLOQ, as lower limits can influence estimated parameters, such as elimination half-life or systemic clearance and have significant impact on dosage regimen selection in clinical practice.