Structure Elucidation of Urinary Metabolites of Fentanyl and Five Fentanyl Analogs using LC-QTOF-MS, Hepatocyte Incubations and Synthesized Reference Standards.

Fentanyl analogs constitute a particularly dangerous group of new psychoactive compounds responsible for many deaths around the world. Little is known about their metabolism, and studies utilizing liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) analysis of hepatocyte incubations and/or authentic urine samples do not allow for determination of the exact metabolite structures, especially when it comes to hydroxylated metabolites. In this study, seven motifs (2-, 3-, 4- and ß-OH as well as 3,4-diOH, 4-OH-3-OMe and 3-OH-4-OMe) of fentanyl and five fentanyl analogs, acetylfentanyl, acrylfentanyl, cyclopropylfentanyl, isobutyrylfentanyl and 4F-isobutyrylfentanyl were synthesized. The reference standards were analyzed by LC-QTOF-MS, which enabled identification of the major metabolites formed in hepatocyte incubations of the studied fentanyls. By comparison with our previous data sets, major urinary metabolites could tentatively be identified. For all analogs, ß-OH, 4-OH and 4-OH-3-OMe were identified after hepatocyte incubation. ß-OH was the major hydroxylated metabolite for all studied fentanyls, except for acetylfentanyl where 4-OH was more abundant. However, the ratio 4-OH/ß-OH was higher in urine samples than in hepatocyte incubations for all studied fentanyls. Also, 3-OH-4-OMe was not detected in any hepatocyte samples, indicating a clear preference for the 4-OH-3-OMe, which was also found to be more abundant in urine compared to hepatocytes. The patterns appear to be consistent across all studied fentanyls and could serve as a starting point in the development of methods and synthesis of reference standards of novel fentanyl analogs where nothing is known about the metabolism.

Detecting fentanyl using point-of-care drug checking technologies: A validation study.

OBJECTIVES: Point-of-care drug checking services, wherein individuals can check the content and purity of their drugs, have emerged as a public health intervention to address the fentanyl crisis; however, there have been no rigorous evaluations of the technologies against reference standard laboratory techniques. METHODS: Two point-of-care technologies, fentanyl immunoassay strips and Fourier-Transform Infrared (FTIR) spectroscopy, were implemented at two supervised injection sites in Vancouver, Canada. We calculated sensitivity, specificity, and false negative rate for both testing methods as compared to a laboratory reference standard. RESULTS: Between October 2017 and 2018, 331 samples were sent for confirmatory testing. Immunoassay strips had a sensitivity of 87.5% and specificity of 95.2%, with a false negative rate of 12.5%. FTIR spectroscopy had a sensitivity of 72.1% and specificity of 99.0%, with a false negative rate of 27.9%. CONCLUSION: As expected, while FTIR spectroscopy can quantify concentrations on a wide array of compounds, it can only do so above the detection limit. Using FTIR spectroscopy and immunoassay strips in combination has the potential to offset the limitations of each technology when used alone.

Comparison of the Analgesic Effect of Ropivacaine with Fentanyl and Ropivacaine Alone in Continuous Epidural Infusion for Acute Herpes Zoster Management: A Retrospective Study.

Background and Objectives: Currently, few studies have reported the effects of opioids during continuous epidural infusion (CEI) to control pain owing to herpes zoster (HZ). This study aimed to retrospectively compare the effectiveness of epidural opioids in the treatment of acute HZ pain. Materials and Methods: We reviewed medical records of 105 patients who were divided into two groups: R group (CEI with ropivacaine) and RF group (CEI with ropivacaine and fentanyl). Clinical efficacy was evaluated using the numeric rating scale (NRS) score for 6 months after the procedures. We compared the percentage of patients with complete remission in each group. We investigated the complication rates during CEI. Results: No significant differences in the NRS scores were observed between the two groups in the 6-month period. The adjusted odds ratio (OR) for patients included in the complete remission was 0.6 times lower in the RF group than in the R group (95% confidence interval: 0.22-1.71, p = 0.35). The OR for complications during CEI was higher in the RF group than in the R group. However, the difference was not statistically significant. Conclusions: No difference was observed in the management of HZ pain and the prevention of postherpetic neuralgia between the two groups. The incidence of complications tended to be higher in the RF group than in the R group.

Ropivacaine/Fentanyl vs. Bupivacaine/Fentanyl for Pain Control in Children after Thoracic Surgery: A Randomized Study.

BACKGROUND: Although bupivacaine remains a standard local anesthetic for postoperative epidural infusions in pediatric patients, it is increasingly being replaced with ropivacaine by many anesthesiologists. Ropivacaine is associated with less risk for cardiac and central nervous system toxicity. AIMS: The purpose of this study was to compare analgesic efficacy and adverse events of postoperative epidural analgesia with ropivacaine/fentanyl versus bupivacaine/fentanyl in children after the Ravitch procedure and thoracotomy. DESIGN: This was a prospective randomized controlled study. SETTINGS: This study was conducted at the Department of Thoracic Surgery of the Institute of Tuberculosis and Lung Diseases in Rabka Zdroj, Poland. PARTICIPANTS/SUBJECTS: 94 patients undergoing elective thoracic surgery. METHODS: Patients aged 7-17 years were randomly allocated into a ropivacaine 0.2% (RF, n = 45) or bupivacaine 0.125% (BF, n = 45) group; 1 mL of each analgesic solution contained 5 µg fentanyl. All patients received acetaminophen and nonsteroidal anti-inflammatory drugs. Nurses assessed pain intensity and incidence of adverse events over 72 hours after surgery and modified analgesia if patient pain intensity was greater than 2 out of 10. RESULTS: There was no statistically significant difference in median pain scores and incidence of adverse events between the RF group and the BF group. The analgesia was excellent (median pain intensity scores at rest, during deep breathing, and when coughing was less than 1 out of 10 in all patients). Adverse events included incidents of desaturation (64/90), nausea (18/90), vomiting (31/90), pruritus (12/90), urinary retention (2/90), paresthesia (11/90), anisocoria (2/90), and Horner syndrome (2/90). CONCLUSIONS: Thoracic epidural analgesia using an RF and BF solution resulted in similar pain relief and adverse event profiles.

Generic patches containing fentanyl: In vitro equivalence and abuse deterrent evaluation according to EMA and FDA guidelines.

The aim of this work was to characterize in vitro and ex vivo the performances of Durogesic and of two bioequivalent generic products, by evaluating: (a) fentanyl release; (b) fentanyl permeation across porcine skin and (c) fentanyl ease of extraction. Additional characteristics studied are the effect of temperature and skin integrity, applied individually or combined, to check a possible synergism. The two generic patches resulted equivalent to the originator according to the new Guideline. Nevertheless, the same data reported in a different way, i.e. considering the total amount of drug permeated from the whole patch over the application time, highlight differences among the patches. The additional tests performed showed that skin integrity does not represent a barrier for fentanyl permeation across the skin, regardless of the type and complexity of the patch. The effect of temperature resulted critical for two out of three patches, probably due to the different composition and to the different structure. The combination of skin damage and elevated temperature did not produce a synergistic effect. Fentanyl extraction was different for the different products and variable according to the conditions used. The results reported in the present work underline the influence of patch composition and complexity on fentanyl extraction, release and skin permeation, in particular in conditions that can be critical, such as elevated temperature. In particular, the effect of critical variables, such as skin integrity and temperature, should be addressed to in the development of a new or new generic patch and new discriminant tests should be developed.

LC-MS determination of fentanyl in human serum and application to a fentanyl transdermal delivery pharmacokinetic study.

AIM: Fentanyl is an opioid agonist used for acute and chronic pain management. In this report, a highly sensitive and simple LC-MS/MS method using Hydrophilic Interaction Chromatography (HILIC) column was validated and used for fentanyl quantification in human serum. RESULTS: The isocratic mobile phase was composed of acetonitrile: 10 mM ammonium formate buffer (pH = 3.2; 90:10, v/v). The assay was linear over a concentration range of 10-10,000 pg/ml. The accuracy of the validation method ranged from 93.2 to 107%, and the precision was within 6.4%. Fentanyl was stable during short- and long-term storage. CONCLUSION: The assay has been successfully applied to serum samples obtained from healthy subjects of a fentanyl transdermal pharmacokinetic study.

Development and validation of an HPLC/MS/MS method for the determination of sufentanil and morphine in human plasma.

A sensitive and fast HPLC/MS/MS method for measurement of sufentanil and morphine in plasma was developed and validated. A single liquid-liquid extraction in alkaline medium was used for the cleanup of plasma, and fentanyl was added as an internal standard (IS). The analyses were carried out using a C18 column and the mobile phase acetonitrile-5 mM ammonium acetate + 0.25% formic acid (70 + 30, v/v). The triple-quadrupole mass spectrometer equipped with an electrospray source in positive mode was set up in the selective reaction monitoring mode to detect precursor --> product ion transition 387.0 > 238.0, 285.7 > 165.1, and 337.0 > 188.0 for sufentanil, morphine, and IS, respectively. The method was linear in the 0.05 (LOQ) - 500 ng/mL range for sufentanil and 10 (LOQ) - 1000 ng/mL range for morphine. Good selectivity, linearity, precision, accuracy, and robustness were obtained for the HPLC/MS/MS method. The proposed method was successfully applied for the determination of sufentanil and morphine in patients undergoing cardiac surgery.

Use of intranasal fentanyl for the relief of pediatric orthopedic trauma pain.

OBJECTIVES: The objective was to evaluate the use of a single 2 µg/kg dose of intranasal fentanyl as analgesia for painful orthopedic injuries in children presenting to a pediatric emergency department (ED). METHODS: This was a prospective, nonblinded interventional trial, in a convenience sample of patients 3 to 18 years of age seen in a tertiary care pediatric ED. All had clinically suspected fractures and were treated between July and November 2006. Eligible patients had moderate to severe pain based on initial pain scores using the Wong Baker Faces Scale (WBS) for patients aged 3-8 years or the Visual Analog Scale (VAS) for patients aged 9-18 years. All enrolled patients received fentanyl via intranasal atomization. Pain scores were obtained at baseline and at 10, 20, and 30 minutes after intranasal fentanyl administration. Satisfaction scores were obtained using a 100-mm VAS. Vital signs and adverse events were recorded. RESULTS: Eighty-one patients were enrolled, 28 in the VAS group and 53 in the WBS group. The mean patient age was 8 years. Fracture locations included forearm, 38 (47%); supracondylar, 16 (20%); clavicle, 7 (9%); tibia/fibula, 5 (6%); and other, 15 (18%). In the WBS group, the median pain scores decreased from five faces (interquartile range [IQR] = 4-6) at baseline to three faces (IQR = 2-5) at 10 minutes, two faces (IQR = 1-4) at 20 minutes, and two faces (IQR = 1-3) at 30 minutes. The mean pain score in the VAS group at baseline was 70 mm (95% confidence interval [CI] = 63 to 77 mm). In this group, the pain scores decreased by a mean of 21 mm (95% CI = 14 to 28 mm) at 10 minutes, 25 mm (95% CI = 15 to 34 mm) at 20 minutes, and 27 mm (95% CI = 16 to 37 mm) at 30 minutes. Mean satisfaction scores were 79 mm for providers, 74 mm for parents, and 62 mm for patients. No adverse events were recorded. CONCLUSIONS: Intranasal fentanyl at a dose of 2 µg/kg provides effective analgesia for pediatric ED patients with painful orthopedic trauma within 10 minutes of administration.

Oral induction of anesthesia with droperidol and transmucosal carfentanil citrate in chimpanzees (Pan troglodytes).

Five chimpanzees (Pan troglodytes) initially received oral droperidol sedation (1.25 mg for a juvenile chimpanzee, body wt = 18.5 kg, and 2.5 mg for adults, body wt >20 kg, range: 18.5-71 kg) followed by transmucosal carfentanil administration at 2.0 microg/kg. This preinduction regimen was developed to produce heavy sedation or even light anesthesia in order to eliminate the need for or at least minimize the stress of darting with tiletamine/zolazepam at 3 mg/kg i.m. This study was designed to assess the safety and efficacy of transmucosal carfentanil. Once each animal was unresponsive to external stimuli, or at approximately 25 min (range 24-34 min) after carfentanil administration, naltrexone and tiletamine/zolazepam (N/T/Z) were combined into one intramuscular injection for anesthetic induction. Naltrexone was administered at 100 times the carfentanil dose in milligrams. For comparison, two chimpanzees received only droperidol, 2.5 mg p.o., followed by tiletamine/zolazepam, 3 mg/kg i.m. The preinduction period for all animals receiving carfentanil was characterized as smooth, with chimpanzees becoming gradually less active and less responsive to external stimuli. Two animals became very heavily sedated at 24 and 35 min, respectively, and were hand injected with N/T/Z. The other three chimpanzees became sternally recumbent but retained some response to stimuli, and N/T/Z was administered by remote injection with minimal response. Rectal body temperatures, pulse and respiratory rates, arterial oxygen hemoglobin saturation, and arterial blood gases were measured at initial contact (t = 0 min) and at 10-min intervals thereafter. Respiratory depression was present in all chimpanzees, regardless of protocol. Mean hemoglobin saturation was 91% for both groups. Mean partial pressure of oxygen, arterial values for carfentanil-treated and control animals were 64.4 +/- 7.6 and 63.5 +/- 6.0 at t = 0, respectively. Only the partial pressure of carbon dioxide, arterial (Paco2) and pH showed significant differences between treated and control animals. Mean Paco2 was greater and mean pH lower for the carfentanil-treated group compared with the controls at t = 0 (58.9 +/- 3.7 and 50.3 +/- 3.1 for Paco2 and 7.33 +/- 0.02 and 7.40 +/- 0.30 for pH, respectively). The results of this study suggest that oral droperidol followed by transmucosal carfentanil can be used effectively as a premedication regimen to produce profound sedation, which limits the stress of darting during parenteral anesthetic induction with tiletamine/zolazepam in chimpanzees. The main side effect of respiratory depression appears to be adequately managed by reversing the carfentanil at the time of induction.

Comparison of two techniques of narcotic-induced anesthesia for use during recording of magnetic motor evoked potentials in dogs.

OBJECTIVE: To compare 2 types of narcotic-induced anesthesia for recording of transcranial magnetic motor evoked potentials (TMMEP) in dogs. DESIGN: The effect of different doses of sufentanil and midazolam and of sufentanil and nitrous oxide on onset latencies and peak-to-peak, amplitudes of TMMEP was evaluated and compared. ANIMALS: 18 neurologically normal dogs. PROCEDURE: Premedication with droperidol and fentanyl. Induction and maintenance of anesthesia either with sufentanil and midazolam or with sufentanil and nitrous oxide. Recording of TMMEP from the extensor carpi radialis muscle of the forelimb and from the cranial tibial muscle of the hind limb. RESULTS: Both types of narcotic anesthesia induced dose-dependent suppression of TMMEP; compared with baseline recordings, latencies increased, amplitudes decreased, and reproducibility became poorer with increasing dose of the anesthetics. Using surgical-depth doses of the anesthetics, TMMEP could still be recorded in all dogs with sufentanil and nitrous oxide, but not with sufentanil and midazolam anesthesia. CONCLUSIONS: Sufentanil and nitrous oxide anesthesia was superior to sufentanil and midazolam anesthesia for TMMEP recording. CLINICAL RELEVANCE: In small animal medicine, and in dogs in particular, spinal cord diseases are among the most frequently encountered neurologic disorders. The development of techniques for recording TMMEP in anesthetized dogs allows noninvasive evaluation of transmission along descending motor pathways of the spinal cord.

The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision.

BACKGROUND: We have previously demonstrated that the minimum alveolar concentration of isoflurane at 1 atm that is required to prevent movement in 50% of patients or animals exposed to a maximal noxious stimulus is markedly reduced by increasing fentanyl concentrations. Total intravenous anesthesia with propofol is increasing in popularity, yet the propofol concentrations required for total intravenous anesthesia or the interaction between propofol and fentanyl have not yet been defined. METHODS: Propofol and fentanyl were administered via computer-assisted continuous infusion to provide pseudo-steady-state concentrations and allow equilibration between plasma-blood concentration and their biophase concentration. For the induction of anesthesia patients were randomly allocated to receive propofol only or propofol plus fentanyl 0.2, 0.8, 1.5, 3.0, and 4.5 ng/ml. In each group patients were randomized to target propofol concentrations of 1.5-10 micrograms/ml. At 7 and 10 min arterial blood samples were taken for subsequent measurement of propofol and fentanyl concentrations. At 10 min loss of consciousness was assessed by the patients' ability to respond to a simple verbal command. Thereafter a new target concentration of propofol was entered to ensure loss of consciousness, and succinylcholine was administered to facilitate tracheal intubation. Patients were rerandomized to a new target concentration of propofol (1-19 micrograms/ml) until skin incision. Before skin incision and 1 min after skin incision, arterial blood samples were again obtained for subsequent measurement of fentanyl and propofol concentrations. At skin incision and for 1 min the patient was observed for purposeful movement. Only samples in which the pre- and poststimulus drug concentrations were within 35% of each other were included. The propofol blood concentration at which 50% or 95% of patients did not respond to verbal command (Cp50s and Cp95s, respectively) and to skin incision (Cp50i and Cp95i, respectively), were calculated by logistic regression. RESULTS: There were 56 evaluable patients for calculating the propofol Cp50s and 53 patients for calculating the propofol Cp50i. For propofol alone the Cp50s was 3.3 micrograms/ml and the Cp95s 5.4 microgram/ml. Increasing fentanyl concentrations reduced the Cp50s (P = 0.03), and increasing age decreased the Cp50s (P = 0.04). For propofol alone the Cp50i was 15.2 (95% confidence interval 7.6-22.8) micrograms/ml and the Cp95i 27.4 micrograms/ml. Increasing fentanyl concentrations markedly reduced the Cp50i (P < 0.01), with a 50% reduction in Cp50i produced by 0.63 ng/ml fentanyl. The propofol Cp50i was decreased by 63% with 1 ng/ml fentanyl and 89% by 3 ng/ml fentanyl. At higher fentanyl concentrations the decrease in Cp50i was proportionally less, demonstrating a ceiling effect. CONCLUSIONS: We defined the propofol concentration required for loss of consciousness and showed that it is reduced by increasing fentanyl concentration and by increasing age. The propofol concentration (alone) adequate for skin incision is high but is markedly reduced by fentanyl. A ceiling effect in the Cp50i for propofol is seen with fentanyl concentrations greater than 3 ng/ml.

Calming fears, easing pain. Children's anesthesia tricky.

To a child, pain and fear are inseparable. How to safely relieve both is a subject of growing debate and research. Only recently has a narcotic drug been approved specifically for children, and its use is controversial.

Pseudomonas cepacia bacteraemia due to intrinsic contamination of an anaesthetic. Bacteriological and serological observations.

In November-December 1977 an epidemic of bacteraemia due to P. cepacia was observed in Odense, Denmark (nine patients), and in Nijmegen, Holland (seven patients). All patients recovered. The epidemic was traced to intrinsic contamination of two batches of the anaesthetic fentanyl. All isolates from the patients and from the two batches belonged to the same biotype, had identical sensitivity patterns, and identical antigens. The P. cepacia strain differed from stock strains in being able to grow in two passages in methyl-p-hydroxi-benzoate, 0.5 mg/ml, which promoted the growth of the microorganism: inocula of 2-20 cfu were sufficient to initiate growth in the drug or preservative. These facts indicate the inadvisability of using p-hydroxi-benzoates as preservatives in vials. The strain was inhibited at temperatures above 38.5 degrees C, corresponding to the recovery of the patients after a period with fever above 39 degrees C. Fourteen out of 15 patients examined had agglutinin titres greater than or equal to 320, while 36 blood donors had titres less than 40. Of 12 patients with postoperative fever in the same period whose blood cultures did not yield P. cepacia, three had titres greater than 320.