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

PubMed

Padula, Cristina; Pescina, Silvia; Nicoli, Sara; Santi, Patrizia

2018-02-15

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. Copyright © 2017 Elsevier B.V. All rights reserved.

Complications of oral exposure to fentanyl transdermal delivery system patches.

PubMed

Prosser, Jane M; Jones, Brent E; Nelson, Lewis

2010-12-01

Fentanyl is a synthetic opioid available therapeutically as an intravenous, transbucal, or transdermal preparation. It is also used as a drug of abuse through a variety of different methods, including the oral abuse of transdermal fentanyl patches. This is a series of patients with oral fentanyl patch exposure reported to our center and represents the first series of oral fentanyl patch exposures collected outside of the postmortem setting. In this series, we examined the New York Poison Control Center database for all cases of oral abuse of fentanyl reported between January 2000 and April 2008. Twenty cases were reported, nine were asymptomatic or had symptoms of opioid withdrawal; 11 had symptoms of opioid intoxication. Eight patients were administered naloxone and all showed improvement in clinical status. Only one case resulted in a confirmed fatality-this patient had an orally adherent patch discovered at intubation. Oral exposure may result in life-threatening toxicity. Patients should be closely assessed and monitored for the opioid toxidrome, and if symptomatic, should be managed with opioid antagonists and ventilatory support.

Post-mortem review of fentanyl-related overdose deaths among identified drug users in Southern Bavaria, Germany, 2005-2014.

PubMed

Sinicina, Inga; Sachs, Hans; Keil, Wolfgang

2017-11-01

Two decades ago, there were only single case reports on deaths in Europe following the consumption of illicitly manufactured fentanyl by problem drug users. Today, lethal fentanyl intoxication is now no longer a rarity. Since 2005, a rapid increase of lethal fentanyl-related intoxications in the drug scene has been observed at the Institute of Legal Medicine, Ludwig Maximilians University, Munich. We hypothesized that this rise is the result of the launch of fentanyl matrix patches in Germany in 2004, their broad acceptance, their diversion from the regulated supply chain, and incautious prescription by medical care providers. Post-mortem toxicological reports were reviewed for lethal fentanyl-related intoxications between 2004 und 2014. Blood and tissue samples were tested by GC/MS or LC-MS/MS. The results of police investigations, autopsy reports, and the database of the Institute of Legal Medicine, LMU, were analysed to identify problem drug users and to detect the source of fentanyl as well as the routes of administration. Between 2005 and 2014, 242 overdose victims with post-mortem toxicological detection of fentanyl were found. In the majority of cases, fentanyl matrix patches were the source of fentanyl. The onset of fentanyl-related deaths coincided with the launch of transdermal fentanyl matrix patches in Germany in 2004. Several approaches, such as providing drug users with information on the possible risks of fentanyl consumption, education of medical caregivers, and also monitoring of the prescription of fentanyl patches, are required to reduce the number of fentanyl-related deaths in drug addicts. Copyright © 2017 Elsevier B.V. All rights reserved.

[Dose-finding for treatment with a transdermal fentanyl patch : Titration with oral transmucosal fentanyl citrate and morphine sulfate].

PubMed

Mücke, M; Conrad, R; Marinova, M; Cuhls, H; Elsner, F; Rolke, R; Radbruch, L

2016-12-01

To date, no studies investigating titration with oral transmucosal fentanyl for the dose-finding of transdermal fentanyl treatment have been published. In an open randomized study 60 patients with chronic malignant (n = 39) or nonmalignant pain (n = 21), who required opioid therapy according to step three of the guidelines of the World Health Organization (WHO), were investigated. In two groups of 30 patients each titration with immediate release morphine (IRM) or oral transmucosal fentanyl citrate (OTFC) was undertaken. For measurement purposes the Brief Pain Inventory (BPI) and Minimal Documentation System (MIDOS) were used. After a 24-h titration phase, in which patients documented the intensity of pain, nausea, and tiredness, treatment with transdermal fentanyl was evaluated over a 10-day period by means of the necessary dose adaptation (responder ≤ 1 dose adaptation; conversion formula 1:1 [OTFC group] vs 100:1 [IRM group]).The pain reduction over the first 24 h (titration phase) did not differ significantly between the groups. The number of responders (17 OTFC vs. 21 IRM) over the 10-day period did not show any difference either. In both groups there was a significant reduction in pain intensity (p < 0.001). Over the course of the study, there were significantly more drop-outs because of adverse effects in the OTFC group than in the IRM group (8 vs 1, p = 0.028).Oral transmucosal fentanyl citrate can be applied for the titration of transdermal fentanyl, but it does not show any clinically relevant advantage. For example, the risk of side effects-induced drop-outs was greater in the present study. Whether the unnecessary opioid switching to treat chronic pain and breakthrough pain is advantageous with regard to minimizing conversion errors cannot be definitively answered within the scope of this study.

Myocardial protection induced by fentanyl in pigs exposed to high-dose adrenaline.

PubMed

da Luz, Vinicius Fernando; Otsuki, Denise Aya; Gonzalez, Maria Margarita Castro; Negri, Elnara Marcia; Caldini, Elia Garcia; Damaceno-Rodrigues, Nilsa Regina; Malbouisson, Luiz Marcelo Sá; Viana, Bruno Gonçalves; Vane, Matheus Fachini; Carmona, Maria Jose Carvalho

2015-10-01

The use of high doses of adrenaline is common in critical patients, especially during cardiac arrest. During these situations, myocardial dysfunction can be a result of multiple factors, including adrenaline use. In addition, opioids have been shown to have anti-arrhythmic and anti-ischemic mechanisms that may confer cardiac protection. This study aimed to evaluate the effects of fentanyl on myocardial function in pigs exposed to high-dose adrenaline. After institutional ethics committee approval, 26 pigs were randomly allocated to receive either 20 μg/kg fentanyl (n = 10; fentanyl group) administered 5 min before five doses of adrenaline (20 μg/kg), equivalent-volume saline (n = 10; saline group) using the same adrenaline dosing protocol, or neither fentanyl nor adrenaline (n = 6; sham group). The fentanyl group showed lower levels of troponin at the end of the sixth hour compared with the saline group (1.91 ± 1.47 vs 5.44 ± 5.35 ng/mL, P = 0.019). Transmission electron microscopy and immunohistochemistry also showed less myocardial injury in the fentanyl group. The conclusion was reached that fentanyl attenuates myocardial injury caused by high-dose adrenaline without blunting the hemodynamic effect of adrenaline. © 2015 Wiley Publishing Asia Pty Ltd.

A review of factors explaining variability in fentanyl pharmacokinetics; focus on implications for cancer patients

PubMed Central

Zandvliet, Maarten L.; Koolen, Stijn L. W.; Mathijssen, Ron H. J.; van der Rijt, Carin C. D.

2016-01-01

Fentanyl is a strong opioid that is available for various administration routes, and which is widely used to treat cancer‐related pain. Many factors influence the fentanyl pharmacokinetics leading to a wide inter‐ and intrapatient variability. This systematic review summarizes multiple studied factors that potentially influence fentanyl pharmacokinetics with a focus on implications for cancer patients. The use of CYP3A4 inhibitors and inducers, impaired liver function, and heating of the patch potentially influence fentanyl pharmacokinetics in a clinically relevant way. In elderly patients, current data suggest that we should carefully dose fentanyl due to alterations in absorption and metabolism. The influence of BMI and gender on fentanyl pharmacokinetics is questionable, most probably due to a large heterogeneity in the published studies. Pharmacogenetics, e.g. the CYP3A5*3 gene polymorphism, may influence fentanyl pharmacokinetics as well, although further study is warranted. Several other factors have been studied but did not show significant and clinically relevant effects on fentanyl pharmacokinetics. Unfortunately, most of the published papers that studied factors influencing fentanyl pharmacokinetics describe healthy volunteers instead of cancer patients. Results from the studies in volunteers may not be simply extrapolated to cancer patients because of multiple confounding factors. To handle fentanyl treatment in a population of cancer patients, it is essential that physicians recognize factors that influence fentanyl pharmacokinetics, thereby preventing potential side‐effects and increasing its efficacy. PMID:27619152

Fatal overdose after ingestion of a transdermal fentanyl patch in two non-human primates.

PubMed

Deschamps, Jack-Yves; Gaulier, Jean-Michel; Podevin, Guillaume; Cherel, Yan; Ferry, Nicolas; Roux, Françoise A

2012-11-01

CASE HISTORY AND PRESENTATION: Two non-human primates (Macaca fascicularis), weight 3.5 kg, enrolled in an experimental protocol received a 25 μg hour(-1) transdermal fentanyl patch for postoperative analgesia. The following day both animals were clinically normal, but after a new induction of anaesthesia with ketamine, they developed severe and prolonged respiratory distress, profound coma and myosis. MANAGEMENT AND FOLLOW-UP: Attempted reversal with naloxone was ineffective. After several hours of ventilation, both primates eventually died, 7 and 15 hours after ketamine injection, respectively. In both cases, the patch was discovered in the animal's cheek pouch. Subsequent fentanyl serum concentration measurements (8.29 and 14.80 μg L(-1) ) confirmed fentanyl overdose. This report of two fatal intoxications in non-human primates secondary to ingestion of a transdermal fentanyl patch demonstrates that this method of analgesia is inappropriate for non-human primates, because of their tendency to chew almost anything they can reach. © 2012 The Authors. Veterinary Anaesthesia and Analgesia. © 2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.

A case of overdose via tattoo.

PubMed

Borg, Roberta; Ashton, Antony

2015-08-01

Transdermal fentanyl patches are used frequently for the management of both acute and chronic pain. Adverse events with their use, in particular overdose, are not uncommon. We describe a case of fentanyl overdose from transdermal patch placed over a five-day old tattoo. The report will review the pharmacology of transdermal fentanyl and the physiology of tattooing, as well as the potential link between the two, which may have lead to the overdose.

Could chest wall rigidity be a factor in rapid death from illicit fentanyl abuse?

PubMed

Burns, Glenn; DeRienz, Rebecca T; Baker, Daniel D; Casavant, Marcel; Spiller, Henry A

2016-06-01

There has been a significant spike in fentanyl-related deaths from illicit fentanyl supplied via the heroin trade. Past fentanyl access was primarily oral or dermal via prescription fentanyl patch diversion. One factor potentially driving this increase in fatalities is the change in route of administration. Rapid intravenous (IV) fentanyl can produce chest wall rigidity. We evaluated post-mortem fentanyl and norfentanyl concentrations in a recent surge of lethal fentanyl intoxications. Fentanyl related deaths from the Franklin County coroner's office from January to September 2015 were identified. Presumptive positive fentanyl results were confirmed by quantitative analysis using liquid chromatography tandem mass spectrometry (LC/MS/MS) and were able to quantify fentanyl, norfentanyl, alfentanyl, and sufentanyl. 48 fentanyl deaths were identified. Mean fentanyl concentrations were 12.5 ng/ml, (range 0.5 ng/ml to >40 ng/ml). Mean norfentanyl concentrations were 1.9 ng/ml (range none detected to 8.3 ng/ml). No appreciable concentrations of norfentanyl could be detected in 20 of 48 cases (42%) and were less than 1 ng/ml in 25 cases (52%). Elevated fentanyl concentrations did not correlate with rises in norfentanyl levels. In several cases fentanyl concentrations were strikingly high (22 ng/ml and 20 ng/ml) with no norfentanyl detected. The lack of any measurable norfentanyl in half of our cases suggests a very rapid death, consistent with acute chest rigidity. An alternate explanation could be a dose-related rapid onset of respiratory arrest. Deaths occurred with low levels of fentanyl in the therapeutic range (1-2 ng/ml) in apparent non-naïve opiate abusers. Acute chest wall rigidity is a well-recognized complication in the medical community but unknown within the drug abuse community. The average abuser of illicit opioids may be unaware of the increasing fentanyl content of their illicit opioid purchase. In summary we believe sudden onset chest wall rigidity may be a significant and previously unreported factor leading to an increased mortality, from illicit IV fentanyl use. Fentanyl and norfentanyl ratios and concentrations suggest a more rapid onset of death given the finding of fentanyl without norfentanyl in many of the fatalities. Chest wall rigidity may help explain the cause of death in these instances, in contrast to the typical opioid-related overdose deaths. Intravenous heroin users should be educated regarding this potentially fatal complication given the increasingly common substitution and combination with heroin of fentanyl.

Fatal fentanyl patch misuse in a hospitalized patient with a postmortem increase in fentanyl blood concentration.

PubMed

Moore, Philip W; Palmer, Robert B; Donovan, Joseph Ward

2015-01-01

Opioid-related mortality happens, even in healthcare settings. We describe serial postmortem fentanyl blood concentrations in a hospital inpatient who fatally abused transdermal fentanyl. This is a single-patient case report. A 42-year-old man with lymphoma was started on transdermal fentanyl therapy while hospitalized for chronic abdominal pain. The patient was last seen awake 1.3 h prior to being found apneic and cyanotic. During the resuscitation attempt, a small square-shaped film was removed from the patient's oropharynx. Femoral blood was collected 0.5 and 2 h postmortem, and the measured fentanyl concentration increased from 1.6 to 14 ng/mL. Study limitations include potential laboratory or collection errors and missing data. (i) Providers must be vigilant for signs of fentanyl patch abuse. (ii) Postmortem blood concentrations are not static postmortem, likely secondary to decreasing pH, increased aqueous solubility, and tissue redistribution, and are therefore unlikely to accurately represent antemortem blood concentrations. © 2014 American Academy of Forensic Sciences.

Management of an oral ingestion of transdermal fentanyl patches: a case report and literature review.

PubMed

Faust, Andrew C; Terpolilli, Ralph; Hughes, Darrel W

2011-01-01

Purpose. Fentanyl is available as a transdermal system for the treatment of chronic pain in opioid-tolerant patients; however, it carries a black box warning due to both the potency of the product and the potential for abuse. In this report, we describe a case of transbuccal and gastrointestinal ingestion of fentanyl patches and the management of such ingestion. Summary. A 32-year-old man was brought to the emergency department (ED) via emergency medical services for toxic ingestion and suicide attempt. The patient chewed and ingested two illegally purchased transdermal fentanyl patches. In the ED, the patient was obtunded, dizzy and drowsy. Initial vital signs showed the patient to be afebrile and normotensive with a heart rate of 63, respiratory rate of 16, and oxygen saturation of 100% on 2 liters nasal cannula after administration of 2 milligrams of intravenous naloxone. The patient was treated with whole bowel irrigation and continuous intravenous naloxone infusion for approximately 48 hours without complications. Conclusion. Despite numerous case reports describing oral ingestion of fentanyl patches, information on the management of such intoxication is lacking. We report successful management of such a case utilizing whole bowel irrigation along with intravenous push and continuous infusion naloxone.

Management of an Oral Ingestion of Transdermal Fentanyl Patches: A Case Report and Literature Review

PubMed Central

Faust, Andrew C.; Terpolilli, Ralph; Hughes, Darrel W.

2011-01-01

Purpose. Fentanyl is available as a transdermal system for the treatment of chronic pain in opioid-tolerant patients; however, it carries a black box warning due to both the potency of the product and the potential for abuse. In this report, we describe a case of transbuccal and gastrointestinal ingestion of fentanyl patches and the management of such ingestion. Summary. A 32-year-old man was brought to the emergency department (ED) via emergency medical services for toxic ingestion and suicide attempt. The patient chewed and ingested two illegally purchased transdermal fentanyl patches. In the ED, the patient was obtunded, dizzy and drowsy. Initial vital signs showed the patient to be afebrile and normotensive with a heart rate of 63, respiratory rate of 16, and oxygen saturation of 100% on 2 liters nasal cannula after administration of 2 milligrams of intravenous naloxone. The patient was treated with whole bowel irrigation and continuous intravenous naloxone infusion for approximately 48 hours without complications. Conclusion. Despite numerous case reports describing oral ingestion of fentanyl patches, information on the management of such intoxication is lacking. We report successful management of such a case utilizing whole bowel irrigation along with intravenous push and continuous infusion naloxone. PMID:21629807

Fatal overdose due to prescription fentanyl patches in a patient with sickle cell/beta-thalassemia and acute chest syndrome: A case report and review of the literature.

PubMed

Biedrzycki, Olaf J; Bevan, David; Lucas, Sebastian

2009-06-01

Introduced into clinical practice in the 1960s, the analgesic fentanyl is 100 times more potent than morphine. Various methods of administration exist including the transdermal Duragesic patch system, widely used in chronic pain and palliative care settings. Numerous, often imaginative methods of abuse of fentanyl patches have been reported; the majority of fatal fentanyl overdose cases resulting from deliberate abuse or suicide. We describe the accidental overdose of a young black male with sickle cell/beta-thalassemia who had been using the Duragesic system for almost 2 years.At autopsy the macroscopic findings were of nonspecific opiate overdose with congested heavy lungs. Histopathological examination revealed severe sickling of red blood cells in the lungs (acute chest syndrome). Toxicological examination revealed blood and urine fentanyl levels of 40 microg/L and 400 microg/L (10 fold and 100 fold higher than therapeutic levels). The mast cell tryptase was also significantly elevated at 76 microg/L, (Normal 2-14 microg/L). We discuss the relevance of these findings with regard to the cause of death, and stress the need to consider fentanyl when confronted with nonspecific signs of opiate overdose as it is not detected in routine toxicological drug screens.

Structural, Morphological, and Functional Correlates of Corneal Endothelial Toxicity Following Corneal Exposure to Sulfur Mustard Vapor

DTIC Science & Technology

2013-10-01

fentanyl patch (25 lg/h) was placed anterior to the scapula. On the day of exposure, rabbits were anesthetized with an intramuscular administration of 15 mg...sterile saline to flush residual agent. Rabbits were returned to cages and provided food and water ad libitum. Fentanyl patches were replaced after 72

Postoperative fentanyl patch versus subacromial bupivacaine infusion in arthroscopic shoulder surgery.

PubMed

Merivirta, Riika; Äärimaa, Ville; Aantaa, Riku; Koivisto, Mari; Leino, Kari; Liukas, Antti; Kuusniemi, Kristiina

2013-07-01

The purpose of our study was to compare the effectiveness of subacromial bupivacaine infusion and a transdermal fentanyl patch in the treatment of postoperative pain after arthroscopic shoulder surgery. Sixty patients with rotator cuff disease scheduled for elective arthroscopic shoulder surgery were enrolled in the study. For the treatment of postoperative pain, 30 patients constituted group F and received a 12.0-μg/h fentanyl patch for 72 hours and saline solution infusion in a subacromial manner at the rate of 4 mL/h. The remaining 30 patients constituted group B and received a placebo patch and an infusion of 2.5-mg/mL bupivacaine in a subacromial manner for 72 hours. The primary outcome measure was the postoperative numerical rating scale pain score. The consumption of opioids, ibuprofen, and acetaminophen was also recorded. The Constant scores and general recovery were followed up until the 90th postoperative day. There was no statistically significant difference in the numerical rating scale scores (P = .60) between the groups. No differences in the use of rescue analgesic were observed except that the patients receiving bupivacaine used more ibuprofen (median, 1,200 mg v 600 mg) during the day of surgery (P = .042). No difference was found in general recovery between the groups. A fentanyl patch delivering 12-μg/h fentanyl offers an easy and safe treatment option as a part of multimodal analgesia with few adverse effects in the treatment of postoperative pain in a carefully selected patient group after arthroscopic shoulder surgery. Level I, randomized controlled trial. Copyright © 2013 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Assisted suicide by fentanyl intoxication due to excessive transdermal application.

PubMed

Juebner, Martin; Fietzke, Mathias; Beike, Justus; Rothschild, Markus A; Bender, Katja

2014-11-01

Herein, we report a case of an assisted suicide committed by application of 34 matrix-based fentanyl-containing transdermal therapeutic systems (TTS) with different release rates. The TTS were supplied by the husband but administered by the deceased herself. Besides routine systematic toxicological analysis (STA), the concentrations of fentanyl and norfentanyl were determined in the blood (femoral and heart), urine, stomach content, brain, lung tissue, musculus iliopsoas, liver, kidney, bile and in some of the used TTS by LC-MS/MS. Blood levels of fentanyl were 60.6 μg/L in femoral blood and 94.1 μg/L in heart blood. These concentrations are in good concordance with levels described in cases with accidental or lethal suicidal fentanyl patch application. The organ distribution indicates an influence of post-mortem redistribution. The levels of residual fentanyl in the TTS were also determined. STA furthermore revealed supratherapeutic levels of bromazepam. Thus, the cause of death was a combination of fentanyl and bromazepam intoxication. However, considering the determined levels of fentanyl and norfentanyl in the entire set of specimens and the high toxicity in comparison to bromazepam, fentanyl was the leading toxic noxa.

Transdermal fentanyl in deliberate overdose in pediatrics.

PubMed

Lyttle, Mark D; Verma, Sapna; Isaac, Rhian

2012-05-01

The use of the fentanyl skin patch to provide pain relief in chronic pain conditions and oncology in adult practice has been common for several years, and an increase in use is now being seen in pediatric practice. Its use in drug misuse and suicide has also increased in recent years. We present the case of an adolescent who deliberately overdosed using fentanyl skin patches and describe the implications for management. This report serves to remind clinicians to consider this method of drug administration in children who display signs of opioid toxicity, where overdose may be subsequent to its use in therapy, recreation, or deliberate self-harm.

A quality improvement project to reduce the intraoperative use of single-dose fentanyl vials across multiple patients in a pediatric institution.

PubMed

Buck, David; Subramanyam, Rajeev; Varughese, Anna

2016-01-01

The use of a single-dose vial across multiple patients presents a risk to sterility and is against CDC guidelines. We initiated a quality improvement (QI) project to reduce the intraoperative use of single-dose vials of fentanyl across multiple patients at Cincinnati Children's Hospital Medical Center (CCHMC). The initial step of the improvement project was the development of a Key Driver Diagram. The diagram has the SMART aim of the project, key drivers inherent to the process we are trying to improve, and specific interventions targeting the key drivers. The number of patients each week receiving an IV dose of fentanyl, from a vial previously accessed for another patient was tracked in a high turnover operating room (OR). The improvement model used was based on the concept of building Plan-Do-Study-Act (PDSA) cycles. Tests of change included provider education, provision of an increased number of fentanyl vials, alternate wasting processes, and provision of single-use fentanyl syringes by the pharmacy. Prior to initiation of this project, it was common for a single fentanyl vial to be accessed for multiple patients. Our data showed an average percentage of failures of just over 50%. During the end of the project, after 7 months, the mean percentage failures had dropped to 5%. Preparation of 20 mcg single-use fentanyl syringes by pharmacy, combined with education of providers on appropriate use, was successful in reducing failures to below our goal of 25%. Appropriately sized fentanyl syringes prepared by pharmacy, education on correct use of single-dose vials, and reminders in the OR, reduced the percentage of patients receiving a dose of fentanyl from a vial previously accessed for another patient in a high-volume otolaryngology room. © 2015 John Wiley & Sons Ltd.

Comparative pharmacokinetics of intravenous fentanyl and buprenorphine in healthy Greyhound dogs

PubMed Central

KuKanich, Butch; Allen, Philip

2014-01-01

The purpose of this study was to compare the pharmacokinetics of two highly protein bound, lipophilic opioid drugs. Fentanyl (10 μg/kg) and buprenorphine (20 μg/kg) were administered intravenously (IV) to six healthy Greyhound dogs (3 males and 3 females). The doses were based on clinically administered doses for dogs. Plasma drug concentrations were determined using liquid chromatography with mass spectrometry and noncompartmental pharmacokinetics were estimated with computer software. The volume of distribution (area) was larger for fentanyl (7.42 L/kg) compared to buprenorphine (3.54 L/kg). The plasma clearance of fentanyl (38.6 mL/min/kg) was faster than buprenorphine (10.3 mL/min/kg). The terminal half-life of fentanyl (2.22 h) was shorter than buprenorphine (3.96 h). Despite similar physicochemical properties including: octanol:water partition coefficient and pKa the pharmacokinetics of fentanyl and buprenorphine were not similar. Both fentanyl (84%) and buprenorphine (95-98%) are considered highly protein bound, but the differences in protein binding may contribute to the lack of similarity of pharmacokinetics in healthy dogs. PMID:24684621

Comparative pharmacokinetics of intravenous fentanyl and buprenorphine in healthy greyhound dogs.

PubMed

KuKanich, B; Allen, P

2014-12-01

The purpose of this study was to compare the pharmacokinetics of two highly protein-bound, lipophilic opioid drugs. Fentanyl (10 μg/kg) and buprenorphine (20 μg/kg) were administered intravenously (IV) to six healthy greyhound dogs (three males and three females). The doses were based on clinically administered doses for dogs. Plasma drug concentrations were determined using liquid chromatography with mass spectrometry, and noncompartmental pharmacokinetics were estimated with computer software. The volume of distribution (area) was larger for fentanyl (7.42 L/kg) compared to buprenorphine (3.54 L/kg). The plasma clearance of fentanyl (38.6 mL·min/kg) was faster than buprenorphine (10.3 mL·min/kg). The terminal half-life of fentanyl (2.22 h) was shorter than buprenorphine (3.96 h). Despite similar physicochemical properties including octanol-water partition coefficient and pKa, the pharmacokinetics of fentanyl and buprenorphine were not similar. Both fentanyl (84%) and buprenorphine (95-98%) are considered highly protein bound, but the differences in protein binding may contribute to the lack of similarity of pharmacokinetics in healthy dogs. © 2014 John Wiley & Sons Ltd.

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

PubMed

Suarez, Martin A; Seddighi, Reza; Egger, Christine M; Rohrbach, Barton W; Cox, Sherry K; KuKanich, Butch K; Doherty, Thomas J

2017-01-01

OBJECTIVE To determine effects of fentanyl, lidocaine, and a fentanyl-lidocaine combination on the minimum alveolar concentration of sevoflurane preventing motor movement (MAC NM ) in dogs. ANIMALS 6 adult Beagles. PROCEDURES Dogs were anesthetized with sevoflurane in oxygen 3 times (1-week intervals). Baseline MAC NM (MAC NM-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 MAC NM (MAC NM-T ) was initiated 90 minutes after start of the CRI. Venous blood samples were collected at the time of each treatment MAC NM measurement for determination of plasma concentrations of fentanyl and lidocaine. RESULTS Mean ± SEM overall MAC NM-B for the 3 treatments was 2.70 ± 0.27 vol%. The MAC NM decreased from MAC NM-B to MAC NM-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 MAC NM of sevoflurane in dogs.

Transdermal fentanyl: pharmacology and toxicology.

PubMed

Nelson, Lewis; Schwaner, Robert

2009-12-01

To evaluate the underlying pharmacology, safety, and misuse/abuse of transdermal fentanyl, one of the cornerstone pharmacotherapies for patients with chronic pain. Literature was identified through searches of Medline (PubMed) and several textbooks in the areas of pharmacology, toxicology, and pain management. A bibliographical review of articles identified by these searches was also performed. Search terms included combinations of the following: fentanyl, transdermal, patch, pharmacology, kinetics, toxicity, and poisoning. All pertinent clinical trials, retrospective studies, and case reports relevant to fentanyl pharmacology and transdermal fentanyl administered by any route and published in English were identified. Each was reviewed for data regarding the clinical pharmacology, abuse, misuse, and safety of transdermal fentanyl. Data from these studies and information from review articles and pharmaceutical prescribing information were included in this review. Fentanyl is a high-potency opioid that has many uses in the treatment of both acute and chronic pain. Intentional or unintentional misuse, as well as abuse, may lead to significant clinical consequences, including death. Both the US Food and Drug Administration (FDA) and Health Canada have warned of potential pitfalls associated with transdermal fentanyl, although these have not been completely effective in preventing life-threatening adverse events and fatalities related to its inappropriate use. Clinically consequential adverse effects may occur unexpectedly with normal use of transdermal fentanyl, or if misused or abused. Misuse and therapeutic error may be largely preventable through better education at all levels for both the prescriber and patient. The prevention of intentional misuse or abuse may require regulatory intervention.

75 FR 49992 - Peter W.S. Grigg, M.D.; Revocation of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-16

... denial of any pending application to renew or modify the registration on the ground that his ``continued... also unlawfully distributed four fentanyl 400 mg. tablets and one fentanyl transdermal patch 12 mcg./hr... legitimate medical purposes.'' Id. Respondent also admitted that on this date, he distributed to the officer...

Brain injury and development in preterm infants exposed to fentanyl

PubMed Central

McPherson, Christopher; Haslam, Matthew; Pineda, Roberta; Rogers, Cynthia; Neil, Jeffrey J.; Inder, Terrie E.

2015-01-01

Background Fentanyl is commonly utilized in preterm infants. Relatively little is known regarding the neurodevelopmental outcomes of preterm infants exposed to fentanyl. Objective To investigate the association between cumulative fentanyl dose and brain injury and diameters in a cohort of preterm infants Methods Data on demographics, perinatal course, and neonatal course, including total fentanyl exposure prior to term equivalent age, were retrospectively evaluated for 103 infants born at ≤ 30 weeks gestational age who underwent magnetic resonance imaging at term equivalent age (mean gestational age 26.9 ± 1.8 weeks). Magnetic resonance images were evaluated for brain injury and regional brain diameters. Developmental testing was conducted at term equivalent and 2 years of age. Results Seventy-eight infants (76%) received fentanyl (median cumulative dose 3 μg/kg, interquartile range 1 – 441 μg/kg). Cumulative fentanyl dose in the first week of life correlated with the incidence of cerebellar hemorrhage after correction for covariates (OR 2.1, 95% confidence interval 1.1 – 4.1). Cumulative fentanyl dose before term equivalent age correlated with reductions in transverse cerebellar diameter after correction for covariates including the presence of cerebellar hemorrhage (r = 0.461, p = 0.002). No correlation was detected between cumulative fentanyl dose and development at 2 years of age. Conclusions Higher cumulative fentanyl dose in preterm infants correlated with a higher incidence of cerebellar injury and lower cerebellar diameter at term equivalent age. Our findings must be taken with caution, but emphasize the need for future prospective trials examining the risks and benefits of commonly utilized analgesic agents in preterm infants. PMID:26369570

PDPH in obstetric anesthesia: comparison of 24-gauge Sprotte and 25-gauge Quincke needles and effect of subarachnoid administration of fentanyl.

PubMed

Devcic, A; Sprung, J; Patel, S; Kettler, R; Maitra-D'Cruze, A

1993-01-01

Postdural puncture headache (PDPH) is a frequent complication of spinal anesthesia. Some investigators have recommended the use of the Sprotte needle to reduce the incidence of this serious complication. This study prospectively compared the incidence of PDPH with two spinal needles of different size and design: the 24-gauge Sprotte (noncutting point) versus the 25-gauge Quincke (diamond, cutting point). The hypothesis that subarachnoid fentanyl will reduce the incidence of PDPH, as suggested in the literature, was also studied. Only patients for emergency or elective cesarean delivery were studied. One hundred ninety four patients were randomly assigned to receive spinal anesthesia with one of the two needles (Sprotte, n = 96; Quincke, n = 98). Simultaneously, each patient was assigned to receive hyperbaric 0.75% bupivacaine local anesthetic or a combination of the same concentration of local anesthetic with 20 micrograms of fentanyl (Sprotte with fentanyl, n = 47; Sprotte without fentanyl, n = 49; Quincke with fentanyl, n = 49; Quincke without fentanyl, n = 49). All patients were evaluated during the first 4 postoperative days, and follow-up telephone interviews were conducted 3 weeks after discharge. Four patients (4.2%) in the Sprotte group and seven (7.1%) in the Quincke group developed PDPH. Three out of four patients with headache in the Sprotte and four out of seven in the Quincke group received fentanyl as an adjunct for spinal anesthesia. Two patients in the Sprotte group required an epidural blood patch as a therapy for PDPH. Two patients in the Quincke group had severe headache and required an epidural blood patch. In the current study, the use of the 24-gauge Sprotte spinal needle resulted in a low incidence of severe PDPH, but was not significantly different when compared with the use of a 25-gauge Quincke needle (oriented parallel to the longitudinal dural fibers). The addition of fentanyl to hyperbaric bupivacaine spinal anesthesia did not reduce the risk of PDPH.

Selective enhancement of fentanyl-induced antinociception by the delta agonist SNC162 but not by ketamine in rhesus monkeys: Further evidence supportive of delta agonists as candidate adjuncts to mu opioid analgesics.

PubMed

Banks, Matthew L; Folk, John E; Rice, Kenner C; Negus, S Stevens

2010-12-01

Mu-opioid receptor agonists such as fentanyl are effective analgesics, but their clinical use is limited by untoward effects. Adjunct medications may improve the effectiveness and/or safety of opioid analgesics. This study compared interactions between fentanyl and either the noncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine or the delta-opioid receptor agonist SNC162 [(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-phenyl)methyl]-N,N-diethylbenzamide] in two behavioral assays in rhesus monkeys. An assay of thermal nociception evaluated tail-withdrawal latencies from water heated to 50 and 54°C. An assay of schedule-controlled responding evaluated response rates maintained under a fixed-ratio 30 schedule of food presentation. Effects of each drug alone and of three mixtures of ketamine+fentanyl (22:1, 65:1, 195:1 ketamine/fentanyl) or SNC162+fentanyl (59:1, 176:1, 528:1 SNC162/fentanyl) were evaluated in each assay. All drugs and mixtures dose-dependently decreased rates of food-maintained responding, and drug proportions in the mixtures were based on relative potencies in this assay. Ketamine and SNC162 were inactive in the assay of thermal antinociception, but fentanyl and all mixtures produced dose-dependent antinociception. Drug interactions were evaluated using dose-addition and dose-ratio analysis. Dose-addition analysis revealed that interactions for all ketamine/fentanyl mixtures were additive in both assays. SNC162/fentanyl interactions were usually additive, but one mixture (176:1) produced synergistic antinociception at 50°C. Dose-ratio analysis indicated that ketamine failed to improve the relative potency of fentanyl to produce antinociception vs. rate suppression, whereas two SNC162/fentanyl mixtures (59:1 and 176:1) increased the relative potency of fentanyl to produce antinociception. These results suggest that delta agonists may produce more selective enhancement than ketamine of mu agonist-induced antinociception. Copyright © 2010 Elsevier Inc. All rights reserved.

Psychomotor Functioning: Comparison of Patients Recovering From General Anesthesia With Remifentanil and a Volatile Anesthetic Versus Fentanyl and a Volatile Anesthetic

DTIC Science & Technology

1998-10-01

appears to be more potent. The ED100 dose for loss of righting with remifentanil is 0.020mg/kg/min. 14 and for fentanyl the dose is 0.035 mg/kg/min. (Lozito... Remifentanil and fentanyl cause the same adverse effects to varying degrees which are mediated at the µ-receptor. With rapid infusion of large doses of...the potency of remifentanil in dogs (Westmoreland, et al., 1993a). 16 Fentanyl has a t1/2 of 3 to 3.65 hours at clinically relevant doses . This

Evaluation of the brain anaesthesia response monitor during anaesthesia for cardiac surgery: a double-blind, randomised controlled trial using two doses of fentanyl.

PubMed

Shoushtarian, Mehrnaz; McGlade, Desmond P; Delacretaz, Louis J; Liley, David T J

2016-12-01

The brain anaesthesia response (BAR) monitor uses a method of EEG analysis, based on a model of brain electrical activity, to monitor the cerebral response to anaesthetic and sedative agents via two indices, composite cortical state (CCS) and cortical input (CI). It was hypothesised that CCS would respond to the hypnotic component of anaesthesia and CI would differentiate between two groups of patients receiving different doses of fentanyl. Twenty-five patients scheduled to undergo elective first-time coronary artery bypass graft surgery were randomised to receive a total fentanyl dose of either 12 μg/kg (fentanyl low dose, FLD) or 24 μg/kg (fentanyl moderate dose, FMD), both administered in two divided doses. Propofol was used for anaesthesia induction and pancuronium for intraoperative paralysis. Hemodynamic management was protocolised using vasoactive drugs. BIS, CCS and CI were simultaneously recorded. Response of the indices (CI, CCS and BIS) to propofol and their differences between the two groups at specific points from anaesthesia induction through to aortic cannulation were investigated. Following propofol induction, CCS and BIS but not CI showed a significant reduction. Following the first dose of fentanyl, CI, CCS and BIS decreased in both groups. Following the second dose of fentanyl, there was a significant reduction in CI in the FLD group but not the FMD group, with no significant change found for BIS or CCS in either group. The BAR monitor demonstrates the potential to monitor the level of hypnosis following anaesthesia induction with propofol via the CCS index and to facilitate the titration of fentanyl as a component of balanced anaesthesia via the CI index.

Survey of pain specialists regarding conversion of high-dose intravenous to neuraxial opioids

PubMed Central

Gorlin, Andrew W; Rosenfeld, David M; Maloney, Jillian; Wie, Christopher S; McGarvey, Johnathan; Trentman, Terrence L

2016-01-01

The conversion of high-dose intravenous (IV) opioids to an equianalgesic epidural (EP) or intrathecal (IT) dose is a common clinical dilemma for which there is little evidence to guide practice. Expert opinion varies, though a 100 IV:10:EP:1 IT conversion ratio is commonly cited in the literature, especially for morphine. In this study, the authors surveyed 724 pain specialists to elucidate the ratios that respondents apply to convert high-dose IV morphine, hydromorphone, and fentanyl to both EP and IT routes. Eighty-three respondents completed the survey. Conversion ratios were calculated and entered into graphical scatter plots. The data suggest that there is wide variation in how pain specialists convert high-dose IV opioids to EP and IT routes. The 100 IV:10 EP:1 IT ratio was the most common answer of survey respondent, especially for morphine, though also for hydromorphone and fentanyl. Furthermore, more respondents applied a more aggressive conversion strategy for hydromorphone and fentanyl, likely reflecting less spinal selectivity of those opioids compared with morphine. The authors conclude that there is little consensus on this issue and suggest that in the absence of better data, a conservative approach to opioid conversion between IV and neuraxial routes is warranted. PMID:27703394

Effects of sevoflurane on carrageenan- and fentanyl-induced pain hypersensitivity in Sprague-Dawley rats.

PubMed

Richebé, Philippe; Rivalan, Bertrand; Rivat, Cyril; Laulin, Jean-Paul; Janvier, Gérard; Maurette, Pierre; Simonnet, Guy

2009-02-01

Opioids are widely used for anesthesia but paradoxically induce postoperative pain hypersensitivity via N-methyl-D: -aspartate (NMDA) receptor modulation. Sevoflurane effects on opioid-induced hyperalgesia have not been yet evaluated in vivo. Nevertheless, some experimental in vitro studies reported anti-NMDA receptor properties for sevoflurane. The aim of this study was to evaluate sevoflurane effects on fentanyl-induced hyperalgesia in opioid-naive rats and in rats with inflammatory pain. Sevoflurane effects on hyperalgesia were evaluated in Sprague-Dawley rats: opioid-naive rats, rats treated with fentanyl (4 x 60 microg kg(-1)) and rats with inflammatory pain (carrageenan) treated with fentanyl (4 x 60 microg kg(-1)). On day zero, subcutaneous fentanyl injections were administered and inflammatory pain was induced with one carrageenan injection in one hind paw. Rats were exposed to low concentrations of sevoflurane (1.0 or 1.5%) on day zero prior to fentanyl injections and inflammatory pain induction, and for the duration of the fentanyl analgesic effect. The nociceptive threshold (Randall-Selitto test) was evaluated daily for 7 days. On day seven, naloxone was injected and the nociceptive threshold was assessed 5 min later. In rats without inflammatory pain but treated with fentanyl on day zero, sevoflurane 1.0% reversed the early (day zero) and long-lasting (day zero to day three) hyperalgesia classically described after high-doses of fentanyl (P < 0.05). This sevoflurane concentration antagonized the hyperalgesia induced by naloxone on day seven (P = 0.33). In a second experiment in rats with inflammatory pain, exposure to low concentrations of sevoflurane (1.0 and 1.5%) did not reduce fentanyl-induced hyperalgesia (P > 0.05), but nevertheless antagonized the naloxone induced hyperalgesia on day seven (P = 0.061). Relatively low sevoflurane concentrations (1.0%) reverse fentanyl-induced hyperalgesia in rats without inflammatory pain. Nevertheless, the lack of effect of sevoflurane concentrations of 1.0% and 1.5% to oppose hyperalgesia following high-dose fentanyl and inflammatory pain suggests that sevoflurane anti-hyperalgesic properties are weak.

Case report of severe bradycardia due to transdermal fentanyl.

PubMed

Hawley, Pippa

2013-09-01

This case report describes a patient who developed severe bradycardia due to transdermal fentanyl. There have been no prior case reports of this occurring in palliative care, but the frequency of association of fentanyl with bradycardia in the anesthesia setting suggests it may be more common than realized. Palliative care settings often have a policy of not routinely checking vital signs, and symptoms of bradycardia could be misinterpreted as the dying process. A patient with recurrent ovarian cancer was admitted with nausea and abdominal pain due to bowel obstruction and fever from a urinary tract infection. A switch from injectable hydromorphone to transdermal fentanyl resulted in symptomatic severe bradycardia within 36 h, without any other signs of opioid toxicity and with good analgesic effect. The fentanyl patch was removed. Atropine was not required. The patient made an uneventful recovery. Transdermal buprenorphine was subsequently used satisfactorily for long-term background pain control, with additional hydromorphone when needed. The delayed absorption of fentanyl via the transdermal route makes early identification of fentanyl-induced bradycardia key to prompt reversal. Patients with resting or relative bradycardia may be at higher than average risk.

Synergistic interaction between fentanyl and the histamine H3 receptor agonist R-(alpha)-methylhistamine, on the inhibition of nociception and plasma extravasation in mice.

PubMed

Poveda, Raquel; Fernández-Dueñas, Víctor; Fernández, Alejandro; Sánchez, Sílvia; Puig, Margarita M; Planas, Eulàlia

2006-07-10

Here we report a synergistic interaction between fentanyl and the histamine H(3) receptor agonist R-(alpha)-methylhistamine on the inhibition of nociception and plasma extravasation in mice. Chronic inflammation was induced by subplantar injection of Complete Freund's Adjuvant into the right hind paw, and the effect of the drugs was evaluated 7 days later. Nociception and plasma extravasation were assessed by hot-plate and Evans blue tests respectively. Subcutaneous administration of fentanyl (0.01-0.1 mg/kg) induced dose-related anti-nociceptive and anti-extravasation effects (E(max)=100% and 62%, respectively). R-(alpha)-methylhistamine administration (0.3-3 mg/kg) showed a dose-related inhibitory effect on extravasation (E(max)=65%) but not on nociception. To analyze possible interaction between these two drugs, a dose-response curve to fentanyl plus a fixed dose of R-(alpha)-methylhistamine (0.5 mg/kg) was obtained. The dose-response curve for the combined treatment showed a shift to the left compared with that for fentanyl alone. Our results confirm that fentanyl and R-(alpha)-methylhistamine interact in a synergic way, inhibiting nociception and plasma extravasation.

Pragmatic pharmacology: population pharmacokinetic analysis of fentanyl using remnant samples from children after cardiac surgery

PubMed Central

Van Driest, Sara L.; Marshall, Matthew D.; Hachey, Brian; Beck, Cole; Crum, Kim; Owen, Jill; Smith, Andrew H.; Kannankeril, Prince J.; Woodworth, Alison; Caprioli, Richard M.

2016-01-01

Aims One barrier contributing to the lack of pharmacokinetic (PK) data in paediatric populations is the need for serial sampling. Analysis of clinically obtained specimens and data may overcome this barrier. To add evidence for the feasibility of this approach, we sought to determine PK parameters for fentanyl in children after cardiac surgery using specimens and data generated in the course of clinical care, without collecting additional blood samples. Methods We measured fentanyl concentrations in plasma from leftover clinically‐obtained specimens in 130 paediatric cardiac surgery patients and successfully generated a PK dataset using drug dosing data extracted from electronic medical records. Using a population PK approach, we estimated PK parameters for this population, assessed model goodness‐of‐fit and internal model validation, and performed subset data analyses. Through simulation studies, we compared predicted fentanyl concentrations using model‐driven weight‐adjusted per kg vs. fixed per kg fentanyl dosing. Results Fentanyl clearance for a 6.4 kg child, the median weight in our cohort, is 5.7 l h–1 (2.2–9.2 l h–1), similar to values found in prior formal PK studies. Model assessment and subset analyses indicated the model adequately fit the data. Of the covariates studied, only weight significantly impacted fentanyl kinetics, but substantial inter‐individual variability remained. In simulation studies, model‐driven weight‐adjusted per kg fentanyl dosing led to more consistent therapeutic fentanyl concentrations than fixed per kg dosing. Conclusions We show here that population PK modelling using sparse remnant samples and electronic medical records data provides a powerful tool for assessment of drug kinetics and generation of individualized dosing regimens. PMID:26861166

Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats.

PubMed

Dahan, A; Yassen, A; Bijl, H; Romberg, R; Sarton, E; Teppema, L; Olofsen, E; Danhof, M

2005-06-01

There is evidence from animal studies suggesting the existence of a ceiling effect for buprenorphine-induced respiratory depression. To study whether an apparent ceiling effect exists for respiratory depression induced by buprenorphine, we compared the respiratory effects of buprenorphine and fentanyl in humans and rats. In healthy volunteers, the opioids were infused i.v. over 90 s and measurements of minute ventilation at a fixed end-tidal PCO2 of 7 kPa were obtained for 7 h. Buprenorphine doses were 0.7, 1.4, 4.3 and 8.6 microg kg(-1) (n=20 subjects) and fentanyl doses 1.1, 2.1, 2.9, 4.3 and 7.1 microg kg(-1) (n=21). Seven subjects received placebo. In rats, both opioids were infused i.v. over 20 min, and arterial PCO2 was measured 5, 10, 15 and 20 min after the start of fentanyl infusion and 30, 150, 270 and 390 min after the start of buprenorphine infusion. Doses tested were buprenorphine 0, 100, 300, 1000 and 3000 microg kg(-1) and fentanyl 0, 50, 68 and 90 microg kg(-1). In humans, fentanyl produced a dose-dependent depression of minute ventilation with apnoea at doses > or = 2.9 microg kg(-1); buprenorphine caused depression of minute ventilation which levelled off at doses > or = 3.0 microg kg(-1) to about 50% of baseline. In rats, the relationship of arterial PCO2 and fentanyl dose was linear, with maximum respiratory depression at 20 min (maximum PaCO2 8.0 kPa). Irrespective of the time at which measurements were obtained, buprenorphine showed a non-linear effect on PaCO2, with a ceiling effect at doses > 1.4 microg kg(-1). The effect on PaCO2 was modest (maximum value measured, 5.5 kPa). Our data confirm a ceiling effect of buprenorphine but not fentanyl with respect to respiratory depression.

Heroin Contaminated with Fentanyl Dramatically Enhances Brain Hypoxia and Induces Brain Hypothermia.

PubMed

Solis, Ernesto; Cameron-Burr, Keaton T; Kiyatkin, Eugene A

2017-01-01

While opioid abuse is an established medical and public health issue, the increased availability of highly potent synthetic opioids, such as fentanyl, has given rise to acute health complications, including a comatose state and death during drug overdose. Since respiratory depression that leads to acute hypoxia is the most dangerous complication of opioid drug use, we examined the effects of intravenous heroin and heroin contaminated with 10% fentanyl on oxygen levels in the nucleus accumbens (NAc) monitored using high-speed amperometry in freely moving rats. Additionally, we examined the effects of heroin, fentanyl, and their mixture on locomotion and temperatures in the NAc, temporal muscle, and skin. Both fentanyl and heroin at human-relevant doses (400 and 40 μg/kg, respectively) induced rapid, strong and transient decreases in NAc oxygen, indicative of brain hypoxia. When the heroin-fentanyl mixture was injected, the NAc hypoxic response was greatly potentiated in its duration, suggesting sustained hypoxia. In contrast to modest, monophasic brain temperature increases caused by heroin alone, the heroin-fentanyl mixture induced a biphasic temperature response, with a prominent postinjection decrease resulting from peripheral vasodilation. This hypothermic effect, albeit much smaller and more transient, was typical of fentanyl injected alone. Our findings indicate that accidental use of fentanyl instead of heroin, or even a relatively minor contamination of "street heroin" with fentanyl, poses great danger for acute health complications, including a comatose state and death.

Bispectral index monitoring during infant cardiac surgery: relationship of BIS to the stress response and plasma fentanyl levels.

PubMed

Kussman, B D; Gruber, E M; Zurakowski, D; Hansen, D D; Sullivan, L J; Laussen, P C

2001-11-01

We evaluated the relationship of the bispectral index (BIS) to commonly used indices of depth of anaesthesia in 19 infants enrolled in a prospective study of the stress response to hypothermic cardiopulmonary bypass. Group 1 (n=8) received high-dose fentanyl by bolus technique; group 2 (n=6) received high-dose fentanyl by continuous infusion; and group 3 (n=5) received a fentanyl-midazolam infusion. Blood pressure (BP), heart rate (HR) and plasma epinephrine, norepinephrine, cortisol, ACTH, glucose, lactate and fentanyl were analysed 15 min postinduction, 15 min poststernotomy, 15 min on CPB during cooling and during skin closure. Mean BIS (SD) values for all 19 patients were 45.3 (12.3), 40.4 (14.5), 24.4 (12.4) and 47.9 (13.9), at the successive time points. No significant differences were observed in changes in BIS over time between the groups. A significant correlation was found 15 min postinduction between BIS and BP (systolic r=0.51, mean r=0.56) in all groups, but not between BIS and HR. BIS did not correlate with BP or HR at any other time point. There was no significant correlation between BIS and hormonal, biochemical or plasma fentanyl levels for any group at any time point. We were unable to demonstrate a relationship between the BIS and haemodynamic, metabolic or hormonal indices of anaesthetic depth. Further evaluation of the BIS algorithm is required in neonates and infants.

New Initiation of Long-Acting Opioids in Long-Stay Nursing Home Residents

PubMed Central

Pimentel, Camilla B.; Gurwitz, Jerry H.; Tjia, Jennifer; Hume, Anne L.; Lapane, Kate L.

2016-01-01

BACKGROUND Despite known risks of overdose and respiratory depression when treating opioid-naïve individuals with long-acting opioids, use of these potent agents may be common in nursing homes. OBJECTIVES To estimate prevalence of new initiation of long-acting opioids since national efforts to increase prescriber and public awareness on safe use of transdermal fentanyl patches. DESIGN Cross-sectional. SETTING US nursing homes. PARTICIPANTS 22,253 Medicare-enrolled long-stay nursing home residents. MEASUREMENTS The Minimum Data Set 3.0 linked with Medicare enrollment, hospital claims, and prescription drug transaction data (January–December 2011) were used to determine the prevalence of new initiation among nursing home residents who were prescribed a long-acting opioid in the nursing home. RESULTS Of nursing home residents who were prescribed a long-acting opioid within 30 days of a nursing home admission (n = 12,278), 9.4% (95% confidence interval [CI]: 8.9–9.9%) lacked a prescription drug claim for a short-acting opioid in the previous 60 days. The most common initial prescriptions of long-acting opioids were fentanyl patch (51.9% of opioid-naïve nursing home residents), morphine sulfate (28.1%), and oxycodone (17.2%). CONCLUSION New initiation of long-acting opioids—especially fentanyl patches that have been the subject of safety communications—persists in nursing homes. PMID:27487158

Genetic, pathological and physiological determinants of transdermal fentanyl pharmacokinetics in 620 cancer patients of the EPOS study.

PubMed

Barratt, Daniel T; Bandak, Benedikte; Klepstad, Pål; Dale, Ola; Kaasa, Stein; Christrup, Lona L; Tuke, Jonathan; Somogyi, Andrew A

2014-04-01

This study aimed to investigate whether CYP3A4/5 genetic variants, together with clinical and patient factors, influence serum fentanyl and norfentanyl concentrations and their ratio in cancer pain patients receiving transdermal fentanyl. CYP3A4*22 and CYP3A5*3 polymorphisms were analysed in 620 cancer pain patients receiving transdermal fentanyl (12.5-700 μg/h) from the European Pharmacogenetic Opioid Study. Using stepwise linear regression, CYP3A4/5 genetic variability was examined in combination with patient factors relating to organ drug elimination function and ABCB1 genetics for their association with serum fentanyl and norfentanyl concentrations and metabolic ratio (MR) (norfentanyl : fentanyl). Delivery rate-adjusted serum fentanyl concentrations (0.0012-1.1 nmol/l/μg.h) and MRs (0.08-499) varied widely. Only 43% of variability in serum fentanyl concentrations was accounted for by delivery rate and less than 50% by CYP3A4/5 genotypes and clinical variables (delivery rate, sex, comedications, kidney disease, BMI, serum albumin). CYP3A4*22 and CYP3A5*3 variants, CYP3A inhibitors and variables relating to liver and kidney function (serum albumin, glomerular filtration rate, kidney disease, BMI) were associated with MR, but accounted for only 14% of variability. Serum fentanyl concentrations and MR vary considerably between cancer pain patients on transdermal fentanyl patches. CYP3A4*22 and CYP3A5*3 genotypes, and multiple clinical factors, combine to influence transdermal fentanyl pharmacokinetics, but accounted for only a small proportion of variability in this study. Identification of the remaining factors determining serum fentanyl concentrations, and their relationship to efficacy and adverse effects may aid in improving the safety and effectiveness of transdermal fentanyl.

Medicines for back pain

MedlinePlus

... direct care, they can be effective in reducing pain. Examples of narcotics include: Codeine Fentanyl -- available as a patch Hydrocodone Hydromorphone Morphine Oxycodone Tramadol Possible side effects of these drugs include: Drowsiness ...

Use of Fentanyl in Adolescents with Clinically Severe Obesity Undergoing Bariatric Surgery - a Pilot Study

PubMed Central

Vaughns, Janelle D.; Ziesenitz, Victoria C.; Williams, Elaine F.; Mushtaq, Alvina; Bachmann, Ricarda; Skopp, Gisela; Weiss, Johanna; Mikus, Gerd; van den Anker, Johannes N.

2018-01-01

Background The number of obese pediatric patients requiring anesthesia is rapidly increasing. Although fentanyl is a commonly used narcotic during surgery, there is no pharmacokinetic (PK) data available for optimal dosing of fentanyl in adolescents with clinically severe obesity. Materials and Methods An IRB-approved exploratory pilot study was conducted in 6 adolescents aged 14 to 19 years undergoing bariatric surgery. Mean total body weight (TBW) and mean BMI were 137.4 ± 14.3 kg, and 49.6 ± 6.4 kg/m2 (99.5th BMI percentile), respectively. Fentanyl was dosed intravenously for intraoperative analgesia based on ideal body weight per standard of care. PK blood samples were drawn over a 24 hour post-dose period. Fentanyl PK parameters were calculated by non-compartmental analysis. Results Mean fentanyl AUC0–∞ was 1.5 ± 0.5 h*ng/mL. Systemic clearance of fentanyl was 1522 ± 310 mL/min and 11.2 ± 2.6 mL/min*kg TBW. Volume of distribution was 635 ± 282 L and 4.7 ± 2.1 L/kg TBW. While absolute clearance was increased, absolute volume of distribution was comparable to previously established adult values. Conclusions These results suggest that fentanyl clearance is enhanced in adolescents with clinically severe obesity while volume of distribution is comparable to previously published studies. PMID:28238111

Hypobaric bupivacaine spinal anesthesia for cystoscopic intervention: the impact of adding fentanyl.

PubMed

Atallah, Mohamed M; Helal, Mostafa A; Shorrab, Ahmed A

2003-10-01

Addition of fentanyl to hyperbaric bupivacaine spinal anesthesia prolonged the duration of sensory block. This study seeks to test the hypothesis that adding fentanyl to small dose hypobaric spinal anesthesia will improve intraoperative patients and surgeon satisfaction without delay in recovery. Patients (n = 80) subjected to minor cystoscopic surgery were randomly assigned to have spinal anesthesia with either 5 mg bupivacaine 0.1% or 5 mg bupivacaine 0.1% mixed with 20 micrograms fentanyl. The main outcome measures included intraoperative patient and endoscopist satisfaction, sedative/analgesic supplementation, postoperative side effects and time to ambulation. Patients in the bupivacaine group needed more analgesic supplementation. Analgesia was more adequate in the bupivacaine-fentanyl group. Pruritus was the main side effect in the bupivacaine fentanyl group. Ambulation and discharge of patients were nearly the same in both groups. Spinal anesthesia with small dose (5 mg) hypobaric (0.1%) bupivacaine mixed with fentanyl (20 micrograms) produced adequate anesthesia for short cystoscopic procedures with minimal side effects and without delay in ambulation.

Synergistic interaction between fentanyl and bupivacaine given intrathecally for labor analgesia.

PubMed

Ngan Kee, Warwick D; Khaw, Kim S; Ng, Floria F; Ng, Karman K L; So, Rita; Lee, Anna

2014-05-01

Lipophilic opioids and local anesthetics are often given intrathecally in combination for labor analgesia. However, the nature of the pharmacologic interaction between these drugs has not been clearly elucidated in humans. Three hundred nulliparous women randomly received 1 of 30 different combinations of fentanyl and bupivacaine intrathecally using a combined spinal-epidural technique for analgesia in the first stage of labor. Visual analogue scale pain scores were recorded for 30 min. Response was defined by percentage decrease in pain score from baseline at 15 and 30 min. Dose-response curves for individual drugs were fitted to a hyperbolic dose-response model using nonlinear regression. The nature of the drug interaction was determined using dose equivalence methodology to compare observed effects of drug combinations with effects predicted by additivity. The derived dose-response models for individual drugs (doses in micrograms) at 15 min were: Effect = 100 × dose / (13.82 + dose) for fentanyl, and Effect = 100 × dose / (1,590 + dose) for bupivacaine. Combinations of fentanyl and bupivacaine produced greater effects than those predicted by additivity at 15 min (P < 0.001) and 30 min (P = 0.015) (mean differences, 9.1 [95% CI, 4.1-14.1] and 6.4 [95% CI, 1.2-11.5] units of the normalized response, respectively), indicating a synergistic interaction. The pharmacologic interaction between intrathecal fentanyl and bupivacaine is synergistic. Characterization and quantification of this interaction provide a theoretical basis and support for the clinical practice of combining intrathecal opioids and local anesthetics.

Mu/Kappa Opioid Interactions in Rhesus Monkeys: Implications for Analgesia and Abuse Liability

PubMed Central

Negus, S. Stevens; Katrina Schrode, KA; Stevenson, Glenn W.

2008-01-01

Mu opioid receptor agonists are clinically valuable as analgesics; however, their use is limited by high abuse liability. Kappa opioid agonists also produce antinociception, but they do not produce mu agonist-like abuse-related effects, suggesting that they may enhance the antinociceptive effects and/or attenuate the abuse-related effects of mu agonists. To evaluate this hypothesis, the present study examined interactions between the mu agonist fentanyl and the kappa agonist U69,593 in three behavioral assays in rhesus monkeys. In an assay of schedule-controlled responding, monkeys responded under a fixed-ratio 30 (FR 30) schedule of food presentation. Fentanyl and U69,593 each produced rate-decreasing effects when administered alone, and mixtures of 0.22:1, 0.65:1 and 1.96:1 U69,593/fentanyl usually produced subadditive effects. In an assay of thermal nociception, tail withdrawal latencies were measured from water heated to 50°C. Fentanyl and U69,593 each produced dose-dependent antinociception, and effects were additive for all mixtures. In an assay of drug self-administration, rhesus monkeys responded for i.v. drug injection, and both dose and FR values were manipulated. Fentanyl maintained self-administration, whereas U69,593 did not. Addition of U69,593 to fentanyl produced a proportion-dependent decrease in both rates of fentanyl self-administration and behavioral economic measures of the reinforcing efficacy of fentanyl. Taken together, these results suggest that simultaneous activation of mu and kappa receptors, either with a mixture of selective drugs or with a single drug that targets both receptors, may reduce abuse liability without reducing analgesic effects relative to selective mu agonists administered alone. PMID:18837635

Peripheral opioid analgesia in teeth with symptomatic inflamed pulps.

PubMed Central

Uhle, R. A.; Reader, A.; Nist, R.; Weaver, J.; Beck, M.; Meyers, W. J.

1997-01-01

The purpose of this study was to investigate the ability of low-dose fentanyl to produce analgesia when administered via the periodontal ligament injection in teeth with symptomatic, inflamed pulps. All subjects presented for emergency treatment with moderate to severe pain and had a posterior tooth with a clinical diagnosis of irreversible pulpitis. Twenty subjects randomly received either 10 micrograms fentanyl citrate or saline placebo via the periodontal ligament injection in a double-blind manner. The subjects rated their pain prior to injection and rated pain intensity and pain half gone for 59 min postinjection. Low-dose fentanyl delivered via the periodontal ligament injection in inflamed teeth provided significantly greater analgesia than the saline placebo (P < 0.05). Since the dose of fentanyl used was less than the dose required to provide analgesia by a central mechanism, the results of this study may be consistent with a peripheral opioid mechanism of action. PMID:9481968

Psychomotor Functioning: Comparison of Patients Recovering From General Anesthesia With Remifentanil and a Volatile Anesthetic Versus Fentanyl and a Volatile Anesthetic

DTIC Science & Technology

1998-10-01

remifentanil appears to be more potent. The ED100 dose for loss of righting with remifentanil is 0.020mg/kg/min. 14 and for fentanyl the dose is 0.035 mg/kg...and 1/4600th the potency of remifentanil in dogs (Westmoreland, et al., 1993a). 16 Fentanyl has a t1/2 of 3 to 3.65 hours at clinically relevant doses ...This prolonged t1/2 reflects fentanyl’s lipophilicity (Murphy, et al., 1983). Remifentanil has a t1/2 of 10 minutes at clinically relevant doses

Beneficial Effects of Adding Ketamine to Intravenous Patient-Controlled Analgesia with Fentanyl after the Nuss Procedure in Pediatric Patients

PubMed Central

Cha, Moon Ho; Eom, Ji Hye; Lee, Yoon Sook; Kim, Woon Young; Park, Young Cheol; Min, Sam Hong

2012-01-01

Purpose The aim of this prospective, double-blind, randomized study was to investigate the analgesic effects of low-dose ketamine on intravenous patient-controlled analgesia (IV-PCA) with fentanyl for pain control in pediatric patients following the Nuss procedure for pectus excavatum. Materials and Methods Sixty pediatric patients undergoing the Nuss procedure were randomly assigned to receive fentanyl (Group F, n=30) or fentanyl plus ketamine (Group FK, n=30). Ten minutes before the end of surgery, following the loading dose of each solution, 0.5 µg/kg/hr of fentanyl or 0.5 µg/kg/hr of fentanyl plus 0.15 mg/kg/hr of ketamine was infused via an IV-PCA pump (basal rate, 1 mL/hr; bolus, 0.5 mL; lock out interval, 30 min). Fentanyl consumption, pain score, ketorolac use, nausea/vomiting, ondansetron use, pruritus, respiratory depression, hallucination, dreaming, and parent satisfaction with pain control were measured throughout the 48 hours following surgery. Results The pain scores, ketorolac use, and fentanyl consumption of Group FK were significantly lower than in Group F (p<0.05). The incidence of nausea/vomiting and ondansetron use in Group FK was significantly lower than in Group F (p<0.05). There were no reports of respiratory depression, hallucination or dreaming. Parent satisfaction with pain control was similar between the two groups. Conclusion We concluded that low-dose ketamine added to IV-PCA with fentanyl after the Nuss procedure in pediatric patients can reduce pain scores, consumption of fentanyl, and incidence of nausea/vomiting without increasing side effects. PMID:22318834

A comparison of the antinociceptive and temperature responses to morphine and fentanyl derivatives in rats.

PubMed

Savić Vujović, Katarina R; Vučković, Sonja; Srebro, Dragana; Ivanović, Milovan; Došen-Mićović, Ljiljana; Vučetić, Čedomir; Džoljić, Eleonora; Prostran, Milica

2013-04-01

In addition to producing antinociception, opioids exert profound effects on body temperature. This study aimed at comparing antinociceptive and hyperthermic responses between two groups of μ-opioid receptor agonists: fentanyl (4-anilinopiperidine-type) and morphine (phenanthrene-type) derivatives in rats. Analgesic activity was assessed by tail immersion test and the body temperature by insertion of a thermometer probe into the colon. Fentanyl (F), (±)-cis-3-methyl fentanyl (CM), (±)-cis-3-carbomethoxy fentanyl (C), (±)trans-3-carbomethoxy fentanyl (T) and (±)-cis-3 butyl fentanyl (B) produced dose-dependent increase in antinociception and hyperthermia. The relative order of analgesic potency was: CM(11.27)>F(1)>C(0.35)≥T(0.11)≥B(0.056). Similar to this, the relative order of hyperthermic potency was: CM(8.43)>F(1)>C(0.46)≥T(0.11)≥B(0.076). Morphine (M), oxycodone (O), thebacon (T) and 6,14-ethenomorphinan-7-methanol, 4,5-epoxy-6-fluoro-3-hydroxy-α,α,17-trimethyl-, (5α,7α) (E) also produced dose-dependent increase in antinociception and hyperthermia. Among morphine derivatives the relative order of analgesic potency was: E(56)>O(5)≥T(2.6)>M(1), and similar to this, the relative order of hyperthermic potency was: E(37)>O(3)≥T(2.3)>M(1). Morphine (phenanthrene-type) and fentanyl (4-anilinopiperidine-type) derivatives produced hyperthermia in rats at doses about 2 times lower, and 6-11 times higher, than their median antinociceptive doses, respectively. This study is first to identify difference between these two classes of opioid drugs in their potencies in producing hyperthermia. Further studies are needed to clarify the significance of these findings.

[Assessment of the use of racemic ketamine and its S(+) isomer, associated or not with low doses of fentanyl, in balneotherapy for major burn patients].

PubMed

Cantinho, Fernando Antônio de Freitas; Silva, Antonio Carlos Pereira da

2009-01-01

The care of the wounds of major burn patients triggers severe painful stimuli. The objective of this study was to assess the safety and efficacy of different drug combinations in anesthesia for balneotherapy. After approval by the Ethics Commission, 200 procedures of balneotherapy in 87 major burn adult patients were evaluated. Midazolam was used in all cases. The vials of ketamine were numbered and, therefore, at the time of the use, one did not know whether racemic or S(+)ketamine was being used. Each morning it was decided by drawing lots whether fentanyl would be used or not in the procedures of that day. Patients were included in one of four groups: ISO/sf (S(+) isomer without fentanyl), ISO/cf (S(+) isomer with fentanyl), RAC/sf (racemic ketamine without fentanyl), and RAC/cf (racemic ketamine with fentanyl). The initial doses proposed were as follows: midazolam, 0.06 mg.kg-1; ketamine, 1.0 to 1.1 mg.kg-1; and fentanyl, 0.8 (1/4)g.kg1-1; additional doses were administered as needed. Only one patient recalled the pain of balneotherapy. In the group that received S(+)ketamine, the use of fentanyl did not bring additional advantages; however, when associated with racemic ketamine, fentanyl reduced the total dose and the number of ketamine boluses. The extension of body surface burned was the main determinant of the severity of post-procedure pain. Reduced pain severity was the main factor considered by patients when grading their satisfaction with the anesthesia. The four different drug combinations proved to be safe and guaranteed the absence of pain during balneotherapy. Characteristics not directly related to the anesthetics proved to be more important in the incidence of post-procedure pain, which was the main factor considered by major burn patient to define their satisfaction with the anesthesia used.

Pulmonary administration of aerosolised fentanyl: pharmacokinetic analysis of systemic delivery

PubMed Central

Mather, Laurence E; Woodhouse, Annie; Ward, M Elizabeth; Farr, Stephen J; Rubsamen, Reid A; Eltherington, Lorne G

1998-01-01

Aims Pulmonary drug delivery is a promising noninvasive method of systemic administration. Our aim was to determine whether a novel breath-actuated, microprocessor-controlled metered dose oral inhaler (SmartMist™, Aradigm Corporation) could deliver fentanyl in a way suitable for control of severe pain. Methods Aersolised pulmonary fentanyl base 100–300 μg was administered to healthy volunteers using SmartMist™ and the resultant plasma concentration-time data were compared with those from the same doses administered by intravenous (i.v.) injection in the same subjects. Results Plasma concentrations from SmartMist™ were similar to those from i.v. injection. Time-averaged bioavailability based upon nominal doses averaged 100%, and was >50% within 5 min of delivery. Fentanyl systemic pharmacokinetics were similar to those previously reported with no trends to dose-dependence from either route. Side-effects (e.g. sedation, lightheadedness) were the same from both routes. Conclusions Fentanyl delivery using SmartMist™ can provide analgetically relevant plasma drug concentrations. This, combined with its ease of noninvasive use and transportability, suggests a strong potential for field and domicilliary use, and for patient controlled analgesia without the need for i.v. cannulae. PMID:9690947

Subanalgesic doses of dexketoprofen and HCT-2037 (nitrodexketoprofen) enhance fentanyl antinociception in monoarthritic rats.

PubMed

Gaitan, Gema; Herrero, Juan F

2005-02-01

Subanalgesic doses of the non-steroidal antiinflammatory drugs (NSAID) dexketoprofen trometamol and nitroparacetamol (NCX-701) enhance mu-opiate fentanyl effect in acute nociception. It is not known if a similar combination of drugs is effective in situations of spinal cord sensitization. The aim of this study was to assess if the enhancement of fentanyl antinociception can be observed in carrageenan-induced monoarthritis, when combined with dexketoprofen (DKT) or nitrodexketoprofen (HCT-2037). Withdrawal reflexes were recorded as single motor units in male Wistar rats anesthetized with alpha-chloralose. Fentanyl was studied alone and in the presence of 0.4, 0.8 micromol/kg of DKT or 0.3 micromol/kg of HCT-2037. In responses to noxious mechanical stimulation, the ID50 of fentanyl was enhanced twofold by 0.8 micromol/kg DKT and more than fourfold by HCT-2037 and no significant recovery was observed 45 min later. DKT 0.4 micromol/kg was, however, very little effective. The opioid antagonist naloxone did not reverse the effect. Enhancement of fentanyl effect on wind-up was only observed with HCT-2037 but not with DKT. We conclude that the combined administration of subanalgesic doses of dexketoprofen derivatives, specially its nitroderivative, and the mu-opiate fentanyl is an effective antinociceptive therapy in situations of articular inflammation involving a naloxone-independent mechanism of action.

Trends in opioid analgesics sales to community pharmacies and hospitals in Italy (2000-2010).

PubMed

Caraceni, A T; Brunelli, C; Rocco, P; Minghetti, P

2013-08-01

Opioid consumption data in Italy have been widely studied. However, only aggregate data can be found in the published literature, and differences are expected by distribution setting (community pharmacies and hospitals). The aim of our paper is to analyse opioids sales trends in Italy in the decade 2000-2010, in an effort to explore such differences. Quarterly sales data of opioid medicinal products sold by wholesalers to both community pharmacies (retail) and to hospitals (non-retail) during the time period 2000-2010 were supplied by IMS Italy. Data were standardized using the Defined Daily Doses per day per 1000 inhabitants (DDDd/1000). Opioid sales have steadily increased during the time period considered going from 1.04 DDDd/1000 in 2000 to 4.9 in 2010 (+292%). Nonetheless relevant differences can be found both by distribution setting and drug type. In particular retail sales have increased by 286 % for WHO Step II opioids and by 575% for WHO Step III drugs, while non-retail sales have increased by 48% and 263%, respectively. In 2010, fentanyl and buprenorphine transdermal patches and oxycodone are more widely prescribed than morphine, in the retail setting, with fentanyl at large in the first position. In hospitals morphine and fentanyl almost equally share the 75% of the market. Data suggest that morphine is no more the opioid of first choice for severe pain in Italy, at least for outpatients. This is contradicting most international guidelines available in the 2000-2010 decade.

Prehospital Pain Medication Use by U.S. Forces in Afghanistan

DTIC Science & Technology

2015-03-01

oral transmucosal fentanyl citrate were the most commonly used pain medications during POI care, whereas ketamine and fentanyl predominated during...difference in vital signs on arrival to the hospital between casualties who received no pain medication, morphine, fentanyl , or ketamine during TACEVAC. In...this convenience sample, fentanyl and ketamine were as safe as morphine for prehospital use within the dose ranges administered. Future efforts to

Cardiovascular effects of fentanyl in conscious rats.

PubMed

Baechtold, F; Cavadas, C; Gasser, D; Markert, M; Grouzmann, E; Peterson, K L; Waeber, B; Feihl, F

2001-10-01

The polymicrobial sepsis induced by cecal ligation and puncture (CLP) in the rat is widely used in shock research. For ethical reasons, narcotic analgesics are often administered in this model, with the potential risk of confounding effects. In conscious non-septic rats, we investigated the cardiovascular effects of a continuous i.v. infusion of fentanyl (20 microg/kg per h) administered with fluid loading (10 ml/kg per h) for 24 h, a regimen commonly applied in rat CLP. Animals were randomly allocated to receive analgesia with fluid loading (Fentanyl group), or fluid loading alone (Control). All endpoints were assessed after 24 h of infusion. At that time, Control animals had mild respiratory alkalosis, which was essentially abolished by fentanyl. Analgesia mildly elevated the plasma norepinephrine levels [median (interquartile range): Control 232 pg/ml (0-292), Fentanyl 302 pg/ml (234-676), P=0.045] but was devoid of any effect on blood pressure, heart rate, cardiac output (mean +/-SD: Control 388+/-61 ml/kg per min, Fentanyl 382+/-62 ml/kg per min, P=0.87) and indices of left ventricular function derived from high-fidelity recordings of left ventricular pressure (dP/dtmax: Control 11782+/-2324 mmHg/s, Fentanyl 12107+/-2816 mmHg/s, P=0.77). In ex vivo experiments carried out immediately after animal sacrifice, no differences were noted between the Control and Fentanyl groups in the sensitivity of endothelium-intact aortic rings to norepinephrine-induced vasoconstriction (-logEC50: Control 8.78+/-0.28, Fentanyl 8.83+/-0.26, P=0.52) or acetylcholine-induced vasodilatation (-logEC50: Control 7.00+/-0.37, Fentanyl 7.06+/-0.26+/-0.53, P=0.75). In conclusion, the present data provide no contraindication, and even some support for the ethical use of a high dose i.v. infusion of fentanyl in cardiovascular studies of conscious catheterized rats undergoing CLP or other painful procedures.

The effect of variable-dose diazepam on dreaming and emergence phenomena in 400 cases of ketamine-fentanyl anaesthesia.

PubMed

Grace, R F

2003-09-01

This randomised double-blind field study compared 400 anaesthetics using diazepam (0, 0.025, 0.5, 0.1, 0.175 mg.kg-1) with ketamine (1 mg.kg-1) and fentanyl (1 microg.kg-1) in Melanesian patients. Dreams were very common and generally positive in nature. A minimum of 0.1 mg.kg-1 of diazepam was needed to significantly reduce dreaming when compared with water (67.5% vs. 94.6%; p < 0.0001), and to significantly lower median (95% CI) emergence delirium scores (4 (3-4) vs. 6 (5-7)). Gender and age did not affect the rate of dreaming. Increasing the dose of diazepam did not improve the dream experience. Patient satisfaction scores were similar between groups. Increases in blood pressure and heart rate were greater in dreamers than in non-dreamers. All groups had high rate-pressure products but this was highest when diazepam was not used. Higher diazepam doses significantly reduced the increase in blood pressure and heart rate at 3 and 6 min postketamine. When used with ketamine and fentanyl, 0.1 mg.kg-1 of diazepam has favourable psychic and cardiovascular effects. Lower diazepam doses generally had little effect whereas larger doses did not enhance the benefits further.

Fentanyl, but not haloperidol, entrains persisting circadian activity episodes when administered at 24- and 31-hour intervals

PubMed Central

Leffel, Joseph K.; Kosobud, Ann E; Timberlake, William

2009-01-01

Administration of several drugs of abuse on a 24-hour schedule has been shown to entrain both pre-drug (anticipatory) and post-drug (evoked) circadian activity episodes that persist for several days when the drug is withheld. The present tested the entrainment effects of fentanyl, an opioid agonist with a noted abuse liability, and haloperidol, an antipsychotic dopamine antagonist without apparent abuse liability. Adult female Sprague-Dawley rats housed under constant light in cages with attached running wheels received repeated low, medium, or high doses of either fentanyl or haloperidol on a 24-hour administration schedule followed by a 31-hour schedule (Experiment 1) or solely on a 31-hour schedule (Experiment 2). The results showed that all three doses of fentanyl entrained both pre-drug and post-drug episodes of wheel running when administered every 24░hours, and the combined pre- and post-fentanyl activity episodes persist for at least 3 days when the drug is withheld during test days. On the 31-hour schedule, fentanyl produced an ``ensuing" activity episode approximately 24░hours post-administration, but failed to produce an anticipatory episode 29–31░hours post-administration. In contrast, haloperidol injections failed to produce both pre-drug episodes on the 24-hour schedule and circadian ensuing episodes on the 31-hour schedule, and post-haloperidol suppression of activity appeared to mask the freerunning activity rhythm. Taken together, these results provide additional evidence that drugs of abuse share a common ability to entrain circadian activity episodes. PMID:19595707

Characteristics of Fentanyl Overdose - Massachusetts, 2014-2016.

PubMed

Somerville, Nicholas J; O'Donnell, Julie; Gladden, R Matthew; Zibbell, Jon E; Green, Traci C; Younkin, Morgan; Ruiz, Sarah; Babakhanlou-Chase, Hermik; Chan, Miranda; Callis, Barry P; Kuramoto-Crawford, Janet; Nields, Henry M; Walley, Alexander Y

2017-04-14

Opioid overdose deaths in Massachusetts increased 150% from 2012 to 2015 (1). The proportion of opioid overdose deaths in the state involving fentanyl, a synthetic, short-acting opioid with 50-100 times the potency of morphine, increased from 32% during 2013-2014 to 74% in the first half of 2016 (1-3). In April 2015, the Drug Enforcement Agency (DEA) and CDC reported an increase in law enforcement fentanyl seizures in Massachusetts, much of which was believed to be illicitly manufactured fentanyl (IMF) (4). To guide overdose prevention and response activities, in April 2016, the Massachusetts Department of Public Health and the Office of the Chief Medical Examiner collaborated with CDC to investigate the characteristics of fentanyl overdose in three Massachusetts counties with high opioid overdose death rates. In these counties, medical examiner charts of opioid overdose decedents who died during October 1, 2014-March 31, 2015 were reviewed, and during April 2016, interviews were conducted with persons who used illicit opioids and witnessed or experienced an opioid overdose. Approximately two thirds of opioid overdose decedents tested positive for fentanyl on postmortem toxicology. Evidence for rapid progression of fentanyl overdose was common among both fatal and nonfatal overdoses. A majority of interview respondents reported successfully using multiple doses of naloxone, the antidote to opioid overdose, to reverse suspected fentanyl overdoses. Expanding and enhancing existing opioid overdose education and prevention programs to include fentanyl-specific messaging and practices could help public health authorities mitigate adverse effects associated with overdoses, especially in communities affected by IMF.

Population Pharmacokinetics of Fentanyl in the Critically Ill

PubMed Central

Choi, Leena; Ferrell, Benjamin A; Vasilevskis, Eduard E; Pandharipande, Pratik P; Heltsley, Rebecca; Ely, E Wesley; Stein, C Michael; Girard, Timothy D

2016-01-01

Objective To characterize fentanyl population pharmacokinetics in patients with critical illness and identify patient characteristics associated with altered fentanyl concentrations. Design Prospective cohort study. Setting Medical and surgical ICUs in a large tertiary care hospital in the United States. Patients Patients with acute respiratory failure and/or shock who received fentanyl during the first five days of their ICU stay. Measurements and Main Results We collected clinical and hourly drug administration data and measured fentanyl concentrations in plasma collected once daily for up to five days after enrollment. Among 337 patients, the mean duration of infusion was 58 hours at a median rate of 100 µg/hr. Using a nonlinear mixed-effects model implemented by NONMEM, we found fentanyl pharmacokinetics were best described by a two-compartment model in which weight, severe liver disease, and congestive heart failure most affected fentanyl concentrations. For a patient population with a mean weight of 92 kg and no history of severe liver disease or congestive heart failure, the final model, which performed well in repeated 10-fold cross-validation, estimated total clearance (CL), intercompartmental clearance (Q), and volumes of distribution for the central (V1) and peripheral compartments (V2) to be 35 (95% confidence interval: 32 to 39) L/hr, 55 (42 to 68) L/hr, 203 (140 to 266) L, and 523 (428 to 618) L, respectively. Severity of illness was marginally associated with fentanyl pharmacokinetics but did not improve the model fit after liver and heart disease were included. Conclusions In this study, fentanyl pharmacokinetics during critical illness were strongly influenced by severe liver disease, congestive heart failure, and weight, factors that should be considered when dosing fentanyl in the ICU. Future studies are needed to determine if data-driven fentanyl dosing algorithms can improve outcomes for ICU patients. PMID:26491862

Fentanyl produces an anti-hyperalgesic effect through the suppression of sodium channels in mice with painful diabetic neuropathy.

PubMed

Tanaka, Ken-ichiro; Nakanishi, Yuki; Sekino, Shyota; Ikegami, Megumi; Ikeda, Hiroko; Kamei, Junzo

2014-06-15

Diabetic neuropathy is one of the most frequent complications of diabetes mellitus. Therefore, the present study was designed to investigate the anti-hyperalgesic mechanism of fentanyl in a mouse model of streptozotocin-induced diabetic neuropathy. The antinociceptive response was assessed by recording the latency in a tail-flick test. The tail-flick latency in diabetic mice was significantly shorter than that in non-diabetic mice. Fentanyl, at doses of 3 and 10 μg/kg, s.c., produced a dose-dependent increase in the tail-flick latencies in diabetic mice. While fentanyl (3 μg/kg, s.c.) did not produce a significant inhibition of the tail-flick response in non-diabetic mice, it significantly prolonged the tail-flick latency in diabetic mice to the same level as the baseline latency in non-diabetic mice. Although pretreatment with naloxone (3mg/kg, s.c.) completely antagonized fentanyl-induced antinociception in non-diabetic mice, it had no effect on the antinociceptive effect of fentanyl in diabetic mice. Pretreatment with either of the voltage-gated sodium channel openers fenvarelarte and veratridine practically abolished the antinociceptive effects of fentanyl in diabetic mice. However, neither fenvarelate nor veratridine affected the antinociceptive effect of fentanyl in non-diabetic mice. These results suggest that the anti-hyperalgesic effect of fentanyl is mediated through the blockade of sodium channels in diabetic mice, whereas opioid receptors mediate the antinociceptive effect of fentanyl in non-diabetic mice. Copyright © 2014 Elsevier B.V. All rights reserved.

Differential development of antinociceptive tolerance to morphine and fentanyl is not linked to efficacy in the ventrolateral periaqueductal gray of the rat

PubMed Central

Bobeck, Erin N.; Haseman, Rachel A.; Hong, Dana; Ingram, Susan L.; Morgan, Michael M.

2012-01-01

Systemic administration of morphine typically produces greater tolerance than higher efficacy mu-opioid receptor (MOPr) agonists, such as fentanyl. The objective of the present study was to test this relationship by measuring antinociceptive efficacy and tolerance to morphine and fentanyl microinjected into the ventrolateral periaqueductal gray (vlPAG). MOPr agonist efficacy was evaluated by microinjecting the irreversible opioid receptor antagonist β-funaltrexamine hydrochloride (β-FNA) into the vlPAG prior to a dose-response analysis of morphine and fentanyl antinociception. In contrast to systemic administration of morphine and fentanyl, microinjection of these drugs into the vlPAG had similar efficacy as measured by similar reductions in maximal antinociception following β-FNA administration. Analysis of tolerance revealed a rightward shift in the dose-response curve to a single pretreatment with morphine, but not fentanyl. Moreover, the magnitude of tolerance to morphine was comparable following one, four, or eight pretreatments. Tolerance to fentanyl also was evident following four or eight microinjections. These data are surprising in that antinociceptive efficacy appears to vary depending on the site of administration. Moreover, the similar efficacy following microinjection of morphine and fentanyl into the vlPAG was associated with comparable tolerance, with the one exception of no tolerance to acute administration of fentanyl. Perspective These data reveal that antinociceptive tolerance following vlPAG administration of opioids develops rapidly, is evident with both morphine and fentanyl, and the magnitude is relatively consistent regardless of the number of pretreatments. PMID:22766006

Study of the newborn feeding behaviors and fentanyl concentration in colostrum after an analgesic dose of epidural and intravenous fentanyl in cesarean section.

PubMed

Goma, Hala M; Said, Reem N; El-Ela, Amr M

2008-05-01

To compare the effects of epidural and intravenous fentanyl on breast feeding behaviors and fentanyl concentration in the colostrum after an analgesic dose. This study was conducted at the Obstetrics Department of Kasr El-Aini Hospital-Cairo University, Cairo, Egypt. The studied mothers were 100 multipara, who have been subjected to cesarean section, and have a previous history of successful breast feeding. The study was conducted from May 2005 to May 2007. They were divided into 2 groups: group I included 50 patients who received epidural anesthesia with fentanyl, and group II included 50 patients who received spinal anesthesia with intravenous fentanyl, and both groups were observed for initial breast feeding behaviors of newborns, and fentanyl concentration in the colostrum at 45 minutes, and 24 hours after birth. The study included 100 multipara, 2 samples of colostrum were taken from each patients at 45 minutes, and at 24 hours. The levels of fentanyl concentration were greatest at 45 minutes of the initial sampling time, reaching 0.40+/-0.059 ng/ml in the epidural group, and 0.19+/-0.019 ng/ml in intravenous fentanyl group. There was no statistical difference in breast feeding behaviors at birth, or at 24 hours of age in both groups. Although the levels of fentanyl concentration were greatest at 45 minutes of the initial sampling time, it can be used safely as intravenous or epidural without affecting the initial breast feeding behaviors of the newborn.

Propofol dose and incidence of dreaming during sedation.

PubMed

Eer, Audrey Singyi; Padmanabhan, Usha; Leslie, Kate

2009-10-01

Dreaming is commonly reported after propofol-based sedation. We measured the incidence of dreaming and bispectral index (BIS) values in colonoscopy patients sedated with combinations of propofol, midazolam and fentanyl. Two hundred patients presenting for elective outpatient colonoscopy were sedated with combinations of propofol, midazolam and fentanyl. BIS was monitored throughout the procedure. Patients were interviewed immediately after they emerged from sedation. The primary end point was a report of dreaming during sedation. Ninety-seven patients were administered propofol alone, 44 were administered propofol and fentanyl, 16 were administered propofol and midazolam and 43 were administered propofol, midazolam and fentanyl. Dreaming was reported by 19% of patients. Dreamers received higher doses of propofol and had lower BIS values during sedation. Age of 50 years or less, preoperative quality of recovery score of less than 14, higher home dream recall, propofol dose of more than 300 mg and time to Observers' Assessment of Alertness/Sedation score equalling 5 of 8 min or less were independent predictors of dreaming. Dreaming during sedation is associated with higher propofol dose and lower BIS values.

An evaluation of total disintegration time for three different doses of sublingual fentanyl tablets in patients with breakthrough pain.

PubMed

Nalamachu, Srinivas

2013-12-01

Breakthrough pain is common among patients with cancer and presents challenges to effective pain management. Breakthrough pain is characterized by rapid onset, severe intensity, and duration typically lasting <1 h. Thus, optimal relief from breakthrough pain is best attained by administering analgesics with dissolution times and bioavailabilities that closely match the onset and duration of breakthrough pain. The objective of this study was to assess complete disintegration time of three different doses of sublingual fentanyl tablets in opioid-tolerant patients. This was a single-center, non-randomized, open-label study. Opioid-tolerant adult patients (N = 30) with chronic pain were assigned to one of three dose groups and self-administered a single 100, 200, or 300 μg sublingual fentanyl tablet (Abstral(®), Galena Biopharma, Portland, OR, USA). Time to complete disintegration was measured by each patient with a stopwatch and independently verified by study personnel. Disintegration time (mean ± SD) for sublingual fentanyl tablets (all doses) was 88.2 ± 55.1 s. Mean disintegration times tended to be slightly longer for the 200 μg (96.7 ± 57.9 s) and 300 μg doses (98.6 ± 64.8 s) compared to the 100 μg dose (69.5 ± 40.5 s). Differences were not statistically significant. Disintegration time was not significantly different between men and women and was not affected by age. Sublingual fentanyl tablets dissolved rapidly (average time <2 min) in all patients, with the higher doses taking slightly more time to dissolve.

The pharmacokinetics of ketoconazole and its effects on the pharmacokinetics of midazolam and fentanyl in dogs.

PubMed

KuKanich, B; Hubin, M

2010-02-01

Ketoconazole inhibits the Cytochrome P450 3A12 (CYP3A12) metabolizing enzyme as well as the p-glycoprotein efflux pump. The extent and clinical consequence of these effects are poorly understood in dogs. The objective was to assess the pharmacokinetics of ketoconazole after single and multiple doses and the effect of multiple doses of ketoconazole on midazolam (a known CYP3A12 substrate) and the opioid fentanyl. Six greyhound dogs were studied. The study consisted of three phases. Phase 1 consisted of i.v. midazolam (0.23 mg/kg base) and fentanyl (15.71 microg/kg base). Phase 2 consisted of a single oral dose of ketoconazole (mean dose 12.34 mg/kg). Phase 3 consisted of i.v. midazolam (0.23 mg/kg) and fentanyl (10 microg/kg) after 5 days of oral ketoconazole (12.25 mg/kg/day). Ketoconazole significantly inhibited its own elimination with the mean residence time (MRT) increasing from 6.24 h in Phase 1 to 12.54 h in Phase 3. Ketoconazole significantly decreased the elimination of midazolam, as expected, with the MRT increasing from 0.81 to 1.49 h. The elimination of fentanyl was not significantly altered by co-administration of ketoconazole with the MRT being 3.90 and 6.35 h. The MRT was the most robust estimate of decreased drug elimination.

An autopsy case of acetyl fentanyl intoxication caused by insufflation of 'designer drugs'.

PubMed

Takase, Izumi; Koizumi, Takako; Fujimoto, Ihoko; Yanai, Aya; Fujimiya, Tatsuya

2016-07-01

We present a fatal case of intoxication due to insufflation of acetyl fentanyl. His blood concentration of acetyl fentanyl was 270ng/mL, and the manner of death was classified as an accident. This is the first report of an autopsy case of acetyl fentanyl delivered by insufflation, rather than intravenous administration. He had been snoring loudly for at least 12h prior to death, and transport to a hospital during this time and treatment with naloxone may have saved his life. In this sense, it can be said that his death was preventable. This case reemphasizes the risk of death associated with drug overdose and the narrow range of acetyl fentanyl between the effective dose (ED50) and lethal dose (LD50). The case should also raise awareness among medical professionals of the effectiveness of naloxone and the need to establish a comprehensive system for toxicological analysis while keeping the possibility of use of 'designer drugs' in mind. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans

PubMed Central

Manini, Alex F.; Yiannoulos, Georgia; Bergamaschi, Mateus M.; Hernandez, Stephanie; Olmedo, Ruben; Barnes, Allan J.; Winkel, Gary; Sinha, Rajita; Jutras-Aswad, Didier; Huestis, Marilyn A.; Hurd, Yasmin L.

2015-01-01

Objectives Cannabidiol (CBD) is hypothesized as a potential treatment for opioid addiction, with safety studies an important first step for medication development. We determined CBD safety and pharmacokinetics when administered concomitantly with a high-potency opioid in healthy subjects. Methods This double-blind, placebo-controlled cross-over study of CBD co-administered with intravenous fentanyl, was conducted at the Clinical Research Center in Mount Sinai Hospital, a tertiary care medical center in New York City. Participants were healthy volunteers aged 21–65 years with prior opioid exposure, regardless of route. Blood samples were obtained before and after 400 or 800 mg CBD pretreatment, followed by a single 0.5 (Session 1) or 1.0mcg/Kg (Session 2) intravenous fentanyl dose. The primary outcome was the Systematic Assessment for Treatment Emergent Events (SAFTEE) to assess safety and adverse effects. CBD peak plasma concentrations, time to reach peak plasma concentrations (tmax), and area under the curve (AUC) were measured. Results SAFTEE data were similar between groups without respiratory depression or cardiovascular complications during any test session. Following low dose CBD, tmax occurred at 3 and 1.5h (Sessions 1 and 2, respectively). Following high dose CBD, tmax occurred at 3 and 4h in Sessions 1 and 2, respectively. There were no significant differences in plasma CBD or cortisol (AUC p=NS) between sessions. Conclusions CBD does not exacerbate adverse effects associated with intravenous fentanyl administration. Co-administration of CBD and opioids was safe and well tolerated. These data provide the foundation for future studies examining CBD as a potential treatment for opioid abuse. PMID:25748562

Opiate self-administration as a measure of chronic nociceptive pain in arthritic rats.

PubMed

Colpaert, F C; Tarayre, J P; Alliaga, M; Bruins Slot, L A; Attal, N; Koek, W

2001-03-01

The study examined the validity of oral fentanyl self-administration (FSA) as a measure of the chronic nociceptive pain that develops in rats with adjuvant arthritis independently of acute noxious challenges. Arthritic rats self-administered more of a 0.008 mg/ml fentanyl solution (up to 3.4 g/rat per day) than non-arthritic controls (0.5 g/rat per day) and did so with a biphasic time course that reached peak during weeks 3 and 4 after inoculation with Mycobacterium butyricum. The time course paralleled both the disease process and the chronic pain. Continuous infusion of dexamethasone during weeks 3 and 4 via subcutaneous osmotic pumps at 0.0025-0.04 mg/rat per day disrupted the arthritic disease and decreased FSA to a level (i.e. by 65%) similar to that observed in non-arthritic rats. Continuous naloxone (2.5 mg/rat per day) decreased FSA (by 55%) in arthritic but not in non-arthritic animals. Continuous, subcutaneous infusion of fentanyl also decreased arthritic FSA in a manner that varied with dose at 0.04-0.16 mg/rat per day doses, but leveled off at 47% of controls with 0.31 mg/rat per day. The effects of continuous fentanyl on arthritic FSA occurred only with those doses and dose-dependent dynamics with which fentanyl also induced dependence in non-arthritic rats. The findings indicate that pain, rather than the rewarding or dependence-inducing action of fentanyl mediates FSA in arthritic rats. Paralleling patient-controlled analgesic drug intake, FSA offers a specific measure allowing the dynamic effects of neurobiological agents to be studied in this unique animal model of persistent nociceptive pain.

Use of fentanyl and midazolam in mechanically ventilated children--Does the method of infusion matter?

PubMed

da Silva, Paulo Sérgio Lucas; Reis, Maria Eunice; de Aguiar, Vânia Euzébio; Fonseca, Marcelo Cunio Machado

2016-04-01

Benzodiazepines and opioids are commonly used in pediatric intensive care unit. However, there is no previous study assessing the use of administering these drugs combined (single solution) or separately. We sought to evaluate the impact of these 2 different methods of providing sedation/analgesia in pediatric intensive care unit. One hundred twelve patients mechanically ventilated for more than 48 hours were randomized to receive a protocolized sedation regime comprising midazolam and fentanyl either separately (group 1, 57 patients) or combined as a single solution (group 2, 55 patients). Primary end point variable was the cumulated dose of midazolam and fentanyl. The median cumulated doses of both fentanyl (0.19 vs 0.37 mg/kg, P < .05) and midazolam (28.8 vs 45.6 mg/kg, P < .05) required in group 2 were higher when compared with those of group 1. Moreover, group 2 patients had a significantly longer time of vasopressor drugs requirement and a higher number of patients developing tolerance. Patients who received a single solution of midazolam and fentanyl had a higher cumulated dose of compared with those patients who did not. The potential risk for long-term neurologic effects on developing brains associated with this finding should be considered. Copyright © 2015 Elsevier Inc. All rights reserved.

Physiologically-based pharmacokinetic model for Fentanyl in support of the development of Provisional Advisory Levels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shankaran, Harish, E-mail: harish.shankaran@pnnl.gov; Adeshina, Femi; Teeguarden, Justin G.

Provisional Advisory Levels (PALs) are tiered exposure limits for toxic chemicals in air and drinking water that are developed to assist in emergency responses. Physiologically-based pharmacokinetic (PBPK) modeling can support this process by enabling extrapolations across doses, and exposure routes, thereby addressing gaps in the available toxicity data. Here, we describe the development of a PBPK model for Fentanyl – a synthetic opioid used clinically for pain management – to support the establishment of PALs. Starting from an existing model for intravenous Fentanyl, we first optimized distribution and clearance parameters using several additional IV datasets. We then calibrated the modelmore » using pharmacokinetic data for various formulations, and determined the absorbed fraction, F, and time taken for the absorbed amount to reach 90% of its final value, t90. For aerosolized pulmonary Fentanyl, F = 1 and t90 < 1 min indicating complete and rapid absorption. The F value ranged from 0.35 to 0.74 for oral and various transmucosal routes. Oral Fentanyl was absorbed the slowest (t90 ∼ 300 min); the absorption of intranasal Fentanyl was relatively rapid (t90 ∼ 20–40 min); and the various oral transmucosal routes had intermediate absorption rates (t90 ∼ 160–300 min). Based on these results, for inhalation exposures, we assumed that all of the Fentanyl inhaled from the air during each breath directly, and instantaneously enters the arterial circulation. We present model predictions of Fentanyl blood concentrations in oral and inhalation scenarios relevant for PAL development, and provide an analytical expression that can be used to extrapolate between oral and inhalation routes for the derivation of PALs. - Highlights: • We develop a Fentanyl PBPK model for relating external dose to internal levels. • We calibrate the model to oral and inhalation exposures using > 50 human datasets. • Model predictions are in good agreement with the available pharmacokinetic data. • The model can be used for extrapolating across routes, doses and exposure durations. • We illustrate how the model can be used for developing Provisional Advisory Levels.« less

Fentanyl by continuous subcutaneous infusion for the management of cancer pain: a retrospective study.

PubMed

Watanabe, S; Pereira, J; Hanson, J; Bruera, E

1998-11-01

Twenty-two patients who received fentanyl by continuous subcutaneous infusion for treatment of cancer pain were evaluated retrospectively. No local toxicities were noted. Five patients were switched from transdermal fentanyl due to uncontrolled pain; three achieved stability, accompanied by improvement in visual analogue scores for pain. Seventeen patients were switched from other opioids due to toxicity; 10 achieved stability, with documented improvement in toxicity in seven. The median dose ratio of opioid prior to switchover (mg/day) to fentanyl at stabilization (mg/day) was 85.4 (range 65-112.5) for morphine and 23.0 (range 10.7-29.7) for hydromorphone. Of six stable patients switched from subcutaneous to transdermal fentanyl, four maintained stability. We conclude that fentanyl by continuous subcutaneous infusion is a useful alternative for cancer patients who experience uncontrolled pain while receiving transdermal fentanyl or who experience toxicity on other opioids.

Toxic leukoencephalopathy due to transdermal fentanyl overdose.

PubMed

Foy, Lindsey; Seeyave, Desiree M; Bradin, Stuart A

2011-09-01

Children with altered mental status who present to the emergency department have a broad differential diagnosis. We report a case of a 19-month-old girl who presented in coma and who was later found to have a fentanyl patch adhered to her back. She was found to have changes on brain magnetic resonance imaging consistent with a toxic spongiform leukoencephalopathy but had a good neurologic outcome. This case report illustrates the importance of a thorough physical examination in children in coma and a rarely reported magnetic resonance imaging finding that has been seen in opioid intoxication and is usually associated with severe morbidity and mortality.

Laparoscopic cholecystectomy under spinal anesthesia: comparative study between conventional-dose and low-dose hyperbaric bupivacaine

PubMed Central

Imbelloni, Luiz Eduardo; Sant’Anna, Raphael; Fornasari, Marcos; Fialho, José Carlos

2011-01-01

Background Laparoscopic cholecystectomy has the advantages of causing less postoperative pain and requiring a short hospital stay, and therefore is the treatment of choice for cholelithiasis. This study was designed to compare spinal anesthesia using hyperbaric bupivacaine given as a conventional dose by lumbar puncture or as a low-dose by thoracic puncture. Methods A total of 140 patients with symptomatic gallstone disease were randomized to undergo laparoscopic cholecystectomy with low-pressure CO2 pneumoperitoneum under spinal anesthesia using either conventional lumbar spinal anesthesia (hyperbaric bupivacaine 15 mg and fentanyl 20 mg) or low-dose thoracic spinal anesthesia (hyperbaric bupivacaine 7.5 mg and fentanyl 20 μg). Intraoperative parameters, postoperative pain, complications, recovery time, and patient satisfaction at follow-up were compared between the two treatment groups. Results All procedures were completed under spinal anesthesia, with no cases needing conversion to general anesthesia. Values for time for block to reach the T3 dermatomal level, duration of motor and sensory block, and hypotensive events were significantly lower with low-dose bupivacaine. Postoperative pain was higher for low-dose hyperbaric bupivacaine at 6 and 12 hours. All patients were discharged after 24 hours. Follow-up 1 week postoperatively showed all patients to be satisfied and to be keen advocates of spinal anesthesia. Conclusion Laparoscopic cholecystectomy can be performed successfully under spinal anesthesia. A small dose of hyperbaric bupivacaine 7.5 mg and 20 μg fentanyl provides adequate spinal anesthesia for laparoscopy and, in comparison with hyperbaric bupivacaine 15% and fentanyl 20 μg, causes markedly less hypotension. The low-dose strategy may have an advantage in ambulatory patients because of the earlier recovery of motor and sensory function and earlier discharge. PMID:22915892

Synthesis and biological evaluation of some novel 1-substituted fentanyl analogs in Swiss albino mice

PubMed Central

Yadav, Shiv Kumar; Maurya, Chandra Kant; Gupta, Pradeep Kumar; Jain, Ajai Kumar; Ganesan, Kumaran

2014-01-01

Fentanyl [N-(1-phenethyl-4-piperidinyl)propionanilide] is a potent opioid analgesic agent, but a has narrow therapeutic index. We reported earlier on the synthesis and bioefficacy of fentanyl and its 1-substituted analogs (1–4) in mice. Here we report the synthesis and biological evaluation of four additional analogs, viz. N-isopropyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (5), N-t-butyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (6), isopropyl 2-[4-(N-phenylpropionamido)piperidin-1-yl]propionate (7) and t-butyl 2-[4-(N-phenylpropionamido)piperidin-1-yl]propionate (8). The median lethal dose (LD50) determined by intravenous, intraperitoneal and oral routes suggests these analogs to be comparatively less toxic than fentanyl. On the basis of observational assessment on spontaneous activities of the central, peripheral, and autonomic nervous systems, all the analogs were found to be similar to fentanyl. Naloxone hydrochloride abolished the neurotoxic effects of these analogs, thereby ascertaining their opioid receptor-mediated effects. All the analogs displayed significant analgesic effects, measured by formalin-induced hind paw licking and tail immersion tests at their respective median effective dose (ED50). They also exhibited 8–12 fold increase in therapeutic index over fentanyl. However, 5 and 6 alone produced lower ED50 (20.5 and 21.0 µg/kg, respectively) and higher potency ratio (1.37 and 1.33, respectively) compared to fentanyl. They could thus be considered for further studies on pain management. PMID:26109885

The Efficacy and Safety of the Novel Peripheral Analgesic Isovaline as an Adjuvant to Propofol for General Anesthesia and Conscious Sedation: A Proof-of-Principle Study in Mice.

PubMed

Whitehead, Ryan A; Schwarz, Stephan K W; Asiri, Yahya I; Fung, Timothy; Puil, Ernest; MacLeod, Bernard A

2015-12-01

The combination of propofol and an opioid analgesic is widely used for procedural sedation, as well as total IV anesthesia. However, opioids produce respiratory depression, a primary cause of death due to these agents. We recently reported on the antinociceptive actions of isovaline, a small nonbiogenic amino acid that does not readily cross the blood-brain barrier and acts on peripheral γ-aminobutyric acid type B receptors. Here, we explored the possibility that isovaline may be an effective and safe alternative to opioids as an adjunct to propofol for producing anesthesia. With approval from our Animal Care Committee, we conducted an in vivo study in adult female CD-1 mice using Dixon's "up-and-down" method for dose assessment. Animals received intraperitoneal saline, propofol, isovaline, fentanyl, or coadministration of propofol with isovaline or fentanyl. We assessed hypnosis by a loss of righting reflex and immobility by an absence of motor response to tail clip application. General anesthesia was defined as the presence of both hypnosis and immobility. We assessed conscious sedation as a decrease in time on a rotarod. The maximal dose without respiratory rates of <4 per minute, apnea, or death was defined as the maximal tolerated dose. Either isovaline or fentanyl coadministered with propofol at its half-maximal effective dose (ED50) for hypnosis produced general anesthesia (isovaline ED50, 96 mg/kg [95% confidence interval {CI}, 88-124 mg/kg]; fentanyl ED50, 0.12 mg/kg [95% CI, 0.08-3.5 mg/kg]). Propofol produced hypnosis (ED50, 124 mg/kg [95% CI, 84-3520 mg/kg]) but did not block responses to tail clip application. Neither isovaline nor fentanyl produced hypnosis at doses which produced immobility (isovaline ED50, 350 mg/kg [95% CI, 286-1120 mg/kg]; fentanyl ED50, 0.35 mg/kg [95% CI, 0.23-0.51 mg/kg]). Isovaline at its analgesic ED50, coadministered with a subhypnotic dose of propofol (40 mg/kg), did not exacerbate propofol-induced deficits in rotarod performance. The median maximal tolerated dose of fentanyl coadministered with the hypnotic ED50 of propofol was 11 mg/kg (95% CI, 8-18 mg/kg). Isovaline at a maximal deliverable (soluble) dose of 5000 mg/kg produced no apparent respiratory depression or other adverse effects. The novel analgesic, isovaline, coadministered with propofol, produced general anesthesia and conscious sedation in mice. The margin of safety for propofol-isovaline was considerably higher than that for propofol-fentanyl. This study's results show that propofol-based sedation and general anesthesia can be effectively and safely produced by replacing the conventional opioid component with a brain-impermeant peripherally acting γ-aminobutyric acid type B receptor agonist. The results provide proof of the principle of combining a peripheral analgesic with a centrally acting hypnotic to produce general anesthesia. This principle suggests a novel approach to clinical general anesthesia and conscious sedation.

Effects of Pre-Existing Liver Disease on Acute Pain Management Using Patient-Controlled Analgesia Fentanyl With Parecoxib After Major Liver Resection: A Retrospective, Pragmatic Study.

PubMed

Lim, K I; Chiu, Y C; Chen, C L; Wang, C H; Huang, C J; Cheng, K W; Wu, S C; Shih, T H; Yang, S C; Juang, S E; Huang, C E; Jawan, B; Lee, Y E

2016-05-01

The aim of this study was to compare the outcomes of pain management with the use of patient-controlled analgesia (PCA) fentanyl with IV parecoxib between patients with healthy liver with patients with diseased liver undergoing major liver resection. Patients with healthy liver undergoing partial hepatectomy as liver donors for liver transplantation (group 1) and patients with liver cirrhosis (Child's criteria A) undergoing major liver resection for hepatoma (group 2) were identified retrospectively. Both groups routinely received post-operative IV PCA fentanyl and a single dose of parecoxib 40 mg. They were followed up for 3 days or until PCA fentanyl was discontinued post-operatively. Daily Visual Analog Scale, PCA fentanyl usage, rescue attempts, and common drug side effects were collected and analyzed with the use of SPSS version 20. One hundred one patients were included in the study: 54 in group 1, and 47 in group 2. There were no statistical differences between the two groups in terms of the daily and total fentanyl usage, VAS resting, and incidence of itchiness. The rate of rescue analgesia on post-operative day (POD) 1 was lower in group 2, with a value of P = .045. VAS dynamics were better on POD 1 and 2 for group 2, with P = .05 and P = .012, respectively. We found that combining a single dose of IV parecoxib 40 mg with PCA fentanyl is an easy and effective method of acute pain control after major liver resection. We propose the careful usage of post-operative fentanyl and parecoxib in patients with diseased liver, given the difference in effect as compared with healthy liver. Copyright © 2016 Elsevier Inc. All rights reserved.

Fentanyl Iontophoretic Transdermal System (IONSYS(®)) can be Safely used in the Hospital Environment with X-Rays, Computerized Tomography and Radiofrequency Identification Devices.

PubMed

Lemke, John; Sardariani, Edmond; Phipps, Joseph Bradley; Patel, Niki; Itri, Loretta M; Caravelli, James; Viscusi, Eugene R

2016-09-01

Fentanyl iontophoretic transdermal system (fentanyl ITS, IONSYS(®)) is a patient-controlled analgesia system used for the management of acute postoperative pain, designed to be utilized in a hospital setting. The objective of the two studies was to determine if fentanyl ITS could be safely used with X-rays, computerized tomography (CT) scans and radiofrequency identification (RFID) devices. The ITS system has two components: controller and drug unit; the studies utilized ITS systems without fentanyl, referred to as the ITS Placebo system. The first study evaluated the effect of X-radiation on the operation of an ITS Placebo system. Five ITS Placebo systems were exposed to X-rays (20 and 200 mSv total radiation dose-the 200 mSv radiation dose represents a tenfold higher exposure than in clinical practice) while operating in the Ready Mode and five were exposed while operating in the Dose Mode. The second study evaluated the effect of RFID (worst-case scenario of direct contact with an RFID transmitter) on the operation of an ITS Placebo system. During these tests, observations of the user interface and measurements of output voltage confirmed proper function throughout all operational modes (Ready Mode, Dose Mode, End-of-Use Mode, and End-of-Life Mode). The ITS Placebo system met all specifications and no functional anomalies were observed during and following X-ray exposure at two radiation dose levels or exposure at six different combinations of RFID frequencies and field strengths. The performance of the ITS system was unaffected by X-ray exposure levels well beyond those associated with diagnostic X-rays and CT scans, and by exposure to radiofrequency field strengths typically generated by RFID devices. These results provide added confidence to clinicians that the fentanyl ITS system does not need to be removed during diagnostic X-rays and CT scans and can also be utilized in close proximity to RFID devices. The studies and writing of this manuscript were supported financially by The Medicines Company.

The dexmedetomidine concentration required after remifentanil anesthesia is three-fold higher than that after fentanyl anesthesia or that for general sedation in the ICU

PubMed Central

Kunisawa, Takayuki; Fujimoto, Kazuhiro; Kurosawa, Atsushi; Nagashima, Michio; Matsui, Koji; Hayashi, Dai; Yamamoto, Kunihiko; Goto, Yuya; Akutsu, Hiroaki; Iwasaki, Hiroshi

2014-01-01

Purpose The general dexmedetomidine (DEX) concentration required for sedation of intensive care unit patients is considered to be approximately 0.7 ng/mL. However, higher DEX concentrations are considered to be required for sedation and/or pain management after major surgery using remifentanil. We determined the DEX concentration required after major surgery by using a target-controlled infusion (TCI) system for DEX. Methods Fourteen patients undergoing surgery for abdominal aortic aneurysms (AAA) were randomly, double-blindly assigned to two groups and underwent fentanyl- or remifentanil-based anesthetic management. DEX TCI was started at the time of closing the peritoneum and continued for 12 hours after stopping propofol administration (M0); DEX TCI was adjusted according to the sedation score and complaints of pain. The doses and concentrations of all anesthetics and postoperative conditions were investigated. Results Throughout the observation period, the predicted plasma concentration of DEX in the fentanyl group was stable at approximately 0.7 ng/mL. In contrast, the predicted plasma concentration of DEX in the remifentanil group rapidly increased and stabilized at approximately 2 ng/mL. The actual DEX concentration at 540 minutes after M0 showed a similar trend (0.54±0.14 [fentanyl] versus 1.57±0.39 ng/mL [remifentanil]). In the remifentanil group, the dopamine dose required and the duration of intubation decreased, and urine output increased; however, no other outcomes improved. Conclusion The DEX concentration required after AAA surgery with remifentanil was three-fold higher than that required after AAA surgery with fentanyl or the conventional DEX concentration for sedation. High DEX concentration after remifentanil affords some benefits in anesthetic management. PMID:25328395

Cardiorespiratory effects of epidural administration of morphine and fentanyl in dogs anesthetized with sevoflurane.

PubMed

Naganobu, Kiyokazu; Maeda, Noriaki; Miyamoto, Toru; Hagio, Mitsuyoshi; Nakamura, Tadashi; Takasaki, Mayumi

2004-01-01

To determine the cardiorespiratory effects of epidural administration of morphine alone and in combination with fentanyl in dogs anesthetized with sevoflurane. Prospective study. 6 dogs. Dogs were anesthetized with sevoflurane and allowed to breathe spontaneously. After a stable plane of anesthesia was achieved, morphine (0.1 mg/kg [0.045 mg/lb]) or a combination of morphine and fentanyl (10 microg/kg [4.5 microg/lb]) was administered through an epidural catheter, the tip of which was positioned at the level of L6 or L7. Cardiorespiratory variables were measured for 90 minutes. Epidural administration of morphine alone did not cause any significant changes in cardiorespiratory measurements. However, epidural administration of morphine and fentanyl induced significant decreases in diastolic and mean arterial blood pressures and total peripheral resistance. Stroke volume was unchanged, PaCO2 was significantly increased, and arterial pH and base excess were significantly decreased. Heart rate was significantly lower after epidural administration of morphine and fentanyl than after administration of morphine alone. None of the dogs had any evidence of urine retention, vomiting, or pruritus after recovery from anesthesia. Results suggest that epidural administration of morphine at a dose of 0.1 mg/kg in combination with fentanyl at a dose of 10 microg/kg can cause cardiorespiratory depression in dogs anesthetized with sevoflurane.

Pain Levels Within 24 Hours After UFE: A Comparison of Morphine and Fentanyl Patient-Controlled Analgesia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Hyun S., E-mail: sikhkim@jhmi.edu; Czuczman, Gregory J.; Nicholson, Wanda K.

The purpose of this study was to assess the presence and severity of pain levels during 24 h after uterine fibroid embolization (UFE) for symptomatic leiomyomata and compare the effectiveness and adverse effects of morphine patient-controlled analgesia (PCA) versus fentanyl PCA. We carried out a prospective, nonrandomized study of 200 consecutive women who received UFE and morphine or fentanyl PCA after UFE. Pain perception levels were obtained on a 0-10 scale for the 24-h period after UFE. Linear regression methods were used to determine pain trends and differences in pain trends between two groups and the association between pain scoresmore » and patient covariates. One hundred eighty-five patients (92.5%) reported greater-than-baseline pain after UFE, and 198 patients (99%) required IV opioid PCA. One hundred thirty-six patients (68.0%) developed nausea during the 24-h period. Seventy-two patients (36%) received morphine PCA and 128 (64%) received fentanyl PCA, without demographic differences. The mean dose of morphine used was 33.8 {+-} 26.7 mg, while the mean dose of fentanyl was 698.7 {+-} 537.4 {mu}g. Using this regimen, patients who received morphine PCA had significantly lower pain levels than those who received fentanyl PCA (p < 0.0001). We conclude that patients develop pain requiring IV opioid PCA within 24 h after UFE. Morphine PCA is more effective in reducing post-uterine artery embolization pain than fentanyl PCA. Nausea is a significant adverse effect from opioid PCA.« less

Dose fentanyl injection for blunting the hemodynamic response to intubation increase the risk of reflex bradycardia during major abdominal surgery?

PubMed Central

Kim, Jin-Kyoung; Park, Jung-Min; Lee, Cheol-Hee

2012-01-01

Background Although supplemental fentanyl has been widely used to blunt the hemodynamic responses to laryngoscopic intubation, its residual vagotonic effect may increase the risk of reflex bradycardia. We compared the incidence and severity of significant reflex bradycardia after a bolus injection of equivalent doses of fentanyl and remifentanil (control drug). Methods In this prospective, randomized, double-blind study, 220 adult patients undergoing major abdominal surgery were randomly assigned to receive fentanyl (1.5 µg/kg) or remifentanil (1.5 µg/kg). No anticholinergic prophylaxis was administered. Symptomatic reflex bradycardia was defined as a sudden decrease in heart rate to < 50 beats per minute (bpm) or to 50-59 bpm associated with a systolic arterial pressure < 70 mmHg in connection with surgical maneuvers. If bradycardia or hypotension developed, atropine or ephedrine was administered following a predefined treatment protocol. Results In total, 188 subjects (remifentanil, 95; fentanyl, 93) were included. The proportion of subjects with symptomatic reflex bradycardia in the fentanyl group was similar to that in the remifentanil group (30.1% vs. 28.4%, respectively). Atropine and/or ephedrine were needed similarly in both groups. The differences between the group of 55 patients who presented with symptomatic reflex bradycardia were not statistically significant with respect to the lowest heart rate, anesthetic depth-related data (bispectral index and end-tidal sevoflurane concentration), or the proportion of causative surgical maneuvers. Conclusions Fentanyl (1.5 µg/kg) administered intravenously during anesthetic induction is unlikely to increase the incidence and severity of significant reflex bradycardia in patients undergoing major abdominal surgery. PMID:23198032

Low-dose levobupivacaine plus fentanyl combination for spinal anesthesia in anorectal surgery.

PubMed

Honca, Mehtap; Dereli, Necla; Kose, Emine Arzu; Honca, Tevfik; Kutuk, Selcen; Unal, Selma Savas; Horasanli, Eyup

2015-01-01

the aim of this study was to investigate the effects of spinal anesthesia using two different doses of fentanyl combined with low-dose levobupivacaine in anorectal surgery. in this prospective, double-blind study, 52 American Society of Anaesthesiologists I-II patients scheduled for elective anorectal surgery were randomized into two groups. The patients in group I received intrathecal 2.5mg hyperbaric levobupivacaine plus 12.5 μg fentanyl and in group II received intrathecal 2.5mg hyperbaric levobupivacaine plus 25 μg fentanyl. All the patients remained in the seated position for 5 min after completion of the spinal anesthesia. Sensory block was evaluated with pin-prick test and motor block was evaluated with a modified Bromage scale. motor block was not observed in both of the groups. The sensory block was limited to the S2 level in group I, and S1 level in group II. None of the patients required additional analgesics during the operation. Time to two-segment regression was shorter in group I compared with group II (p<0.01). One patient in group I and 5 patients in group II had pruritus. Hemodynamic parameters were stable during the operation in both of the groups. spinal saddle block using hyperbaric levobupivacaine with both 12.5 μg and 25 μg fentanyl provided good quality of anesthesia without motor block for anorectal surgery in the prone position. Copyright © 2014 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

[Low-dose levobupivacaine plus fentanyl combination for spinal anesthesia in anorectal surgery].

PubMed

Honca, Mehtap; Dereli, Necla; Kose, Emine Arzu; Honca, Tevfik; Kutuk, Selcen; Unal, Selma Savas; Horasanli, Eyup

2015-01-01

The aim of this study was to investigate the effects of spinal anesthesia using two different doses of fentanyl combined with low-dose levobupivacaine in anorectal surgery. In this prospective, double-blind study, 52 American Society of Anaesthesiologists I-II patients scheduled for elective anorectal surgery were randomized into two groups. The patients in group I received intrathecal 2.5mg hyperbaric levobupivacaine plus 12.5μg fentanyl and in group II received intrathecal 2.5mg hyperbaric levobupivacaine plus 25μg fentanyl. All the patients remained in the seated position for 5min after completion of the spinal anesthesia. Sensory block was evaluated with pin-prick test and motor block was evaluated with a modified Bromage scale. Motor block was not observed in both of the groups. The sensory block was limited to the S2 level in group I, and S1 level in group II. None of the patients required additional analgesics during the operation. Time to two-segment regression was shorter in group I compared with group II (p<0.01). One patient in group I and 5 patients in group II had pruritus. Hemodynamic parameters were stable during the operation in both of the groups. Spinal saddle block using hyperbaric levobupivacaine with both 12.5μg and 25μg fentanyl provided good quality of anesthesia without motor block for anorectal surgery in the prone position. Copyright © 2014 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

PATIENTS' KNOWLEDGE OF MEDICAL PATCHES IN HUNGARY.

PubMed

Somogyi, Orsolya; Zelko, Romana

2016-11-01

Transdermal therapy with medical patches is a simple possibility in home medication. As the correct use of patches has a decisive impact from the point of its modulator effect.A questionnaire survey was developed to explore level of patients' knowledge of the correct use of transdermal patches. A survey was administered in thirteen Hungarian community pharmacies from October of 2012 to May of 2015. Most of the participants, men and women over 18 years of age (n = 233), used major analgesic patches (fentanyl); the remainder were given nitroglycerin, NSAID analgesics patches during the survey. For the hypothesis testing it was assumed that men were more likely to use a razor for skin depilation before patch application than women as their denser pelage hinders patch adhesion. The hypothesis testing showed no significant gender difference in razor use (X² = 0.201; p = 0.654). Pharmacists should direct patients to avoid using soap for skin cleansing before patch application because only 22 percent of the participants always avoided its use. Since only 9 tests were flawless from 233 completed questionnaires. Many patients do not understand how to correctly apply a transdermal dosage patch. Pharmacists should teach their correct application based on results.

Role of central and peripheral opiate receptors in the effects of fentanyl on analgesia, ventilation and arterial blood-gas chemistry in conscious rats

PubMed Central

Henderson, Fraser; May, Walter J.; Gruber, Ryan B.; Discala, Joseph F.; Puscovic, Veljko; Young, Alex P.; Baby, Santhosh M.; Lewis, Stephen J.

2015-01-01

This study determined the effects of the peripherally restricted µ-opiate receptor (µ-OR) antagonist, naloxone methiodide (NLXmi) on fentanyl (25 µg/kg, i.v.)-induced changes in (1) analgesia, (2) arterial blood gas chemistry (ABG) and alveolar-arterial gradient (A-a gradient), and (3) ventilatory parameters, in conscious rats. The fentanyl-induced increase in analgesia was minimally affected by a 1.5 mg/kg of NLXmi but was attenuated by a 5.0 mg/kg dose. Fentanyl decreased arterial blood pH, pO2 and sO2 and increased pCO2 and A-a gradient. These responses were markedly diminished in NLXmi (1.5 mg/kg)-pretreated rats. Fentanyl caused ventilatory depression (e.g., decreases in tidal volume and peak inspiratory flow). Pretreatment with NLXmi (1.5 mg/kg, i.v.) antagonized the fentanyl decrease in tidal volume but minimally affected the other responses. These findings suggest that (1) the analgesia and ventilatory depression caused by fentanyl involve peripheral µ-ORs and (2) NLXmi prevents the fentanyl effects on ABG by blocking the negative actions of the opioid on tidal volume and A-a gradient. PMID:24284037

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

PubMed

Oosten, Astrid W; Abrantes, João A; Jönsson, Siv; de Bruijn, Peter; Kuip, Evelien J M; Falcão, Amílcar; van der Rijt, Carin C D; Mathijssen, Ron H J

2016-04-01

Transdermal 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. Fifty-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. A 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. We 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.

LC-MS/MS analysis of fentanyl and norfentanyl in a fatality due to application of multiple Durogesic transdermal therapeutic systems.

PubMed

Coopman, Vera; Cordonnier, Jan; Pien, Karen; Van Varenbergh, Dirk

2007-07-04

Fentanyl is a potent synthetic narcotic analgesic administered in the form of a transdermal patch for the management of chronic pain. A 78-year-old woman with a history of cancer was found dead in bed. She was lying on her back. The external examination revealed 10 Durogesic transdermal therapeutic systems (100 microg/h fentanyl) on the body. Liquid-liquid extraction and liquid chromatography tandem mass spectrometry with electrospray source in positive ionization mode was applied for the quantitation of fentanyl and its major metabolite norfentanyl in the post-mortem samples. Fentanyl-d5 and norfentanyl-d5 were used as internal standards. Multiple reaction monitoring was used for specific detection. Calibration was performed by addition of standard solutions to drug-free matrix (blood, urine and liver) prior to extraction. The method showed good linearity for fentanyl and norfentanyl over a concentration range of 5-150 microg/L in reconstituted extracts with coefficients of determination equal or greater than 0.998. Percent mean within-day precision and accuracy of 0.9-1.0% and 99.4-101.1% for fentanyl and 2.0-4.5% and 93.1-101.0% for norfentanyl were obtained. Mean extraction recoveries varied between 95.5% and 100.3% for fentanyl and 39.2-57.4% for norfentanyl. The following fentanyl (norfentanyl) concentration in the post-mortem samples were measured; 28.6 microg/L (3.0 microg/L) in right and 28.2 microg/L (3.5 microg/L) in left subclavian blood, 21.3 microg/L (<2 microg/L) in right and 20.9 microg/L (<2 microg/L) in left femoral blood, 37.6 microg/L (4.2 microg/L) in right and 33.9 microg/L (4.4 microg/L) in left ventricular blood, 282.9 microg/L (121.2 microg/L) in urine, 688.2 microg/L in stomach contents, 122.5 microg/L (25.4 microg/L) in bile, 19.5 microg/L (< 2 microg/L) in vitreous humour, 203.0 microg/kg (26.6 microg/kg) in liver and 78.6 microg/kg (46.3 microg/kg) in kidney. We concluded that the woman's death was caused by acute intoxication with fentanyl. The manner of death was presumed to be suicide due to excessive administered Durogesic transdermal therapeutic systems.

Intranasal Opioid Administration in Rhesus Monkeys: PET Imaging and Antinociception.

PubMed

Saccone, Phillip A; Lindsey, Angela M; Koeppe, Robert A; Zelenock, Kathy A; Shao, Xia; Sherman, Phillip; Quesada, Carole A; Woods, James H; Scott, Peter J H

2016-11-01

The goal of this study was to evaluate the effects of intranasally administered opioids in rhesus monkeys using the tail-withdrawal assay, and to correlate these effects with measures of receptor occupancy using positron emission tomography (PET) imaging. Initial experiments characterized the antinociceptive effects of intranasal (IN) fentanyl and buprenorphine relative to intramuscular (IM) injection. Fentanyl (0.010-0.032 mg/kg) and buprenorphine (0.1-1.0 mg/kg) produced dose-dependent increases in tail-withdrawal latency that did not differ between routes of delivery. The second experiment compared the ability of IN and intravenous (IV) naloxone (NLX) to block the antinociceptive effects IV fentanyl, and to measure receptor occupancy at equipotent doses of NLX using PET imaging. IN and IV NLX (0.0032-0.032 mg/kg) produced dose-dependent decreases in fentanyl-induced antinociception. Again, there was no difference observed in overall potency between routes. PET imaging showed that IV and IN NLX produced similar decreases in receptor occupancy as measured by [ 11 C]carfentanil blocking, although there was a trend for IV NLX to produce marginally greater occupancy changes. This study validated the first procedures to evaluate the IN effects of opioids in rhesus monkeys. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Opiate sensitivity test in patients with stereotypic movement disorder and trichotillomania.

PubMed

Frecska, Ede; Arato, Mihaly

2002-06-01

Preliminary data about the therapeutic effect of opiate receptor manipulation in self-injurious behavior (SIB) suggest that endogenous opioid mechanisms may have a pathophysiological role in that condition and their involvement may be dependent on the severity of the SIB. The aim of this study was to use fentanyl-induced prolactin response as an opiate receptor sensitivity test in patients with stereotypic movement disorder (SMD) manifesting SIB (skin picking). Healthy volunteers and trichotillomanic patients were enrolled as comparison subjects. Individuals with trichotillomania (TTM) manifest repetitive, less serious self-mutilation (hair pulling) and are classified under different DSM-IV category than SMD. Therefore, they were considered as patient controls. Ten healthy subjects received 0.05 mg/70 kg and another 10 were given 0.1 mg/70 kg dose of fentanyl intravenously in the AM hours. Five of them had placebo trials. A dose of 0.05 mg/70 kg fentanyl was administered to patients with SMD (n = 10) and TTM (n = 12). Serial blood sampling was performed for prolactin measurements. Fentanyl elevated plasma prolactin in a dose-dependent manner. Patients with skin picking, but not with hair pulling, showed significantly increased responses. This finding supports the involvement of endogenous opioids in the pathomechanism of serious SIB.

Opioid Overdose Outbreak - West Virginia, August 2016.

PubMed

Massey, Joel; Kilkenny, Michael; Batdorf, Samantha; Sanders, Sarah K; Ellison, Debra; Halpin, John; Gladden, R Matthew; Bixler, Danae; Haddy, Loretta; Gupta, Rahul

2017-09-22

On August 15, 2016, the Mayor's Office of Drug Control Policy in Huntington, West Virginia, notified the Cabell-Huntington Health Department (CHHD) of multiple calls regarding opioid overdose received by the emergency medical system (EMS) during 3 p.m.-8 p.m. that day. A public health investigation and response conducted by the West Virginia Bureau for Public Health (BPH) and CHHD identified 20 opioid overdose cases within a 53-hour period in Cabell County; all cases included emergency department (ED) encounters. EMS personnel, other first responders, and ED providers administered the opioid antidote naloxone to 16 (80%) patients, six of whom were administered multiple doses, suggesting exposure to a highly potent opioid. No patients received referral for recovery support services. In addition to the public health investigation, a public safety investigation was conducted; comprehensive opioid toxicology testing of clinical specimens identified the synthetic opioid fentanyl* and novel fentanyl analogs, including carfentanil, † which had been used by patients who overdosed in Huntington. Results of these two investigations highlight the importance of collaboration between public health and public safety agencies to provide in-depth surveillance data from opioid overdose outbreaks that involve high-potency fentanyl analogs. These data facilitated a public health response through increased awareness of powerful opioid substances requiring multiple naloxone doses for reversal, and improved patient linkage to recovery support services and a harm reduction program from the ED after opioid overdose.

Consumption of three strong opioids (morphine, oxycodone and fentanyl) in seven European countries during seven years (2003-2009).

PubMed

Hudec, R; Tisonova, J; Foltan, V; Kristova, V

2013-01-01

The aim was to analyse the consumption of selected strong opioid analgesics during a seven-year period of 2003-2009 in order to compare Slovak consumption with that in six other European countries and to determine our position. Drug consumption data from the State Institute for Drug Control in Slovak Republic were used. As to the data from other countries, annual health statistics published on websites were used in comparison. Obviously the consumption of one of studied opioid drugs with transdermal aplication route, particularly fentanyl, tended to increase in all countries during the observed period. Oxycodone tends to yield a rapid increase in consumption as well. As opposed to the latter drugs, the consumption of morphine was decreasing throughout the observed period. The consumption of these drugs in Slovakia remains low (except for that of fentanyl). Our analysis confirmed a clear shift from oral to transdermal therapy as well as usage of newer drugs. Drug consumption data are a relatively new source of information for health research. Our analysis showed increasing trends in fentanyl (patch opioid) consumption in all compared countries as well as an increasing consumption of oxycodone and decreasing consumption of morphine (Fig. 3, Ref. 17).

Cardiovascular effects, induction and recovery characteristics and alfaxalone dose assessment in alfaxalone versus alfaxalone-fentanyl total intravenous anaesthesia in dogs.

PubMed

Dehuisser, Virginie; Bosmans, Tim; Kitshoff, Adriaan; Duchateau, Luc; de Rooster, Hilde; Polis, Ingeborgh

2017-11-01

To compare cardiovascular effects and anaesthetic quality of alfaxalone alone or in combination with a fentanyl constant rate infusion (CRI) when used for total intravenous anaesthesia (TIVA) in dogs. Prospective, blinded, randomized, experimental study. A group of 12 intact female dogs. Following intramuscular dexmedetomidine (10 μg kg -1 ) and methadone (0.1 mg kg -1 ) administration, anaesthesia was induced intravenously with alfaxalone (2 mg kg -1 ) (group AP) or alfaxalone (2 mg kg -1 ) preceded by fentanyl (2 μg kg -1 ) (group AF). Anaesthetic maintenance was obtained with an alfaxalone variable rate infusion (VRI) started at 0.15 mg kg -1 minute -1 (group AP) or an alfaxalone VRI (same starting rate) combined with a CRI of fentanyl (10 μg kg -1 hour -1 ) (group AF). The alfaxalone VRI was adjusted every 5 minutes, based on clinical assessment. Cardiovascular parameters (recorded every 5 minutes) and recovery characteristics (using a numerical rating scale) were compared between groups. A mixed model statistical approach was used to compare the mean VRI alfaxalone dose and cardiovascular parameters between groups; recovery scores were analysed using the Wilcoxon rank-sum test (α = 0.05). The mean CRI alfaxalone dose for anaesthetic maintenance differed significantly between treatments [0.16 ± 0.01 mg kg -1 minute -1 (group AP) versus 0.13 ± 0.01 mg kg -1 minute -1 (group AF)]. Overall heart rate, systolic, mean and diastolic arterial pressures were lower in group AF than in group AP (p < 0.0001, p = 0.0058, p < 0.0001 and p < 0.0001, respectively. Recovery quality scores did not differ significantly and were poor in both groups. In combination with a fentanyl CRI, an alfaxalone TIVA provides a cardiovascular stable anaesthesia in dogs. The addition of fentanyl results in a significant dose reduction. The quality of anaesthetic recovery remains poor. Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.

Effects of conventional vs high-dose rocuronium on the QTc interval during anesthesia induction and intubation in patients undergoing coronary artery surgery: a randomized, double-blind, parallel trial

PubMed Central

Öztürk, T.; Ağdanlı, D.; Bayturan, Ö.; Çıkrıkcı, C.; Keleş, G.T.

2015-01-01

Myocardial ischemia, as well as the induction agents used in anesthesia, may cause corrected QT interval (QTc) prolongation. The objective of this randomized, double-blind trial was to determine the effects of high- vs conventional-dose bolus rocuronium on QTc duration and the incidence of dysrhythmias following anesthesia induction and intubation. Fifty patients about to undergo coronary artery surgery were randomly allocated to receive conventional-dose (0.6 mg/kg, group C, n=25) or high-dose (1.2 mg/kg, group H, n=25) rocuronium after induction with etomidate and fentanyl. QTc, heart rate, and mean arterial pressure were recorded before induction (T0), after induction (T1), after rocuronium (just before laryngoscopy; T2), 2 min after intubation (T3), and 5 min after intubation (T4). The occurrence of dysrhythmias was recorded. In both groups, QTc was significantly longer at T3 than at baseline [475 vs 429 ms in group C (P=0.001), and 459 vs 434 ms in group H (P=0.005)]. The incidence of dysrhythmias in group C (28%) and in group H (24%) was similar. The QTc after high-dose rocuronium was not significantly longer than after conventional-dose rocuronium in patients about to undergo coronary artery surgery who were induced with etomidate and fentanyl. In both groups, compared with baseline, QTc was most prolonged at 2 min after intubation, suggesting that QTc prolongation may be due to the nociceptive stimulus of intubation. PMID:25714880

Identification of factors associated with sedation tolerance in 5000 patients undergoing outpatient colonoscopy: Canadian tertiary center experience.

PubMed

Shingina, Alexandra; Ou, George; Takach, Oliver; Svarta, Sigrid; Kwok, Ricky; Tong, Jessica; Donaldson, Kieran; Lam, Eric; Enns, Robert

2016-12-16

To develop a prediction model aimed at identifying patients that may require higher than usual sedation doses during colonoscopy. A retrospective chart review on 5000 patients who underwent an outpatient colonoscopy at St. Paul's Hospital from 2009 to 2010 was conducted in order to develop a model for identifying patients who will require increased doses of sedatives. Potential predictor variables including age, gender, endoscopy indication, high sedation requirements during previous endoscopies, difficulty of the procedure, bowel preparation quality, interventions, findings as well as current use of benzodiazepines, opioids and alcohol were analyzed. The outcome of study was the use of high dose of sedation agents for the procedure. In particular, the high dose of sedation was defined as fentanyl greater than 50 mcg and midazolam greater than 3 mg. Analysis of 5282 patients (mean age 57 ± 12, 49% female) was performed. Most common indication for the procedure was screening colonoscopy (57%). Almost half of our patients received doses exceeding Fentanyl 50 mcg and Midazolam 3 mg. Logistic regression models identified the following variables associated with high sedation: Younger age (OR = 0.95 95%CI: 0.94-0.95; P < 0.0001); abdominal pain (OR = 1.45, 95%CI: 1.08-1.96); P = 0.01) and Inflammatory Bowel Disease (OR = 1.45, 95%CI: 1.04-2.03; P = 0.02) as indications for the procedure; difficult procedure as defined by gastroenterologist (OR = 1.73, 95%CI: 1.48-2.03; P < 0.0001); past history of abdominal surgery (OR = 1.33, 95%CI: 1.17-1.52; P <0.0001) and previous colonoscopy (OR = 1.39, 95%CI: 1.21-1.60; P = 0.0001) and alcohol use (OR = 1.26, 95%CI: 1.03-1.54; P = 0.02). Age and gender adjusted analysis yielded inflammatory bowel disease as an indication (OR = 3.17, 95%CI: 1.58-6.37; P = 0.002); difficult procedure as defined by an endoscopist (OR = 5.13 95%CI: 2.97-8.85; P = 0.0001) and current use of opioids, benzodiazepines or antidepressants (OR = 2.88, 95%CI: 1.74-4.77; P = 0.001) having the highest predictive value of high sedation requirements. Our prediction model using the following pre-procedural variables including age, gender, indication for the procedure, medication/substance use, previous surgeries, previous high sedation requirements for colonoscopy yielded an area under the curve of 0.76 for Fentanyl ≥ 100 mcg and Midazolam ≥ 3 mg. Pre-procedural planning is the key in conducting successful, efficient colonoscopy. Logistic regression analysis of 5000 patients who underwent out-patient colonoscopy revealed the following factors associated with increased sedation requirement: Younger age, female gender, difficult endoscopy, specific indications as well as cardiopulmonary complications and current use of opioids/benzodiazepines. Age and gender adjusted analysis yielded similar results. These patients are more likely to need a longer recovery periods post-endoscopy, which could result in additional time and personnel requirements. The final predictive model has good predictive ability for Fentanyl ≥ 100 mcg and Midazolam ≥ 3 mg and fair predictive ability for Fentanyl ≥ 50 mcg and Midazolam ≥ 2 mg. The external validity of this model is planned to be tested in another center.

Role of central and peripheral opiate receptors in the effects of fentanyl on analgesia, ventilation and arterial blood-gas chemistry in conscious rats.

PubMed

Henderson, Fraser; May, Walter J; Gruber, Ryan B; Discala, Joseph F; Puskovic, Veljko; Young, Alex P; Baby, Santhosh M; Lewis, Stephen J

2014-01-15

This study determined the effects of the peripherally restricted μ-opiate receptor (μ-OR) antagonist, naloxone methiodide (NLXmi) on fentanyl (25μg/kg, i.v.)-induced changes in (1) analgesia, (2) arterial blood gas chemistry (ABG) and alveolar-arterial gradient (A-a gradient), and (3) ventilatory parameters, in conscious rats. The fentanyl-induced increase in analgesia was minimally affected by a 1.5mg/kg of NLXmi but was attenuated by a 5.0mg/kg dose. Fentanyl decreased arterial blood pH, pO2 and sO2 and increased pCO2 and A-a gradient. These responses were markedly diminished in NLXmi (1.5mg/kg)-pretreated rats. Fentanyl caused ventilatory depression (e.g., decreases in tidal volume and peak inspiratory flow). Pretreatment with NLXmi (1.5mg/kg, i.v.) antagonized the fentanyl decrease in tidal volume but minimally affected the other responses. These findings suggest that (1) the analgesia and ventilatory depression caused by fentanyl involve peripheral μ-ORs and (2) NLXmi prevents the fentanyl effects on ABG by blocking the negative actions of the opioid on tidal volume and A-a gradient. Copyright © 2013 Elsevier B.V. All rights reserved.

Investigations Regarding Anesthesia during Hypovolemic Conditions.

DTIC Science & Technology

1983-09-25

Wilson N, Ngsee J, Turnbull KW, Leighton K: Haemodynamics and plasma vasopressin responses with high-dose fentanyl anaesthesia dur- ing aorto-coronary...on the binding of CO2 to human haemoglobin and , . . 5. Christiansen J, Douglas CG, and Haldane on CO2 transport in the circulating blood. JS: The

Inhibition of protein kinase A and GIRK channel reverses fentanyl-induced respiratory depression.

PubMed

Liang, Xiaonan; Yong, Zheng; Su, Ruibin

2018-06-11

Opioid-induced respiratory depression is a major obstacle to improving the clinical management of moderate to severe chronic pain. Opioids inhibit neuronal activity via various pathways, including calcium channels, adenylyl cyclase, and potassium channels. Currently, the underlying molecular pathway of opioid-induced respiratory depression is only partially understood. This study aimed to investigate the mechanisms of opioid-induced respiratory depression in vivo by examining the effects of different pharmacological agents on fentanyl-induced respiratory depression. Respiratory parameters were detected using whole body plethysmography in conscious rats. We show that pre-treatment with the protein kinase A (PKA) inhibitor H89 reversed the fentanyl-related effects on respiratory rate, inspiratory time, and expiratory time. Pre-treatment with the G protein-gated inwardly rectifying potassium (GIRK) channel blocker Tertiapin-Q dose-dependently reversed the fentanyl-related effects on respiratory rate and inspiratory time. A phosphodiesterase 4 (PDE4) inhibitor and cyclic adenosine monophosphate (cAMP) analogs did not affect fentanyl-induced respiratory depression. These findings suggest that PKA and GIRK may be involved in fentanyl-induced respiratory depression and could represent useful therapeutic targets for the treatment of fentanyl-induced ventilatory depression. Copyright © 2018 Elsevier B.V. All rights reserved.

Misuse of Novel Synthetic Opioids: A Deadly New Trend

PubMed Central

Prekupec, Matthew P.; Mansky, Peter A.; Baumann, Michael H.

2017-01-01

Novel synthetic opioids (NSOs) include various analogs of fentanyl and newly emerging non-fentanyl compounds. Together with illicitly manufactured fentanyl (IMF), these drugs have caused a recent spike in overdose deaths, whereas deaths from prescription opioids have stabilized. NSOs are used as stand-alone products, as adulterants in heroin, or as constituents of counterfeit prescription medications. During 2015 alone, there were 9580 deaths from synthetic opioids other than methadone. Most of these fatalities were associated with IMF rather than diverted pharmaceutical fentanyl. In opioid overdose cases, where the presence of fentanyl analogs was examined, analogs were implicated in 17% of fatalities. Recent data from law enforcement sources show increasing confiscation of acetylfentanyl, butyrylfentanyl, and furanylfentanyl, in addition to non-fentanyl compounds such as U-47700. Since 2013, deaths from NSOs in the United States were 52 for acetylfentanyl, 40 for butyrylfentanyl, 128 for furanylfentanyl, and 46 for U-47700. All of these substances induce a classic opioid toxidrome, which can be reversed with the competitive antagonist naloxone. However, due to the putative high potency of NSOs and their growing prevalence, it is recommended to forgo the 0.4 mg initial dose of naloxone and start with 2 mg. Because NSOs offer enormous profit potential, and there is strong demand for their use, these drugs are being trafficked by organized crime. NSOs present major challenges for medical professionals, law enforcement agencies, and policymakers. Resources must be distributed equitably to enhance harm reduction though public education, medication-assisted therapies, and improved access to naloxone. PMID:28590391

Use of rivastigmine transdermal patch in the treatment of Alzheimer's disease.

PubMed

Winblad, Bengt; Machado, João Carlos

2008-12-01

Cholinesterase inhibitors such as rivastigmine and donepezil exhibit a dose-response relationship, with higher doses of the drugs demonstrating greater efficacy. Transdermal patches provide smooth continuous drug delivery, with the potential to offer efficacious levels of drug exposure while avoiding the peaks and troughs associated with side effects. As a small, lipophilic and hydrophilic molecule, rivastigmine (C14H22N2O2) is chemically well-suited to transdermal delivery. The technology underlying the rivastigmine patch allows it to be discreetly small and thin. The target dose 9.5 mg/24 h rivastigmine patch has a diameter of just 3.5 cm and a surface area of 10 cm2. A large randomized controlled trial has demonstrated that the target dose 9.5 mg/24 h rivastigmine patch provided similar efficacy to the highest rivastigmine capsule doses, yet with three times fewer reports of nausea and vomiting. Thus, the rivastigmine patch enables quick and easy access to high dose efficacy. The skin tolerability profile is good, and the patch has demonstrated excellent adhesion. The apparent success of rivastigmine patch, in terms of clinical utility and patient acceptability, suggests that it may mark the next generation of dementia treatment.

Intrathecal versus IV fentanyl in pediatric cardiac anesthesia.

PubMed

Pirat, Arash; Akpek, Elif; Arslan, Gülnaz

2002-11-01

Systemic large-dose opioids are widely used in pediatric cardiac anesthesia, but there are no randomized, prospective studies regarding the use of intrathecal (IT) opioids for these procedures. In this randomized, prospective study, we compared cardiovascular and neurohumoral responses during IT or IV fentanyl anesthesia for pediatric cardiac surgery. Thirty children aged 6 mo to 6 yr were anesthetized with an IV fentanyl bolus of 10 micro g/kg. This was followed by a fentanyl infusion of 10 micro g. kg(-1). h(-1) (Group IV; n = 10), 2 micro g/kg of IT fentanyl (Group IT; n = 10), or combined IV and IT protocols (Group IV + IT; n = 10). Heart rate, mean arterial blood pressure, additional fentanyl doses, time to first analgesic requirement, COMFORT and Children's Hospital of Eastern Ontario Pain Scale scores, and extubation time were recorded. Blood cortisol, insulin, glucose, and lactate levels were measured presurgery, poststernotomy, during the rewarming phase of cardiopulmonary bypass (CPB), and 6 and 24 h after surgery. The patients' urinary cortisol excretion rates were also measured during the first postoperative day. The findings in all three groups were statistically similar, except for higher blood glucose levels during CPB in Group IT compared with Group IV (P < 0.004). Group IV + IT was the only group in which the increases in heart rate and mean arterial blood pressure from presurgery to poststernotomy were not significant. The 24-h urinary cortisol excretion rates ( micro g. kg(-1). d(-1)) were 61.51 +/- 39, 92.54 +/- 67.55, and 40.15 +/- 29.69 for Groups IV, IT, and IV + IT, respectively (P > 0.05). A single IT injection of fentanyl 2 micro g/kg offers no advantage over systemic fentanyl (10 micro g/kg bolus and 10 micro g. kg(-1). h(-1)) with regard to hemodynamic stability or suppression of stress response. The combination of these two regimens may provide better hemodynamic stability during the pre-CPB period and may be associated with a decreased 24-h urinary cortisol excretion rate. In this prospective, randomized study, we investigated the adequacy of a single intrathecal injection of fentanyl for intraoperative analgesia, compared the effects of IT and IV fentanyl on stress response, and assessed for an additive effect of IT and IV fentanyl administration in pediatric cardiac anesthesia. The results with these three different anesthetic regimens were similar regarding anesthesia depth and level of stress response. However, the combination of IT and IV routes may provide better hemodynamic stability and a less pronounced stress response, as reflected by 24-h urinary cortisol excretion.

Oscillation patterns are enhanced and firing threshold is lowered in medullary respiratory neuron discharges by threshold doses of a μ-opioid receptor agonist

PubMed Central

Mifflin, Steve W.

2017-01-01

μ-Opioid receptors are distributed widely in the brain stem respiratory network, and opioids with selectivity for μ-type receptors slow in vivo respiratory rhythm in lowest effective doses. Several studies have reported μ-opioid receptor effects on the three-phase rhythm of respiratory neurons, but there are until now no reports of opioid effects on oscillatory activity within respiratory discharges. In this study, effects of the μ-opioid receptor agonist fentanyl on spike train discharge properties of several different types of rhythm-modulating medullary respiratory neuron discharges were analyzed. Doses of fentanyl that were just sufficient for prolongation of discharges and slowing of the three-phase respiratory rhythm also produced pronounced enhancement of spike train properties. Oscillation and burst patterns detected by autocorrelation measurements were greatly enhanced, and interspike intervals were prolonged. Spike train properties under control conditions and after fentanyl were uniform within each experiment, but varied considerably between experiments, which might be related to variability in acid-base balance in the brain stem extracellular fluid. Discharge threshold was shifted to more negative levels of membrane potential. The effects on threshold are postulated to result from opioid-mediated disinhibition and postsynaptic enhancement of N-methyl-d- aspartate receptor current. Lowering of firing threshold, enhancement of spike train oscillations and bursts and prolongation of discharges by lowest effective doses of fentanyl could represent compensatory adjustments in the brain stem respiratory network to override opioid blunting of CO2/pH chemosensitivity. PMID:28202437

Oscillation patterns are enhanced and firing threshold is lowered in medullary respiratory neuron discharges by threshold doses of a μ-opioid receptor agonist.

PubMed

Lalley, Peter M; Mifflin, Steve W

2017-05-01

μ-Opioid receptors are distributed widely in the brain stem respiratory network, and opioids with selectivity for μ-type receptors slow in vivo respiratory rhythm in lowest effective doses. Several studies have reported μ-opioid receptor effects on the three-phase rhythm of respiratory neurons, but there are until now no reports of opioid effects on oscillatory activity within respiratory discharges. In this study, effects of the μ-opioid receptor agonist fentanyl on spike train discharge properties of several different types of rhythm-modulating medullary respiratory neuron discharges were analyzed. Doses of fentanyl that were just sufficient for prolongation of discharges and slowing of the three-phase respiratory rhythm also produced pronounced enhancement of spike train properties. Oscillation and burst patterns detected by autocorrelation measurements were greatly enhanced, and interspike intervals were prolonged. Spike train properties under control conditions and after fentanyl were uniform within each experiment, but varied considerably between experiments, which might be related to variability in acid-base balance in the brain stem extracellular fluid. Discharge threshold was shifted to more negative levels of membrane potential. The effects on threshold are postulated to result from opioid-mediated disinhibition and postsynaptic enhancement of N -methyl-d- aspartate receptor current. Lowering of firing threshold, enhancement of spike train oscillations and bursts and prolongation of discharges by lowest effective doses of fentanyl could represent compensatory adjustments in the brain stem respiratory network to override opioid blunting of CO 2 /pH chemosensitivity. Copyright © 2017 the American Physiological Society.

Small-dose hypobaric lidocaine-fentanyl spinal anesthesia for short duration outpatient laparoscopy. I. A randomized comparison with conventional dose hyperbaric lidocaine.

PubMed

Vaghadia, H; McLeod, D H; Mitchell, G W; Merrick, P M; Chilvers, C R

1997-01-01

A randomized, single-blind trial of two spinal anesthetic solutions for outpatient laparoscopy was conducted to compare intraoperative conditions and postoperative recovery. Thirty women (ASA physical status I and II) were assigned to one of two groups. Group I patients received a small-dose hypobaric solution of 1% lidocaine 25 mg made up to 3 mL by the addition of fentanyl 25 micrograms. Group II patients received a conventional-dose hyperbaric solution of 5% lidocaine 75 mg (in 7.5% dextrose) made up to 3 mL by the addition of 1.5 mL 10% dextrose. All patients received 500 mL of crystalloid preloading. Spinal anesthesia was performed at L2-3 or L3-4 with a 27-gauge Quincke point needle. Surgery commenced when the level of sensory anesthesia reached T-6. Intraoperative hypotension requiring treatment with ephedrine occurred in 54% of Group II patients but not in any Group I patients. Median (range) time for full motor recovery was 50 (0-95) min in Group I patients compared to 90 (50-120) min in Group II patients (P = 0.0005). Sensory recovery also occurred faster in Group I patients (100 +/- 22 min) compared with Group II patients (140 +/- 27 min, P = 0.0001). Postoperative headache occurred in 38% of all patients and 70% of these were postural in nature. Oral analgesia was the only treatment required. Spinal anesthesia did not result in a significant incidence of postoperative backache. On follow-up, 96% said they found spinal needle insertion acceptable, 93% found surgery comfortable, and 90% said they would request spinal anesthesia for laparoscopy in future. Overall, this study found spinal anesthesia for outpatient laparoscopy to have high patient acceptance and a comparable complication rate to other studies. The small-dose hypobaric lidocaine-fentanyl technique has advantages over conventional-dose hyperbaric lidocaine of no hypotension and faster recovery.

Fentanyl Law Enforcement Submissions and Increases in Synthetic Opioid-Involved Overdose Deaths - 27 States, 2013-2014.

PubMed

Gladden, R Matthew; Martinez, Pedro; Seth, Puja

2016-08-26

In March and October 2015, the Drug Enforcement Administration (DEA) and CDC, respectively, issued nationwide alerts identifying illicitly manufactured fentanyl (IMF) as a threat to public health and safety (1,2). IMF is unlawfully produced fentanyl, obtained through illicit drug markets, includes fentanyl analogs, and is commonly mixed with or sold as heroin (1,3,4). Starting in 2013, the production and distribution of IMF increased to unprecedented levels, fueled by increases in the global supply, processing, and distribution of fentanyl and fentanyl-precursor chemicals by criminal organizations (3). Fentanyl is a synthetic opioid 50-100 times more potent than morphine (2).* Multiple states have reported increases in fentanyl-involved overdose (poisoning) deaths (fentanyl deaths) (2). This report examined the number of drug products obtained by law enforcement that tested positive for fentanyl (fentanyl submissions) and synthetic opioid-involved deaths other than methadone (synthetic opioid deaths), which include fentanyl deaths and deaths involving other synthetic opioids (e.g., tramadol). Fentanyl deaths are not reported separately in national data. Analyses also were conducted on data from 27 states(†) with consistent death certificate reporting of the drugs involved in overdoses. Nationally, the number of fentanyl submissions and synthetic opioid deaths increased by 426% and 79%, respectively, during 2013-2014; among the 27 analyzed states, fentanyl submission increases were strongly correlated with increases in synthetic opioid deaths. Changes in fentanyl submissions and synthetic opioid deaths were not correlated with changes in fentanyl prescribing rates, and increases in fentanyl submissions and synthetic opioid deaths were primarily concentrated in eight states (high-burden states). Reports from six of the eight high-burden states indicated that fentanyl-involved overdose deaths were primarily driving increases in synthetic opioid deaths. Increases in synthetic opioid deaths among high-burden states disproportionately involved persons aged 15-44 years and males, a pattern consistent with previously documented IMF-involved deaths (5). These findings, combined with the approximate doubling in fentanyl submissions during 2014-2015 (from 5,343 to 13,882) (6), underscore the urgent need for a collaborative public health and law enforcement response.

Evaluation of Fentanyl Disposition and Effects in Newborn Piglets as an Experimental Model for Human Neonates

PubMed Central

Valls-i-Soler, Adolfo; Encinas, Esther; Lukas, John C.; Vozmediano, Valvanera; Suárez, Elena

2014-01-01

Background Fentanyl is widely used off-label in NICU. Our aim was to investigate its cerebral, cardiovascular and pulmonary effects as well as pharmacokinetics in an experimental model for neonates. Methods Fentanyl (5 µg/kg bolus immediately followed by a 90 minute infusion of 3 µg/kg/h) was administered to six mechanically ventilated newborn piglets. Cardiovascular, ventilation, pulmonary and oxygenation indexes as well as brain activity were monitored from T = 0 up to the end of experiments (T = 225–300 min). Also plasma samples for quantification of fentanyl were drawn. Results A “reliable degree of sedation” was observed up to T = 210–240 min, consistent with the selected dosing regimen and the observed fentanyl plasma levels. Unlike cardiovascular parameters, which were unmodified except for an increasing trend in heart rate, some of the ventilation and oxygenation indexes as well as brain activity were significantly altered. The pulmonary and brain effects of fentanyl were mostly recovered from T = 210 min to the end of experiment. Conclusion The newborn piglet was shown to be a suitable experimental model for studying fentanyl disposition as well as respiratory and cardiovascular effects in human neonates. Therefore, it could be extremely useful for further investigating the drug behaviour under pathophysiological conditions. PMID:24595018

Supraspinally-administered agmatine attenuates the development of oral fentanyl self-administration

PubMed Central

Wade, Carrie L.; Schuster, Daniel J.; Domingo, Kristine M.; Kitto, Kelley F.; Fairbanks, Carolyn A.

2009-01-01

The decarboxylation product of arginine, agmatine, has effectively reduced or prevented opioid-induced tolerance and dependence when given either systemically (intraperitoneally or subcutaneously) or centrally (intrathecally or intracerebroventricularly). Systemically administered agmatine also reduces the escalation phase of intravenous fentanyl self-administration in rats. The present study assessed whether centrally (intracerebroventricular, i.c.v.) delivered agmatine could prevent the development of fentanyl self-administration in mice. Mice were trained to respond under a fixed-ratio 1 (FR1) schedule for either fentanyl (0.7 μg/70 μl, p.o.) or food reinforcement. Agmatine (10 nmol/5 μl), injected i.c.v. 12-14h before the first session and every other evening (12-14h before session) for 2 weeks, completely attenuated oral fentanyl self-administration (but not food-maintained responding) compared to saline-injected controls. When agmatine was administered after fentanyl self-administration had been established (day 8) it had no attenuating effects on bar pressing. This dose of agmatine does not decrease locomotor activity as assessed by rotarod. The present findings significantly extend the previous observation that agmatine prevents opioid-maintained behavior to a chronic model of oral fentanyl self-administration as well as identifying a supraspinal site of action for agmatine inhibition of drug addiction. PMID:18495108

Factors predisposing to coma and delirium: fentanyl and midazolam exposure; CYP3A5, ABCB1, and ABCG2 genetic polymorphisms; and inflammatory factors.

PubMed

Skrobik, Yoanna; Leger, Caroline; Cossette, Mariève; Michaud, Veronique; Turgeon, Jacques

2013-04-01

Delirium and sedative-induced coma are described as incremental manifestations of cerebral dysfunction. Both may be associated with sedative or opiate doses and pharmacokinetic or pharmacogenetic variables, such as drug plasma levels (exposure), drug metabolism, and/or their transport across the blood-brain barrier. To compare biological and drug treatment characteristics in patients with coma and/or delirium while in the ICU. In 99 patients receiving IV fentanyl, midazolam, or both, we evaluated drug doses, covariates likely to influence drug effects (age, body mass index, and renal and hepatic dysfunction); delirium risk factors; concomitant administration of CYP3A and P-glycoprotein substrates/inhibitors; ABCB1, ABCG2, and CYP3A5 genetic polymorphisms; and fentanyl and midazolam plasma levels. Delirium and coma were evaluated daily. In patients with only coma (n=15), only delirium (n=7), and neither ever (n=14), we measured plasma levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-1RA, IL-6, IL-8, IL-10, IL-17,macrophage inflammatory protein-1β, and monocyte chemotactic protein-1. Time to first coma was associated with fentanyl and midazolam doses (p=0.03 and p=0.01, respectively). The number of days in coma was associated with the number of days of coadministration of CYP3A inhibitors (r=0.30; p=0.006). Plasma levels of fentanyl were higher in patients with clinical coma (3.7±4.7 vs. 2.0±1.8 ng/mL, p=0.0001) as were midazolam plasma levels (1050±2232 vs. 168±249 ng/mL, p=0.0001). Delirium occurrence was unrelated to midazolam administration, cumulative doses, or serum levels. Days with delirium were associated with days of coadministration of P-glycoprotein inhibitor (r=0.35; p=0.0004). Delirious patients had higher levels of the inflammatory mediator IL-6 than comatose patients (129.3 vs. 35.0 pg/mL, p=0.05). Coma is associated with fentanyl and midazolam exposure; delirium is unrelated to midazolam and may be linked to inflammatory status. These data suggest that iatrogenic coma and delirium are not mechanistically linked.

Fatal Fentanyl: One Pill Can Kill.

PubMed

Sutter, Mark E; Gerona, Roy R; Davis, M Thais; Roche, Bailey M; Colby, Daniel K; Chenoweth, James A; Adams, Axel J; Owen, Kelly P; Ford, Jonathan B; Black, Hugh B; Albertson, Timothy E

2017-01-01

The current national opioid epidemic is a public health emergency. We have identified an outbreak of exaggerated opioid toxicity caused by fentanyl adulterated tablets purchased on the street as hydrocodone/acetaminophen. Over an 8-day period in late March 2016, a total of 18 patients presented to our institution with exaggerated opioid toxicity. The patients provided a similar history: ingesting their "normal dose" of hydrocodone/acetaminophen tablets but with more pronounced symptoms. Toxicology testing and analysis was performed on serum, urine, and surrendered pills. One of the 18 patients died in hospital. Five patients underwent cardiopulmonary resuscitation, one required extracorporeal life support, three required intubation, and two received bag-valve-mask ventilation. One patient had recurrence of toxicity after 8 hours after naloxone discontinuation. Seventeen of 18 patients required boluses of naloxone, and four required prolonged naloxone infusions (26-39 hours). All 18 patients tested positive for fentanyl in the serum. Quantitative assays conducted in 13 of the sera revealed fentanyl concentrations of 7.9 to 162 ng/mL (mean = 52.9 ng/mL). Pill analysis revealed fentanyl amounts of 600-6,900 μg/pill. The pills are virtually indistinguishable from authentic hydrocodone/acetaminophen tablets and are similar in weight. To date, our county has reported 56 cases of fentanyl opioid toxicity, with 15 fatalities. In our institution, the outbreak has stressed the capabilities and resources of the emergency department and intensive care units. A serious outbreak of exaggerated opioid toxicity caused by fentanyl-adulterated tablets purchased on the street as hydrocodone/acetaminophen is under way in California. These patients required higher dosing and prolonged infusions of naloxone. Additionally, observation periods off naloxone were extended due to delayed, recurrent toxicity. The outbreak has serious ramifications for public health and safety, law enforcement, and healthcare facilities and resources. © 2016 by the Society for Academic Emergency Medicine.

A Comparison of Fentanyl and Flurbiprofen Axetil on Serum VEGF-C, TNF-α, and IL-1ß Concentrations in Women Undergoing Surgery for Breast Cancer.

PubMed

Wen, Yiyun; Wang, Mingde; Yang, Jinfeng; Wang, Yichun; Sun, Huiping; Zhao, Jianghong; Liu, Weizhen; Zhou, Zhengyu; Deng, Hongwu; Castillo-Pedraza, Catalina; Zhang, Yi; Candiotti, Keith A

2015-07-01

Vascular endothelial growth factor-C (VEGF-C), tumor necrosis factor-α (TNF-α), and interleukin-1ß(IL-1ß) have been shown to be associated with the recurrence and metastasis of breast cancer after surgery. This study tested the hypothesis that patients undergoing surgery for breast cancer, who received postoperative analgesia with flurbiprofen axetil combined with small doses of fentanyl (FA), exhibited reduced levels of VEGF-C, TNF-α, and IL-1ß compared with those patients receiving fentanyl alone (F). Forty-women with primary breast cancer undergoing a modified radical mastectomy were randomized to receive postoperative analgesia with flurbiprofen axetil combined with fentanyl or fentanyl alone. Venous blood was sampled before anesthesia, at the end of surgery, and at 48 hours after surgery, and the serum was analyzed. The primary endpoint was changes in the VEGF-C concentrations in serum. Group FA patients reported similar analgesic effects as group F patients at 2, 24, and 48 hours. At 48 hours, mean postoperative concentrations of VEGF-C in group F patients were higher than in group FA patients, 730.9 versus. 354.1 pg/mL (P = 0.003), respectively. The mean postoperative concentrations of TNF-α in group F patients were also higher compared with group FA patients 27.1 vs. 15.8 pg/mL (P = 0.005). Finally, the mean postoperative concentrations of IL-1ß in group F were also significantly higher than in group FA 497.5 vs. 197.7 pg/mL (P = 0.001). In patients undergoing a mastectomy, postoperative analgesia with flurbiprofen axetil, combined with fentanyl, were associated with decreases in serum concentrations of VEGF-C, TNF-α, and IL-1ß compared with patients receiving doses of only fentanyl. © 2014 World Institute of Pain.

Effect of fentanyl target-controlled infusions on isoflurane minimum anaesthetic concentration and cardiovascular function in red-tailed hawks (Buteo jamaicensis).

PubMed

Pavez, Juan C; Hawkins, Michelle G; Pascoe, Peter J; Knych, Heather K DiMaio; Kass, Philip H

2011-07-01

To determine the impact of three different target plasma concentrations of fentanyl on the minimum anaesthetic concentration (MAC) for isoflurane in the red-tailed hawk and the effects on the haemodynamic profile. Experimental study. Six healthy adult red-tailed hawks (Buteo jamaicensis) of unknown sex with body weights (mean ± SD) of 1.21 ± 0.15 kg. This study was undertaken in two phases. In the first phase anaesthesia was induced with isoflurane in oxygen via facemask and maintained with isoflurane delivered in oxygen via a Bain circuit. Following instrumentation baseline determination of the MAC for isoflurane was made for each animal using the bracketing method and a supramaximal electrical stimulus. End-tidal isoflurane concentration (E'Iso) was then set at 0.75 × MAC and after an appropriate equilibration period a bolus of fentanyl (20 μg kg(-1)) was administered intravenously (IV) in order to determine the pharmacokinetics of fentanyl in the isoflurane-anaesthetized red-tailed hawk. During the second phase anaesthesia was induced in a similar manner and E'Iso was set at 0.75 × MAC for each individual. Fentanyl was infused IV to achieve target plasma concentrations between 8 and 32 ng mL(-1). At each fentanyl plasma concentration, the MAC for isoflurane and cardiovascular variables were determined. Data were analyzed by use of repeated-measures anova. Mean ± SD fentanyl plasma concentrations and isoflurane MACs were 0 ± 0, 8.51 ± 4, 14.85 ± 4.82 and 29.25 ± 11.52 ng mL(-1), and 2.05 ± 0.45%, 1.42 ± 0.53%, 1.14 ± 0.31% and 0.93 ± 0.32% for the target concentrations of 0, 8, 16 and 32 ng mL(-1), respectively. At these concentrations fentanyl significantly (p = 0.0016) decreased isoflurane MAC by 31%, 44% and 55%, respectively. Dose had no significant effect on heart rate, systolic, diastolic or mean arterial blood pressure. Fentanyl produced a dose-related decrease of isoflurane MAC with minimal effects on measured cardiovascular parameters in red-tailed hawks. © 2011 The Authors. Veterinary Anaesthesia and Analgesia. © 2011 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.

Inhaled fentanyl citrate improves exercise endurance during high-intensity constant work rate cycle exercise in chronic obstructive pulmonary disease.

PubMed

Jensen, Dennis; Alsuhail, Abdullah; Viola, Raymond; Dudgeon, Deborah J; Webb, Katherine A; O'Donnell, Denis E

2012-04-01

Activity limitation and dyspnea are the dominant symptoms of chronic obstructive pulmonary disease (COPD). Traditionally, efforts to alleviate these symptoms have focused on improving ventilatory mechanics, reducing ventilatory demand, or both of these in combination. Nevertheless, many patients with COPD remain incapacitated by dyspnea and exercise intolerance despite optimal therapy. To determine the effect of single-dose inhalation of nebulized fentanyl citrate (a μ-opioid agonist drug) on exercise tolerance and dyspnea in COPD. In a randomized, double-blind, placebo-controlled, crossover study, 12 stable patients with COPD (mean ± standard error of the mean post-β(2)-agonist forced expiratory volume in one second [FEV(1)] and FEV(1) to forced vital capacity ratio of 69% ± 4% predicted and 49% ± 3%, respectively) received either nebulized fentanyl citrate (50 mcg) or placebo on two separate days. After each treatment, patients performed pulmonary function tests and a symptom-limited constant work rate cycle exercise test at 75% of their maximum incremental work rate. There were no significant postdose differences in spirometric parameters or plethysmographic lung volumes. Neither the intensity nor the unpleasantness of perceived dyspnea was, on average, significantly different at isotime (5.0 ± 0.6 minutes) or at peak exercise after treatment with fentanyl citrate vs. placebo. Compared with placebo, fentanyl citrate was associated with 1) increased exercise endurance time by 1.30 ± 0.43 minutes or 25% ± 8% (P=0.01); 2) small but consistent increases in dynamic inspiratory capacity by ∼0.10 L at isotime and at peak exercise (both P≤0.03); and 3) no concomitant change in ventilatory demand, breathing pattern, pulmonary gas exchange, and/or cardiometabolic function during exercise. The mean rate of increase in dyspnea intensity (1.2 ± 0.3 vs. 2.9 ± 0.8 Borg units/minute, P=0.03) and unpleasantness ratings (0.5 ± 0.2 vs. 2.9 ± 1.3 Borg units/minute, P=0.06) between isotime and peak exercise was less after treatment with fentanyl citrate vs. placebo. Single-dose inhalation of fentanyl citrate was associated with significant and potentially clinically important improvements in exercise tolerance in COPD. These improvements were accompanied by a delay in the onset of intolerable dyspnea during exercise near the limits of tolerance. Copyright © 2012 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Functionally Selective Signaling for Morphine and Fentanyl Antinociception and Tolerance Mediated by the Rat Periaqueductal Gray

PubMed Central

Morgan, Michael M.; Reid, Rachel A.; Saville, Kimber A.

2014-01-01

Functionally selective signaling appears to contribute to the variability in mechanisms that underlie tolerance to the antinociceptive effects of opioids. The present study tested this hypothesis by examining the contribution of G protein-coupled receptor kinase (GRK)/Protein kinase C (PKC) and C-Jun N-terminal kinase (JNK) activation on both the expression and development of tolerance to morphine and fentanyl microinjected into the ventrolateral periaqueductal gray of the rat. Microinjection of morphine or fentanyl into the periaqueductal gray produced a dose-dependent increase in hot plate latency. Microinjection of the non-specific GRK/PKC inhibitor Ro 32-0432 into the periaqueductal gray to block mu-opioid receptor phosphorylation enhanced the antinociceptive effect of morphine but had no effect on fentanyl antinociception. Microinjection of the JNK inhibitor SP600125 had no effect on morphine or fentanyl antinociception, but blocked the expression of tolerance to repeated morphine microinjections. In contrast, a microinjection of Ro 32-0432 blocked the expression of fentanyl, but not morphine tolerance. Repeated microinjections of Ro 32-0432 blocked the development of morphine tolerance and inhibited fentanyl antinociception whether rats were tolerant or not. Repeated microinjections of SP600125 into the periaqueductal gray blocked the development of tolerance to both morphine and fentanyl microinjections. These data demonstrate that the signaling molecules that contribute to tolerance vary depending on the opioid and methodology used to assess tolerance (expression vs. development of tolerance). This signaling difference is especially clear for the expression of tolerance in which JNK contributes to morphine tolerance and GRK/PKC contributes to fentanyl tolerance. PMID:25503060

High-dose 8% capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy: single-center experience.

PubMed

Filipczak-Bryniarska, Iwona; Krzyzewski, Roger M; Kucharz, Jakub; Michalowska-Kaczmarczyk, Anna; Kleja, Justyna; Woron, Jarosław; Strzepek, Katarzyna; Kazior, Lucyna; Wordliczek, Jerzy; Grodzicki, Tomasz; Krzemieniecki, Krzysztof

2017-08-17

High-dose capsaicin patch is effective in treatment of neuropathic pain in HIV-associated neuropathy and diabetic neuropathy. There are no studies assessing effectiveness of high-dose capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy. We sought to determine the effectiveness of treatment of pain associated with chemotherapy-induced peripheral neuropathy with high-dose capsaicin patch. Our study group consisted of 18 patients with clinically confirmed oxaliplatin-induced neuropathy. Baseline characteristic including underling disease, received cumulative dose of neurotoxic agent, neuropathic symptoms, prior treatment and initial pain level were recorded. Pain was evaluated with Numeric Rating Scale prior to treatment with high-dose capsaicin and after 1.8 day and after 8 and 12 weeks after introducing treatment. Patients were divided into two groups accordingly to the amount of neurotoxic agent that caused neuropathy (high sensitivity and low sensitivity group). Most frequent symptoms of chemotherapy-induced neuropathy were: pain (88.89%), paresthesis (100%), sock and gloves sensation (100%) and hypoesthesis (100%). Initial pain level was 7.45 ± 1.14. Mean cumulative dose of oxaliplatin after which patients developed symptoms was 648.07 mg/m 2 . Mean pain level after 12 weeks of treatment was 0.20 ± 0.41. When examined according to high and low sensitivity to neurotoxic agent patients with low sensitivity had higher pain reduction, especially after 8 days after introducing treatment (69.55 ± 12.09 vs. 49.40 ± 20.34%; p = 0.02) and after 12 weeks (96.96 ± 5.56 vs. 83.93 ± 18.59%; p = 0.04). High-dose capsaicin patch is an effective treatment for pain associated with chemotherapy-induced neuropathy in patients treated with oxaliplatin. Patients with lower sensitivity to neurotoxic agents have better response to treatment and pain reduction.

The fentanyl HCl patient-controlled transdermal system (PCTS): an alternative to intravenous patient-controlled analgesia in the postoperative setting.

PubMed

Sinatra, Raymond

2005-01-01

Inadequate pain control in the postoperative period not only contributes to patient discomfort, but also causes physiological changes that may result in increased risk of myocardial ischaemia, deep vein thrombosis and pulmonary embolism. These events complicate postoperative recovery and may lead to longer hospital stays as well as increased healthcare costs. Patient-controlled analgesia (PCA) has emerged as an effective way for patients to manage their pain, allowing self-administration of small doses of analgesics to maintain a certain level of pain control. PCA is most commonly delivered via an intravenous (IV) or epidural route, and while patient satisfaction is higher with PCA than with conventional methods of analgesic administration, the invasiveness, costs and risk of errors associated with currently available modalities may limit their utility. These systems also require significant healthcare resources, as nurses must manually program the pumps to deliver the correct amount of medication. Several new PCA modalities are being developed to address these limitations. These systems deliver drug through a variety of routes, including nasal transmucosal and transdermal. Most notably, a self-contained, credit card-sized, transdermal PCA system is currently in the final stages of development. The fentanyl HCl patient-controlled transdermal system (PCTS; IONSYS, Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ) uses an imperceptible, low-intensity direct current to transfer fentanyl on demand across the skin into the systemic circulation. This compact system is patient-activated, can be applied to the patient's upper arm or chest, and is designed to manage moderate-to-severe pain requiring opioid analgesia. The system delivers a preprogrammed amount of fentanyl HCI over 10 minutes, for a total of 80 doses, or for 24 hours, whichever occurs first. The on-demand dosing and pharmacokinetics of this system differentiate it from the passive transdermal formulation of fentanyl designed for the management of chronic pain. Clinical studies have shown that the fentanyl HCl PCTS is effective in the management of acute postoperative pain. These studies have also demonstrated that the system is safe and well tolerated by patients.

Effects of fentanyl on pain and motor behaviors following a collagenase-induced intracerebral hemorrhage in rats

PubMed Central

Saine, Laurence; Hélie, Pierre; Vachon, Pascal

2016-01-01

Purpose Intracerebral hemorrhage (IH) and cephalalgia are common consequences of traumatic brain injury. One of the primary obstacles for patient recovery is the paucity of treatments to support an appropriate analgesic protocol. The present study aimed to assess pain and motor behaviors following different doses of fentanyl on a rat model of IH. Methods Twenty-one male Sprague Dawley rats underwent a stereotaxic surgery to produce a collagenase-induced IH in the right caudoputamen nucleus. The control group (n=6) received saline subcutaneously (SC), and experimental groups received either 5 (n=6), 10 (n=6), or 20 (n=3) µg/kg of fentanyl SC, 2 hours following surgery and on 2 subsequent days. Only 3 animals received 20 µg/kg because this dose caused catalepsy for 15–20 minutes following the injection. The rat grimace scale, a neurological examination, balance beam test, and rotarod test were performed for 5 consecutive days postoperatively to evaluate pain and motor performance. At the end of the experimentation, the brains were evaluated to determine hematoma volume, and the number of reactive astrocytes and necrotic neurons. Results When compared to controls, the grimace scale showed that 5 µg/kg fentanyl significantly alleviated pain on day 2 only (P<0.01) and that 10 µg/kg alleviated pain on days 1 (P<0.01), 2 (P<0.001), and 3 (P<0.01). For the rotarod test, only the 10 µg/kg group showed significant decreases in performance on days 5 (P<0.05) and 6 (P<0.02). The neurological examination was not significantly different between the groups, but only the hopping test showed poor recuperation for the 5 and 10 µg/kg fentanyl group when compared to saline (P<0.01). No differences were found between the groups for the balance beam test, the histopathological results. Conclusion Fentanyl, at a dose of 10 µg/kg SC, provides substantial analgesia following a collagenase-induced IH in rats; however, it can alter motor performance following analgesic treatments. PMID:27895509

Optimal dose of rocuronium bromide undergoing adenotonsillectomy under 5% sevoflurane with fentanyl.

PubMed

Huh, Hyub; Park, Jeong Jun; Kim, Ji Yeong; Kim, Tae Hoon; Yoon, Seung Zhoo; Shin, Hye Won; Lee, Hye-Won; Lim, Hye-Ja; Cho, Jang Eun

2017-10-01

Adenotonsillectomy is a short surgical procedure under general anaesthesia in children. An ideal muscle relaxant for adenotonsillectomy would create an intense neuromuscular block while having a quick recovery time without postoperative morbidity. We compared the effect of different doses of rocuronium for the tracheal intubation in children under 5% sevoflurane and fentanyl. 75 children (aged 3-10 years, ASA I) scheduled for adenotonsillectomy were enrolled. Anaesthesia was induced with propofol 2.5 mg/kg, followed by fentanyl 2 μg/kg. After mask ventilation with 5 vol% sevoflurane in 100% oxygen for 2 min, 2 ml of study drug was administered intravenously, i.e., either normal saline (S Group) or one of two doses (0.15 or 0.3 mg/kg) of rocuronium. We assessed conditions during tracheal intubation and also recorded the surgical condition, the time from discontinuation of sevoflurane to extubation and PAED scale, pain scores in PACU. Rocuronium groups (96% and 100%, respectively; P < 0.01) showed statistically superior clinically acceptable intubating conditions than the saline group (72%). The 0.3 mg/kg rocuronium (80%) treatment clearly resulted in excellent intubating conditions compared with the 0.15 mg/kg group (44%; p = 0.028). There was no significant difference in the time to extubation and surgical condition, and in the postoperative measures of emergence delirium, pain, and recovery time among the three groups. A dose of 0.3 mg/kg rocuronium may provide optimal intubating conditions without delayed recovery in 5% sevoflurane anaesthesia with fentanyl in children undergoing adenotonsillectomy. NCT02467595. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparison of Propofol, Propofol-Remifentanil, and Propofol-Fentanyl Administrations with Each Other Used for the Sedation of Patients to Undergo ERCP

PubMed Central

Haytural, Candan; Aydınlı, Bahar; Demir, Berna; Bozkurt, Elif; Parlak, Erkan; Dişibeyaz, Selçuk; Saraç, Ahmet; Özgök, Ayşegül; Kazancı, Dilek

2015-01-01

Introduction. Using single anesthetic agent in endoscopic retrograde cholangiopancreatography (ERCP) may lead to inadequate analgesia and sedation. To achieve the adequate analgesia and sedation the single anesthetic agent doses must be increased which causes undesirable side effects. For avoiding high doses of single anesthetic agent nowadays combination with sedative agents is mostly a choice for analgesia and sedation for ERCP. Aim. The aim of this study is to investigate the effects of propofol alone, propofol + remifentanil, and propofol + fentanyl combinations on the total dose of propofol to be administered during ERCP and on the pain scores after the process. Materials and Method. This randomized study was performed with 90 patients (ASA I-II-III) ranging between 18 and 70 years of age who underwent sedation/analgesia for elective ERCP. The patients were administered only propofol (1.5 mg/kg) in Group Ι, remifentanil (0.05 μg/kg) + propofol (1.5 mg/kg) combination in Group II, and fentanyl (1 μg/kg) + propofol (1.5 mg/kg) combination in Group III. All the patients' sedation levels were assessed with the Ramsey Sedation Scale (RSS). Their recovery was assessed with the Aldrete and Numerical Rating Scale Score (NRS) at 10 min intervals. Results. The total doses of propofol administered to the patients in the three groups in this study were as follows: 375 mg in Group I, 150 mg in Group II, and 245 mg in Group III. Conclusion. It was observed that, in the patients undergoing ERCP, administration of propofol in combination with an opioid provided effective and reliable sedation, reduced the total dose of propofol, increased the practitioner satisfaction, decreased the pain level, and provided hemodynamic stability compared to the administration of propofol alone. PMID:26576424

Chemical anesthesia of Northern sea otters (Enhydra lutris): Results of past field studies

USGS Publications Warehouse

Monson, Daniel H.; McCormick, C.; Ballachey, Brenda E.

2001-01-01

Between 1987 and 1997, we chemically immobilized 597 wild sea otters (Enhydra lutris) in Alaska for the collection of biological samples or for surgical instrumentation. One drug-related sea otter fatality occurred during this time. Fentanyl in combination with diazepam produced consistent, smooth inductions with minimal need for supplemental anesthetics during procedures lasting 30-40 min. Antagonism with naltrexone or naloxone was rapid and complete, although we observed narcotic recycling in sea otters treated with naloxone. For surgical procedures, we recommend a fentanyl target dose of 0.33 mg/kg of body mass and diazepam at 0.11 mg/kg. For nonsurgical biological sample collection procedures, we recommend fentanyl at 0.22 mg/kg and diazepam at 0.07 mg/kg. We advise the use of the opioid antagonist naltrexone at a ratio of 2:1 to the total fentanyl administered during processing.

Synergism between fentanyl and tramadol in tonic inflammatory pain: the orofacial formalin test.

PubMed

Miranda, Hugo F; Noriega, Viviana; Zepeda, Ramiro J; Sierralta, Fernando; Prieto, Juan C

2012-06-01

Opioids have been used for long time to management of pain, the coadministration of two opioids may induce synergism. The present study was conducted to determine the antinociceptive interaction between the dual mechanism of action of tramadol compared to the main of fentanyl antinociception in the orofacial formalin which represents a model of persistent cutaneous nociception in the region innervated by the trigeminal nerve. The i.p. administration of tramadol and fentanyl induced a dose-dependent antinociception with an ED(50) of 2.97 ± 0.32 mg/kg for phase I and 1.79 ± 0.30 mg/kg for phase II and 0.062 ± 0.0040 mg/kg in phase I and 0.041 ± 0.0039 mg/kg in phase II, respectively. The coadministration of fentanyl with tramadol induced synergism in both phases of the test with an interaction index of 0.343 and 0.163 for phase I and phase II, respectively. This finding could be explained by the more complex pharmacology of tramadol compared to fentanyl.

Trans-Dermal Fentanyl Patches are a Cost-Effective Method of Long-Term Analgesic Delivery Following Corneal Exposure to Sulfur Mustard Vapor

DTIC Science & Technology

2012-01-01

SM) exposure in rabbits involves delivery of the opioid receptor agonist buprenorphine using subcutaneously implanted osmotic pumps. The...significantly lower than the costs of purchasing and loading an osmotic pump with buprenorphine . Pump implantation took approximately 10 min per...general distress than did the buprenorphine cohort. The elevated behavioral changes exhibited by the rabbits with implanted pumps were likely a

The Behavioral Effects of a Mixed Efficacy Antinociceptive Peptide, VRP26, Following Chronic Administration in Mice

PubMed Central

Anand, Jessica P.; Boyer, Brett T.; Mosberg, Henry I.; Jutkiewicz, Emily M.

2016-01-01

Rationale VRP26 displays mu opioid receptor agonist and delta opioid receptor antagonist activity in vitro, a pharmacological profile purported to produce reduced tolerance, dependence, and rewarding effects. We hypothesized that VRP26 would display reduced adverse effects after chronic administration as compared with the traditional opioid analgesic fentanyl. Objective To explore the development of tolerance, dependence and conditioned place preference of VRP26 as compared with the traditional opioid analgesic fentanyl. Methods The antinociceptive effects of VRP26 and fentanyl were assessed using the mouse warm water tail withdrawal (WWTW) assay. Measurement of antinociceptive tolerance and physical dependence occurred after seven days of continuous administration of either fentanyl (0.3 mg/kg/day) or VRP26 (10 mg/kg/day); tolerance was measured by a shift in the antinociceptive dose response curve in the WWTW assay. Physical dependence was determined by observation of withdrawal symptoms after precipitated withdrawal. Rewarding effects were measured by the ability of VRP26 or fentanyl to produce conditioned place preference. Results Fentanyl produced significant tolerance and dependence, as well as significant conditioned place preference. VRP26 produced neither tolerance nor physical dependence, nor did it produce significant conditioned place preference. Conclusions These results suggest that chronic treatment with VRP26 may produce less tolerance or physical dependence than chronic treatment with clinically available mu opioid analgesics such as fentanyl. Additionally, VRP26 produces less rewarding effects than fentanyl. This desirable in vivo profile may be due to the mixed efficacy nature of VRP26 and could provide the framework for safer opioid analgesics. PMID:27117141

Trends in opioid use and dosing among socio-economically disadvantaged patients

PubMed Central

Gomes, Tara; Juurlink, David N; Dhalla, Irfan A; Mailis-Gagnon, Angela; Paterson, J Michael; Mamdani, Muhammad M

2011-01-01

Background Opioid therapy for patients with chronic nonmalignant pain remains controversial, primarily because of safety concerns and the potential for abuse. The objective of this study was to examine trends in opioid utilization for nonmalignant pain among recipients of social assistance and to explore the relation between dose of analgesic and mortality. Methods Using a cross-sectional study design, we characterized annual trends in prescriptions for and daily dose of opioid analgesics between 2003 and 2008 for beneficiaries (aged 15 to 64 years) of Ontario’s public drug plan. We defined moderate, high and very high dose thresholds as daily doses of up to 200, 201 to 400, and more than 400 mg oral morphine (or equivalent), respectively. In an exploratory cohort study, we followed, over a 2-year period, patients who received at least one prescription for an opioid in 2004 to investigate the relation between opioid dose and opioid-related mortality. Results Over the study period, opioid prescribing rates rose by 16.2%, and 180 974 individuals received nearly 1.5 million opioid prescriptions in 2008. Also by 2008, the daily dose dispensed exceeded 200 mg morphine equivalent for almost a third (32.6%) of recipients of long-acting oxycodone but only 20.3% of those treated with fentanyl or other long-acting opioids. Among patients for whom high or very high doses of opioids were dispensed in 2004, 19.3% of deaths during the subsequent 2 years were opioid-related, occurring at a median age of 46 years. Two-year opioid-related mortality rates were 1.63 per 1000 population (95% confidence interval [CI] 1.42–1.85) among people with moderate-dose prescriptions, 7.92 per 1000 population (95% CI 5.25–11.49) among those with high-dose prescriptions, and 9.94 per 1000 population (95% CI 2.78–25.12) among those with very-high-dose prescriptions. Interpretation Among socio-economically disadvantaged patients in Ontario, the use and dose of opioids for nonmalignant pain has increased substantially, driven primarily by the use of long-acting oxycodone and, to a lesser extent, fentanyl. The findings of our exploratory study suggested a strong association between opioid-related mortality and the dose of opioid dispensed. PMID:22046214

Effect of ketamine versus thiopental sodium anesthetic induction and a small dose of fentanyl on emergence agitation after sevoflurane anesthesia in children undergoing brief ophthalmic surgery.

PubMed

Jung, Hyun Ju; Kim, Jong Bun; Im, Kyong Shil; Oh, Seung Hwa; Lee, Jae Myeong

2010-02-01

Emergence agitation (EA) in children after sevoflurane anesthesia is common. The purpose of this study was to compare the incidences of EA between ketamine and thiopental sodium induction in children underwent sevoflurane anesthesia. We also evaluated if a small dose of fentanyl could reduce the incidence of EA. The patients who were scheduled for strabismus or entropion surgery were divided into 4 groups. The patients in Groups 1 and 2 were induced anesthesia with ketamine 1.5 mg/kg; those in Groups 3 and 4 were induced with thiopental sodium 5 mg/kg. The patients in Groups 1 and 3 received an injection of fentanyl 1.5 microg/kg, whereas the patients in Groups 2 and 4 received IV saline of the same volume. Anesthesia was maintained with sevoflurane. The recovery characteristics and EA in recovery room were assessed. The incidence of EA was significantly higher in Groups 2 and 4 and there was no difference between Groups 2 and 4. Group 2 had almost an eleven-fold higher risk of developing EA than did Group 1, and the incidence of EA in Group 4 was sixty-nine-fold higher than that of Group 1. The risk factor for EA was only the kind of medication. Preoperative anxiety had no significant correlation with EA. The incidence of EA after sevoflurane anesthesia is similar between ketamine and thiopental sodium anesthetic induction in children undergoing pediatric ophthalmic surgery. Also, the addition of a small dose of fentanyl after anesthetic induction decreases the incidence of EA.

Fentanyls: Are we missing the signs? Highly potent and on the rise in Europe.

PubMed

Mounteney, Jane; Giraudon, Isabelle; Denissov, Gleb; Griffiths, Paul

2015-07-01

Fentanyl is a synthetic opioid analgesic historically used as a pain reliever and an anaesthetic. Recent concerns have arisen around the illicit use of fentanyl and its analogues in a number of European countries, linked to their high potency and associated risk of fatal overdose. Evidence has been emerging from Estonia for over a decade of entrenched patterns of fentanyl use, including injection of the drug and hundreds of overdose deaths. More recently, reports indicate that both fentanyl and 3-methylfentanyl (TMF) have been marketed as a replacement for heroin in European countries (e.g. Bulgaria, Slovakia) affected by heroin shortages. In addition, Germany, Finland and the United Kingdom, reported new outbreaks of fentanyl-related deaths. This combination of increasing mortality data alongside law enforcement intelligence suggesting both diversion and illicit production of fentanyls, prompted wider investigation using a targeted multi-source data collection exercise and analysis. This identified that in the European context, fentanyls are 'low use but high risk/harm' substances. Evidence shows that Estonia stands out as having an endemic problem, while the use of fentanyls in other European countries appears to be geographically localised. Developments in illicit supply of fentanyls reflect the complexity of Europe's contemporary drug market: manifesting illicit production and use, the diversion and misuse of medicines, and the online sale of non-controlled new psychoactive substances. Likewise effective and integrated responses will need to address fentanyl production, diversion as well as ensuring the availability of harm reduction measures to users. Copyright © 2015 Elsevier B.V. All rights reserved.

Occlusion-amblyopia following high dose oral levodopa combined with part time patching

PubMed Central

Kothari, Mihir

2014-01-01

Part time occlusion therapy is not reported to cause occlusion (reverse) amblyopia. However, when combined with high dose oral levodopa, an increase in the plasticity of the visual cortex can lead to occlusion amblyopia. In this case report, we describe a six year old child who developed occlusion amblyopia following part time patching combined with oral levodopa. PMID:23571255

Occlusion-amblyopia following high dose oral levodopa combined with part time patching.

PubMed

Kothari, Mihir

2014-12-01

Part time occlusion therapy is not reported to cause occlusion (reverse) amblyopia. However, when combined with high dose oral levodopa, an increase in the plasticity of the visual cortex can lead to occlusion amblyopia. In this case report, we describe a six year old child who developed occlusion amblyopia following part time patching combined with oral levodopa.

Subcutaneous Fentanyl Administration: A Novel Approach for Pain Management in a Rural and Suburban Prehospital Setting.

PubMed

Lebon, Johann; Fournier, Francis; Bégin, François; Hebert, Denise; Fleet, Richard; Foldes-Busque, Guilaume; Tanguay, Alain

2016-01-01

To determine the feasibility, safety, and effectiveness of the subcutaneous route of fentanyl administration by Basic Life Support-Emergency Medical Technicians (BLS-EMT) in a rural and suburban region, with the support of an online pain management medical control center. Retrospective study of patients who received subcutaneous fentanyl and were transported by BLS-EMT to the emergency department (ED) of an academic hospital between July 1, 2013 and January 1, 2014, inclusively. Fentanyl orders were obtained from emergency physicians via an online medical control (OLMC) center. Effectiveness was defined by changes in pain scores 15 minutes, 30 minutes, and 45+ minutes after initial fentanyl administration. Safety was evaluated by measuring vital signs, Ramsay sedation scores, and adverse events subsequent to fentanyl administration. Feasibility was defined as successful fentanyl administration by BLS-EMT. SPSS-20 was used for descriptive statistics, and independent t-tests and Mann-Whitney U tests were used to determine inter- and intra-group differences based on transport time. Two hundred and eighty-eight patients (288; 14 to 93 years old) with pain scores ≥7 were eligible for the study. Of the 284 (98.6%) who successfully received subcutaneous fentanyl, 35 had missing records or data, and 249 (86.5%) were included in analyses. Average pain score pre-fentanyl was 8.9 ± 1.1. Patients <70 years old received a higher dose of fentanyl than those ≥70 years old (1.4 ± 0.3 vs, 0.8 ± 0.2 mcg/kg, p < 0.05). Pain scores decreased significantly post-fentanyl administration and the proportion of patients achieving pain relief increased significantly (p < 0.05) over the course of transport to ED (15 minutes, 30 minutes, 45+ minutes). Only 1.6% of patients experienced adverse events, including hypotension (n = 2; 0.8%), nausea (n = 1; 0.4%), and Ramsay level >3 (n = 1; 0.4%). Prehospital subcutaneous fentanyl administration by BLS-EMT with the support of an OLMC center is a safe and feasible approach to pain relief in prehospital settings, and is not associated with major adverse events. Effectiveness, subsequent to subcutaneous fentanyl administration is characterized by a decrease in pain over the course of transport to ED. Further studies are needed to compare the effectiveness of SC administration by EMS with other routes of administration and other analgesics.

Association between Genetic Polymorphisms in Cav2.3 (R-type) Ca2+ Channels and Fentanyl Sensitivity in Patients Undergoing Painful Cosmetic Surgery

PubMed Central

Fukuda, Ken-ichi; Kasai, Shinya; Hasegawa, Junko; Hayashida, Masakazu; Minami, Masabumi; Ikeda, Kazutaka

2013-01-01

Individual differences in the sensitivity to fentanyl, a widely used opioid analgesic, lead to different proper doses of fentanyl, which can hamper effective pain treatment. Voltage-activated Ca2+ channels (VACCs) play a crucial role in the nervous system by controlling membrane excitability and calcium signaling. Cav2.3 (R-type) VACCs have been especially thought to play critical roles in pain pathways and the analgesic effects of opioids. However, unknown is whether single-nucleotide polymorphisms (SNPs) of the human CACNA1E (calcium channel, voltage-dependent, R type, alpha 1E subunit) gene that encodes Cav2.3 VACCs influence the analgesic effects of opioids. Thus, the present study examined associations between fentanyl sensitivity and SNPs in the human CACNA1E gene in 355 Japanese patients who underwent painful orofacial cosmetic surgery, including bone dissection. We first conducted linkage disequilibrium (LD) analyses of 223 SNPs in a region that contains the CACNA1E gene using genomic samples from 100 patients, and a total of 13 LD blocks with 42 Tag SNPs were observed within and around the CACNA1E gene region. In the preliminary study using the same 100 genomic samples, only the rs3845446 A/G SNP was significantly associated with perioperative fentanyl use among these 42 Tag SNPs. In a confirmatory study using the other 255 genomic samples, this SNP was also significantly associated with perioperative fentanyl use. Thus, we further analyzed associations between genotypes of this SNP and all of the clinical data using a total of 355 samples. The rs3845446 A/G SNP was associated with intraoperative fentanyl use, 24 h postoperative fentanyl requirements, and perioperative fentanyl use. Subjects who carried the minor G allele required significantly less fentanyl for pain control compared with subjects who did not carry this allele. Although further validation is needed, the present findings show the possibility of the involvement of CACNA1E gene polymorphisms in fentanyl sensitivity. PMID:23940630

Comparison of epidural butorphanol and fentanyl as adjuvants in the lower abdominal surgery: A randomized clinical study

PubMed Central

Kaur, Jasleen; Bajwa, Sukhminder Jit Singh

2014-01-01

Background: Epidural opioids acting through the spinal cord receptors improve the quality and duration of analgesia along with dose-sparing effect with the local anesthetics. The present study compared the efficacy and safety profile of epidurally administered butorphanol and fentanyl combined with bupivacaine (B). Materials and Methods: A total of 75 adult patients of either sex of American Society of Anesthesiologist physical status I and II, aged 20-60 years, undergoing lower abdominal under epidural anesthesia were enrolled into the study. Patients were randomly divided into three groups of 25 each: B, bupivacaine and butorphanol (BB) and bupivacaine + fentanyl (BF). B (0.5%) 20 ml was administered epidurally in all the three groups with the addition of 1 mg butorphanol in BB group and 100 μg fentanyl in the BF group. The hemodynamic parameters as well as various block characteristics including onset, completion, level and duration of sensory analgesia as well as onset, completion and regression of motor block were observed and compared. Adverse events and post-operative visual analgesia scale scores were also noted and compared. Data was analyzed using ANOVA with post-hoc significance, Chi-square test and Fisher's exact test. Value of P < 0.05 was considered significant and P < 0.001 as highly significant. Results: The demographic profile of patients was comparable in all the three groups. Onset and completion of sensory analgesia was earliest in BF group, followed by BB and B group. The duration of analgesia was significantly prolonged in BB group followed by BF as compared with group B. Addition of butorphanol and fentanyl to B had no effect on the time of onset, completion and regression of motor block. No serious cardio-respiratory side effects were observed in any group. Conclusions: Butorphanol and fentanyl as epidural adjuvants are equally safe and provide comparable stable hemodynamics, early onset and establishment of sensory anesthesia. Butorphanol provides a significantly prolonged post-operative analgesia. PMID:24843326

Preparation and in vitro evaluation of a new fentanyl patch based on acrylic/silicone pressure-sensitive adhesive blends.

PubMed

Taghizadeh, Seyed Mojtaba; Soroushnia, Arezou; Mirzadeh, Hamid; Barikani, Mehdi

2009-04-01

In this study, the influence of the ratio of silicone (Si) to acrylic pressure-sensitive adhesive (PSA), polyvinyl pyrrolidone (PVP), and lauryl alcohol (LA) % (wt/wt) on the properties of a drug in adhesive patch containing 4% (wt/wt) fentanyl as model drug was evaluated. The dependent variables selected were drug solubility, in vitro drug release in the platforms as well as adhesion properties including peel strength and tack value. By using the central composite design of Design Expert software, it was found that the effect of each factor was different, yet all had influenced dependent variables significantly (p < .05). Quadratic model generated for various response variables using backward regression analysis was found to be statistically significant (p < .05). It was deduced that the presence of PVP and Si displayed similar trends on drug solubility and release. Each role played by Si with LA and PVP in release rate was separately investigated, and it was found that the presence of PVP and LA in lowering the amount of drug released was more dominant compared with that of Si. The release patterns at the early and later stages follow the Higuchi and semiempirical models, respectively. Effect of PVP as well as Si and LA were similar on tack value. The influence of LA compared to peeling characteristics of Si system was more pronounced.

The effect of inhalant anesthetic and body temperature on peri-anesthetic serum concentrations of transdermally administered fentanyl in dogs.

PubMed

Pettifer, Glenn R; Hosgood, Giselle

2004-04-01

To determine whether moderate hypothermia during anesthesia significantly affects the serum concentration of transdermally delivered fentanyl and whether halothane or isoflurane affect these concentrations. Randomized cross-over experimental trial. Six mature, healthy Beagles (three males, three females) weighing 10.6 +/- 0.43 kg. A 50-microg hour(-1) fentanyl patch was applied 36 hours prior to anesthesia. Anesthesia was induced at time 0 (t = 0). Each dog received four treatments: isoflurane + normothermia (ISO-NORM), isoflurane + hypothermia (ISO-HYPO), halothane + normothermia (HAL-NORM), and halothane + hypothermia (HAL-HYPO). Dogs were intubated and maintained at 1.5 times MAC. Animals in the hypothermia treatments were cooled to 35 degrees C during anesthesia. Serum fentanyl analysis was performed at -36, -24, -12, 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 18, and 26 hours. Direct arterial blood pressures and arterial blood gases were monitored. The mean body temperatures (+/-SEM) during the anesthetic period for the four treatments were: ISO-NORM = 37.7 +/- 0.07 degrees C, ISO-HYPO = 35.8 +/- 0.1 degrees C, HAL-NORM = 37.7 +/- 0.06 degrees C, and HAL-HYPO = 35.8 +/- 0.13 degrees C. The mean (+/-SEM) serum fentanyl concentrations (SFC) for both hypothermia treatments were significantly lower than baseline concentrations at t = 1 hour and persisted for the duration of anesthesia for the ISO-HYPO treatment but only from t = 1 to 2 hours for the HAL-HYPO treatment. Serum fentanyl concentrations returned to baseline within one hour of the end of anesthesia, regardless of body temperature. There were no significant differences between treatments for systolic or diastolic blood pressure but mean blood pressures were higher during normothermia versus hypothermia during the last hour of anesthesia. Hypothermia during inhalation anesthesia produced a significant reduction in SFC using transdermal administration and was more protracted with isoflurane than halothane anesthesia. While significant reductions in SFC occurred, the SFC were still within the range believed to confer analgesia.

Anaesthetic effects of alfaxalone administered intraperitoneally alone or combined with dexmedetomidine and fentanyl in the rat.

PubMed

Arenillas, Mario; Gomez de Segura, Ignacio A

2018-01-01

Alfaxalone is a neuroactive steroid used as a general anaesthetic in several species including dogs, cats, rabbits and ferrets. It has a wide margin of safety and a similar anaesthetic profile to propofol. To increase its aqueous solubility, a new formulation with cyclodextrins has been marketed recently. The objective of this study was to evaluate the anaesthetic effect of several doses of alfaxalone alone, considering differences between sexes, and alfaxalone combined with dexmedetomidine and fentanyl in the rat administered by the intraperitoneal route. A total of 40 Sprague Dawley rats, involved in three studies, were used. Firstly, 25, 35 and 45 mg kg -1 of alfaxalone alone were tested. In a second study, alfaxalone (25 mg kg -1 , females; 75 mg kg -1 , males) was combined with dexmedetomidine (0.05 mg kg -1 ). Finally, alfaxalone (20 mg kg -1 , females; 60 mg kg -1 , males) was combined with dexmedetomidine (0.05 mg kg -1 ) and fentanyl (0.1 mg kg -1 ). Times of onset and duration of anaesthesia, and analgesia, deemed as losing of withdrawal pedal reflex, were recorded. Alfaxalone alone produced a 2 - to 3-fold longer time of anaesthesia in females, although surgical anaesthesia was not achieved in either sex. The addition of dexmedetomidine and fentanyl to alfaxalone produced a similar time of analgesia as well as increased time of anaesthesia in both sexes. In conclusion, alfaxalone produces light anaesthesia in rats, and males required a higher dose. The combination with other sedatives or analgesics, such as dexmedetomidine or fentanyl, allows a more prolonged anaesthesia with analgesic effects, potentially suitable for invasive procedures.

Analgesic efficacy of low-dose intrathecal neostigmine in combination with fentanyl and bupivacaine for total knee replacement surgery

PubMed Central

Jain, Amit; Jain, Kajal; Bhardawaj, Neerja

2012-01-01

Background and Aim: Intrathecal (IT) neostigmine has been used as an adjunct to spinal anesthesia. The purpose of this study was to determine whether a combination of low-dose neostigmine IT would enhance analgesia of a fixed dose of fentanyl IT, in patients undergoing unilateral total knee replacement (TKR) surgery with spinal anesthesia. Settings and Design: Forty-five patients scheduled for unilateral TKR were randomized to one of the three groups (n = 15) and prospectively studied using placebo-controlled, double-blinded design. Materials and Methods: A 19-G epidural catheter was introduced through the L3–L4 interspace with patient in the sitting position, followed by spinal anesthesia administration through the L3–L4 interspace. Fifteen milligrams of hyperbaric bupivacaine (3 ml) plus the test drug (0.5 ml) was administered IT. The test drug was normal saline (0.5 ml) in group I; fentanyl 20 mcg (0.4 ml) and normal saline (0.1 ml) in group II; and fentanyl 20 mcg (0.4 ml) and neostigmine 1 mcg (0.1 ml) in group III. Characteristics of sensory and motor block, heart rate, and blood pressure were recorded intraoperatively. Postoperatively, pain scores, postoperative nausea and vomiting (PONV) scores, and sedation scores, and postoperative analgesic dose were recorded. Results: Forty-five patients were enrolled in this study and 43 patients were subjected to statistical analysis. Overall 24-h visual analog score in group III was significantly less than in those who received fentanyl alone (P = 0.00). The durations of complete analgesia and effective analgesia were longer for all patients in group III compared with group II (P < 0.05) and group I (P < 0.005) patients. The total number of epidural top ups (rescue analgesia) required was less in group II (P < 0.05) and group III (P < 0.005) patients, compared with the control group. The incidence of nausea and vomiting was not increased in group III patients. Conclusions: The addition of 1 mcg neostigmine IT increased the duration of analgesia and decreased the analgesic consumption in 24 h in TKR. There was no increase in the incidence of adverse effects. PMID:23225930

A 24-Week, Open-Label Extension Study to Investigate the Long-term Safety, Tolerability, and Efficacy of 13.3 mg/24 h Rivastigmine Patch in Patients With Severe Alzheimer Disease.

PubMed

Farlow, Martin R; Grossberg, George T; Sadowsky, Carl H; Meng, Xiangyi; Velting, Drew M

2015-01-01

The long-term safety, tolerability, and efficacy of high-dose 13.3 mg/24 h rivastigmine patch in severe Alzheimer disease was evaluated in a 24-week, open-label extension to the double-blind ACTION study. Safety and tolerability, and efficacy on the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV), Severe Impairment Battery (SIB), and ADCS-Clinical Global Impression of Change (ADCS-CGIC) were assessed. Overall, 197 patients continued on 13.3 mg/24 h patch; 199 uptitrated from 4.6 mg/24 h to 13.3 mg/24 h patch. The incidence of adverse events (AEs), serious AEs and discontinuations due to AEs was similar in patients who continued on, and patients who uptitrated to, 13.3 mg/24 h patch (AEs: 57.9% and 59.8%; serious AEs: 16.2% and 16.1%; discontinuations: 11.2% and 12.1%, respectively). Larger mean changes from double-blind baseline were observed in patients uptitrated on the ADCS-ADL-SIV (-4.6; SD=8.7) and SIB (-7.0; SD=16.6), than those who continued on 13.3 mg/24 h patch (-3.9; SD=8.0 and -4.7; SD=16.8, respectively). ADCS-CGIC scores were comparable. There were no clinically relevant between-group differences in safety and tolerability. Greater decline was observed in patients with delayed uptitration to high-dose 13.3 mg/24 h patch than patients who continued on high-dose patch.

Intramuscular Fentanyl and Ketorolac Associated with Superior Pain Control After Pediatric Bilateral Myringotomy and Tube Placement Surgery: A Retrospective Cohort Study.

PubMed

Stricker, Paul A; Muhly, Wallis T; Jantzen, Ellen C; Li, Yue; Jawad, Abbas F; Long, Alexander S; Polansky, Marcia; Cook-Sather, Scott D

2017-01-01

Bilateral myringotomy and pressure equalization tube insertion (BMT) is the most common surgery in children. Multiple anesthetic techniques for BMT have been proposed, but that which reliably promotes ideal recovery remains unclear. We sought to assess associations between anesthetic regimens that included single-agent (fentanyl or ketorolac) or dual-agent (fentanyl and ketorolac) analgesic therapy and the primary outcome of maximal postanesthesia care unit (PACU) pain score. Secondary outcomes included in-hospital rescue analgesic administration, recovery time, and emesis incidence. Principal analysis was conducted on a retrospective cohort of 3669 children aged 6 months to <7 years who underwent BMT over a 16-month period and received intraoperative fentanyl and/or ketorolac. Routine anesthetic care included preoperative oral midazolam, general anesthesia via a mask maintained with sevoflurane and N2O or air in O2, and intramuscular analgesic administration. Multivariable analyses were performed examining relationships between analgesic regimen with the following outcomes: maximum PACU Face, Legs, Activity, Cry, and Consolability (FLACC) score = 0 or 7 to 10, oxycodone administration, and time to discharge readiness. Demographic variables, midazolam exposure, and location (main hospital vs ambulatory surgery center) were included in the multivariable analyses as potential confounders. Associations with postoperative vomiting were studied separately in 2725 children from a subsequent, nonoverlapping 12-month period using similar inclusion criteria. Fentanyl and ketorolac dose-response relationships were evaluated for selected outcome variables. Maximum FLACC = 0, maximum FLACC score of 7 to 10, and oxycodone rescue were most strongly associated with dual-agent therapy versus single-agent ketorolac: odds ratios 4.89 (95% confidence interval [CI], 4.04-5.93), 0.13 (95% CI, 0.10-0.16), and 0.11 (98.3% CI, 0.09-0.14), respectively, P < .001 for each). Minor associations were found for age, Hispanic ethnicity, midazolam, and location, and none for sex or race. For subjects managed with higher dose fentanyl (≥1.5 µg/kg) and ketorolac (≥0.75 mg/kg), 90% had no demonstrable pain, agitation, or distress. Mean discharge readiness times were 21 ± 11 minutes (ketorolac), 26 ± 16 minutes (fentanyl), and 24 ± 14 minutes (dual) (P < .0001). Postoperative emesis incidences associated with ketorolac (2.7%) versus dual therapy (4.5%) were not different (P = .08). In this large retrospective pediatric BMT study, combination intramuscular fentanyl/ketorolac was strongly associated with superior PACU analgesia and reduced need for oxycodone rescue without clinically significant increases in recovery time or emesis incidence. Combination fentanyl at 1.5 to 2 µg/kg and 1 mg/kg ketorolac was associated with optimal outcomes. Dual therapy appears similarly effective in children of either European Caucasian or African ancestry or of Hispanic ethnicity.

Behavioral economic analysis of drug preference using multiple choice procedure data.

PubMed

Greenwald, Mark K

2008-01-11

The multiple choice procedure has been used to evaluate preference for psychoactive drugs, relative to money amounts (price), in human subjects. The present re-analysis shows that MCP data are compatible with behavioral economic analysis of drug choices. Demand curves were constructed from studies with intravenous fentanyl, intramuscular hydromorphone and oral methadone in opioid-dependent individuals; oral d-amphetamine, oral MDMA alone and during fluoxetine treatment, and smoked marijuana alone or following naltrexone pretreatment in recreational drug users. For each participant and dose, the MCP crossover point was converted into unit price (UP) by dividing the money value ($) by the drug dose (mg/70kg). At the crossover value, the dose ceases to function as a reinforcer, so "0" was entered for this and higher UPs to reflect lack of drug choice. At lower UPs, the dose functions as a reinforcer and "1" was entered to reflect drug choice. Data for UP vs. average percent choice were plotted in log-log space to generate demand functions. Rank of order of opioid inelasticity (slope of non-linear regression) was: fentanyl>hydromorphone (continuing heroin users)>methadone>hydromorphone (heroin abstainers). Rank order of psychostimulant inelasticity was d-amphetamine>MDMA>MDMA+fluoxetine. Smoked marijuana was more inelastic with high-dose naltrexone. These findings show this method translates individuals' drug preferences into estimates of population demand, which has the potential to yield insights into pharmacotherapy efficacy, abuse liability assessment, and individual differences in susceptibility to drug abuse.

Behavioral Economic Analysis of Drug Preference Using Multiple Choice Procedure Data

PubMed Central

Greenwald, Mark K.

2008-01-01

The Multiple Choice Procedure has been used to evaluate preference for psychoactive drugs, relative to money amounts (price), in human subjects. The present re-analysis shows that MCP data are compatible with behavioral economic analysis of drug choices. Demand curves were constructed from studies with intravenous fentanyl, intramuscular hydromorphone and oral methadone in opioid-dependent individuals; oral d-amphetamine, oral MDMA alone and during fluoxetine treatment, and smoked marijuana alone or following naltrexone pretreatment in recreational drug users. For each participant and dose, the MCP crossover point was converted into unit price (UP) by dividing the money value ($) by the drug dose (mg/70 kg). At the crossover value, the dose ceases to function as a reinforcer, so “0” was entered for this and higher UPs to reflect lack of drug choice. At lower UPs, the dose functions as a reinforcer and “1” was entered to reflect drug choice. Data for UP vs. average percent choice were plotted in log-log space to generate demand functions. Rank of order of opioid inelasticity (slope of non-linear regression) was: fentanyl > hydromorphone (continuing heroin users) > methadone > hydromorphone (heroin abstainers). Rank order of psychostimulant inelasticity was d-amphetamine > MDMA > MDMA + fluoxetine. Smoked marijuana was more inelastic with high-dose naltrexone. These findings show this method translates individuals’ drug preferences into estimates of population demand, which has the potential to yield insights into pharmacotherapy efficacy, abuse liability assessment, and individual differences in susceptibility to drug abuse. PMID:17949924

Characterization of methadone as a β-arrestin-biased μ-opioid receptor agonist

PubMed Central

Doi, Seira; Mori, Tomohisa; Uzawa, Naoki; Arima, Takamichi; Takahashi, Tomoyuki; Uchida, Masashi; Yawata, Ayaka; Narita, Michiko; Uezono, Yasuhito; Suzuki, Tsutomu

2016-01-01

Background Methadone is a unique µ-opioid receptor agonist. Although several researchers have insisted that the pharmacological effects of methadone are mediated through the blockade of NMDA receptor, the underlying mechanism by which methadone exerts its distinct pharmacological effects compared to those of other µ-opioid receptor agonists is still controversial. In the present study, we further investigated the pharmacological profile of methadone compared to those of fentanyl and morphine as measured mainly by the discriminative stimulus effect and in vitro assays for NMDA receptor binding, µ-opioid receptor-internalization, and µ-opioid receptor-mediated β-arrestin recruitment. Results We found that fentanyl substituted for the discriminative stimulus effects of methadone, whereas a relatively high dose of morphine was required to substitute for the discriminative stimulus effects of methadone in rats. Under these conditions, the non-competitive NMDA receptor antagonist MK-801 did not substitute for the discriminative stimulus effects of methadone. In association with its discriminative stimulus effect, methadone failed to displace the receptor binding of MK801 using mouse brain membrane. Methadone and fentanyl, but not morphine, induced potent µ-opioid receptor internalization accompanied by the strong recruitment of β-arrestin-2 in µ-opioid receptor-overexpressing cells. Conclusions These results suggest that methadone may, at least partly, produce its pharmacological effect as a β-arrestin-biased µ-opioid receptor agonist, similar to fentanyl, and NMDA receptor blockade is not the main contributor to the pharmacological profile of methadone. PMID:27317580

Radioreceptor assay for analysis of fentanyl and its analogs in biological samples

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alburges, M.E.

The assay is based on the competition of these drugs with ({sup 3}H) fentanyl for opioid receptors in membrane preparations of rat forebrain in vitro. The binding in stereospecific, reversible and saturable. Scatchard plots of saturation suggest the presence of high and low affinity binding sites. Morphine and hydromorphone complete with ({sup 3}H)fentanyl for the opioid receptor, but other morphine-like compounds were relatively weak displacers of ({sup 3}H)fentanyl. Many other commonly abused drugs do not compete with ({sup 3}H)fentanyl for the opioid receptors. Urine samples from animals injected with fentanyl, ({plus minus})-cis-3-methylfentanyl, alpha-methylfentanyl, butyrylfentanyl and benzylfentanyl were analyzed by radioreceptormore » assay, radioimmunoassay, and gas chromatography/mass spectrometry. Urinary analysis of fentanyl showed a good correlation with these three methods; however, discrepancies were observed in the analysis of fentanyl analogs. This radioreceptor assay is well-suited as an initial assay for the detection of active analogs of fentanyl in urine with good correlation with other techniques in the analysis of fentanyl; however, there is substantial disagreement between techniques in the quantitation of fentanyl analogs. The implications of these discrepancies are discussed.« less

Reduced incidence of laryngospasm with remifentanil-midazolam anaesthesia compared to halothane-fentanyl.

PubMed

Ali, Shahriari

2008-03-01

To compare the incidence of laryngospasm by using halothane-fentanyl anaesthesia and midazolam-remifentanil anaesthesia in paediatric patients undergoing eye surgery. We enrolled 120 ASA physical status I children aged 7-12 years scheduled for eye surgery from March 2004 to February 2006 in this prospective clinical trial study. Children suffering from any medical condition that could affect airway reflexes such as active upper respiratory infection, symptomatic asthma, obesity, patients with predicted difficulty in tracheal intubation were not included in the study. Patients with prolonged or difficult intubation or those who received another drug before extubation were excluded from the study. Using a random numbers table, participants were allocated to two equal groups. After induction of anaesthesia, in one group Halothane 1% was administered for the maintenance of anaesthesia in addition with intravenous fentanyl 1.5 microg kg(-1), and for the patients of the other group midazolam with a dose of 0.1 mg kg(-1) and remifentanil infusion by a dose of 0.1 microg kg(-1) min(-1) was administered. The patients were extubated in a unique plan of anaesthesia, using the sign of swallowing as a clinical indicator for extubation of patients. The incidence of laryngospasm was lower in midazolam-remifentanil group (0%) in comparison with halothane-fentanyl group (6.6%). The results of our study suggest that remifentanil combined with midazolam in children undergoing eye surgery provided a better condition for extubation of the patients.

[Low-dose hypobaric spinal anesthesia for anorectal surgery in jackknife position: levobupivacaine-fentanyl compared to lidocaine-fentanyl].

PubMed

de Santiago, J; Santos-Yglesias, J; Girón, J; Jiménez, A; Errando, C L

2010-11-01

To compare the percentage of patients who were able to bypass the postoperative intensive care recovery unit after selective spinal anesthesia with lidocaine-fentanyl versus levobupivacaine-fentanyl for anorectal surgery in jackknife position. Randomized double-blind clinical trial comparing 2 groups of 30 patients classified ASA 1-2. One group received 18 mg of 0.6% lidocaine plus 10 microg of fentanyl while the other group received 3 mg of 0.1% levobupivacaine plus 10 microg of fentanyl. Intraoperative variables were time of start of surgery, maximum extension of sensory blockade, requirement for rescue analgesics, and hemodynamic events. The level of sensory blockade was recorded at 5, 10, and 15 minutes after the start of surgery and at the end of the procedure. The degrees of postoperative motor blockade and proprioception were recorded, as were the results of the Romberg test and whether or not the patient was able to bypass the postoperative recovery unit. Also noted were times of start of ambulation and discharge, complications, and postoperative satisfaction. Intraoperative variables did not differ significantly between groups, and all patients in both groups bypassed the postoperative recovery unit. Times until walking and discharge home, complications, and overall satisfaction after surgery were similar in the 2 groups. Both spinal anesthetic solutions provide effective, selective anesthesia and are associated with similar rates of recovery care unit bypass after anorectal surgery in jackknife position.

Propofol-fentanyl anaesthesia at high altitude: anaesthetic requirements and haemodynamic variations when compared with anaesthesia at low altitude.

PubMed

Puri, G D; Jayant, A; Dorje, M; Tashi, M

2008-03-01

There are few published accounts of anaesthesia delivery at high altitude. Natives at high altitude are known to have altered cardiorespiratory reserve. This study seeks to demonstrate the safety of propofol-fentanyl anaesthesia at high altitude titrated to the bispectral index (BIS) (3505 metres above sea level) in native highlanders. It also shows the differential effects of anaesthesia and surgery on the haemodynamics of such individuals as compared with individuals living at low altitude. Fifteen consenting adults scheduled to undergo general surgical/orthopaedic procedures under general anaesthesia using fentanyl, and propofol infusions titrated to the BIS along with nitrous oxide in oxygen after intubation, were recruited in the high-altitude arm. Their anaesthesia record was compared with retrospective data from low altitude with respect to anaesthetic requirements, recovery after anaesthesia and the haemodynamic responses to surgical stress. The high-altitude dwellers required significantly larger doses of propofol at anaesthetic induction (2.31+/-0.64 vs. 1.41+/-0.24 mg/kg, P<0.0001) and thereafter to maintain designated BIS than their low-altitude counterparts (6.22+/-1.14 vs. 4.61+/-1.29 mg/kg/h, P<0.01). They, however, had uneventful and short recovery times. The high-altitude population also had significantly lower baseline heart rates (72+/-9.83 vs. 88+/-12.1, P<0.04) as also the heart rate responses to noxious stimulation such as direct laryngoscopy or skin incision (P<0.04, P<0.005, respectively). High-altitude dwellers require significantly larger amounts of intravenous anaesthetic propofol. Heart rate at rest as also the heart rate responses to surgical stress were significantly attenuated at high altitude.

Pharmacokinetics of fentanyl in patients undergoing abdominal aortic surgery.

PubMed

Hudson, R J; Thomson, I R; Cannon, J E; Friesen, R M; Meatherall, R C

1986-03-01

The authors determined the pharmacokinetics of fentanyl 100 micrograms X kg-1 iv in patients undergoing elective abdominal aortic surgery. The mean (+/- SD) age of the ten patients was 67.2 +/- 8.7 yr; their mean weight was 78.5 +/- 13.7 kg. Seven patients had aortic aneurysm repair, and the other three patients had aortobifemoral grafts. Serum fentanyl concentrations were determined from samples drawn at increasing intervals over a 24-h period. A three-compartment pharmacokinetic model was fit to the concentration versus time data. Total drug clearance was 9.8 +/- 1.8 ml X min-1 X kg-1. The volume of distribution at steady-state (Vdss) was 5.4 +/- 1.9 X 1 kg-1. Elimination half-time was 8.7 +/- 2.5 h. There were no significant correlations between these pharmacokinetic parameters and patient's age, duration of aortic cross-clamping, duration of surgery, intraoperative blood loss, or volume of iv fluids given intraoperatively. In healthy volunteers or patients undergoing general surgery, other investigators report mean elimination half-times for fentanyl ranging from 1.7 to 4.4 h. The prolonged elimination half-time in patients having abdominal aortic surgery has important clinical implications. In particular, recovery from large doses will take much longer than would have been anticipated from previously published fentanyl pharmacokinetic data.

Opioid neurotoxicity: neuropathologic effects in rats of different fentanyl congeners and the effects of hexamethonium-induced normotension.

PubMed

Kofke, W A; Garman, R H; Janosky, J; Rose, M E

1996-07-01

We tested the hypotheses that convulsant doses of opioids would produce limbic system damage exacerbated by hexamethonium. Ventilated paralyzed rats received intravenous (IV) isovolumic infusion of fentanyl loading dose (LD) 1000 micrograms/kg, maintenance dose (MD) 40 micrograms.kg-1.min-1 (n = 10), sufentanil LD 400 micrograms/kg, MD 13.3 micrograms.kg-1.min-1 (n = 10), alfentanil LD 1500 micrograms/kg, MD 150 micrograms.kg-1.min-1 (n = 10), or 0.9% saline control LD 4 mliter/kg, MD 4 mliter.kg-1.h-1 (n = 10), with O2/N2 30%/70% during opioid infusion and O2/N2O in controls during saline infusion. Hexamethonium (LD 20 mg/kg, MD 40-120 mg.kg-1.h-1) was given IV during opioid infusion to half of the rats. Cerebral perfusion-fixation with formalin was performed 24 h later, followed by histopathologic assessment. None of the control rats showed any histologic abnormalities. Overall summed neuropathologic severity was worse in opioid treated groups (P = 0.01). Lesions occurred primarily in cortical regions and limbic system structures. When arterial blood pressure was controlled to a lower level with hexamethonium (147 vs 100 mm Hg), rats had less severe lesions (P = 0.02). These data indicate that fentanyl, sufentanil, and alfentanil all can produce histopathologic evidence of brain injury in rats mitigated by hexamethonium.

Low-dose CT reconstruction with patch based sparsity and similarity constraints

NASA Astrophysics Data System (ADS)

Xu, Qiong; Mou, Xuanqin

2014-03-01

As the rapid growth of CT based medical application, low-dose CT reconstruction becomes more and more important to human health. Compared with other methods, statistical iterative reconstruction (SIR) usually performs better in lowdose case. However, the reconstructed image quality of SIR highly depends on the prior based regularization due to the insufficient of low-dose data. The frequently-used regularization is developed from pixel based prior, such as the smoothness between adjacent pixels. This kind of pixel based constraint cannot distinguish noise and structures effectively. Recently, patch based methods, such as dictionary learning and non-local means filtering, have outperformed the conventional pixel based methods. Patch is a small area of image, which expresses structural information of image. In this paper, we propose to use patch based constraint to improve the image quality of low-dose CT reconstruction. In the SIR framework, both patch based sparsity and similarity are considered in the regularization term. On one hand, patch based sparsity is addressed by sparse representation and dictionary learning methods, on the other hand, patch based similarity is addressed by non-local means filtering method. We conducted a real data experiment to evaluate the proposed method. The experimental results validate this method can lead to better image with less noise and more detail than other methods in low-count and few-views cases.

A novel approach to pharmaco-EEG for investigating analgesics: assessment of spectral indices in single-sweep evoked brain potentials.

PubMed

Gram, Mikkel; Graversen, Carina; Nielsen, Anders K; Arendt-Nielsen, Thomas; Mørch, Carsten D; Andresen, Trine; Drewes, Asbjørn M

2013-12-01

To compare results from analysis of averaged and single-sweep evoked brain potentials (EPs) by visual inspection and spectral analysis in order to identify an objective measure for the analgesic effect of buprenorphine and fentanyl. Twenty-two healthy males were included in a randomized study to assess the changes in EPs after 110 sweeps of painful electrical stimulation to the median nerve following treatment with buprenorphine, fentanyl or placebo patches. Bone pressure, cutaneous heat and electrical pain ratings were assessed. EPs and pain assessments were obtained before drug administration, 24, 48, 72 and 144 h after beginning of treatment. Features from EPs were extracted by three different approaches: (i) visual inspection of amplitude and latency of the main peaks in the average EPs, (ii) spectral distribution of the average EPs and (iii) spectral distribution of the EPs from single-sweeps. Visual inspection revealed no difference between active treatments and placebo (all P > 0.05). Spectral distribution of the averaged potentials showed a decrease in the beta (12-32 Hz) band for fentanyl (P = 0.036), which however did not correlate with pain ratings. Spectral distribution in the single-sweep EPs revealed significant increases in the theta, alpha and beta bands for buprenorphine (all P < 0.05) as well as theta band increase for fentanyl (P = 0.05). For buprenorphine, beta band activity correlated with bone pressure and cutaneous heat pain (both P = 0.04, r = 0.90). In conclusion single-sweep spectral band analysis increases the information on the response of the brain to opioids and may be used to identify the response to analgesics. © 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.

Increases in self-reported fentanyl use among a population entering drug treatment: The need for systematic surveillance of illicitly manufactured opioids.

PubMed

Cicero, Theodore J; Ellis, Matthew S; Kasper, Zachary A

2017-08-01

Recent reports indicate a sharp increase in fentanyl-related overdose deaths across the United States, much of which is likely related to the introduction of cheap, illicitly manufactured fentanyl derivatives. In this study, we sought to estimate the magnitude of illicit fentanyl use from 2012 to 2016 using a national opioid abuse surveillance system. The study program surveyed 10,900 individuals entering substance abuse treatment for opioid use disorder, with participants asked to endorse past month 'use to get high' of fentanyl drugs, stratified by identifiable (i.e., branded) fentanyl formulations or a 'type unknown' drug alleged to contain fentanyl. Total past-month fentanyl-use rose modestly from 2012 to 2016. While use of known fentanyl products remained relatively stable (mean=10.9%; P=0.25), endorsements of 'unknown' fentanyl products nearly doubled from 9% in 2013 to 15.1% by 2016 (P<0.001). Data show no discernable indication that this increase is diminishing or stabilizing. This first attempt to assess the prevalence of illicit fentanyl use shows that recent increases in fentanyl use seem to be due almost entirely to 'unknown' fentanyl presumed to be illicitly manufactured. Given that it is difficult to assess the extent to which fentanyl may have been substituted for another drug (i.e., oxycodone, alprazolam, etc.) or was used as a heroin admixture, our data likely represent an underestimation of the full magnitude of illicit fentanyl abuse. As such, this growing public health problem requires immediate attention and more systematic efforts to identify and track its abuse. Copyright © 2017. Published by Elsevier B.V.

Fentanyl related overdose in Indianapolis: Estimating trends using multilevel Bayesian models.

PubMed

Phalen, Peter; Ray, Bradley; Watson, Dennis P; Huynh, Philip; Greene, Marion S

2018-03-20

The opioid epidemic has been largely attributed to changes in prescribing practices over the past 20 years. Although current overdose trends appear driven by the opioid fentanyl, heroin has remained the focus of overdose fatality assessments. We obtained full toxicology screens on lethal overdose cases in a major US city, allowing more accurate assessment of the time-course of fentanyl-related deaths. We used coroner data from Marion County, Indiana comprising 1583 overdose deaths recorded between January 1, 2010 and April 30, 2017. Bayesian multilevel models were fitted to predict likelihood of lethal fentanyl-related overdose using information about the victim's age, race, sex, zip code, and date of death. Three hundred and seventy-seven (23.8%) overdose deaths contained fentanyl across the seven-year period. Rates rose exponentially over time, beginning well below 15% from 2010 through 2013 before rising to approximately 50% by 2017. At the beginning of the study period, rates of fentanyl overdose were lowest among Black persons but increased more rapidly, eventually surpassing Whites. Currently, White females are at particularly low risk of fentanyl overdose whereas Black females are at high risk. Rates were highest for younger and middle-aged groups. Over time, fentanyl was more likely detected without the presence of other opioids. Fentanyl has increasingly been detected in fatal overdose deaths in Marion County. Policy and program responses must focus on education for those at highest risk of fentanyl exposure and death. These responses should also be tailored to meet the unique needs of high-risk demographics. Copyright © 2018 Elsevier Ltd. All rights reserved.

Effect of anesthetics on the radiosensitivity of a murine tumor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sheldon, P.W.; Chu, A.M.

The effect of four anesthetics on the single dose of x rays required to locally control 50% of implanted MT tumors was investigated. Compared with unanesthetized animals, no change in radiosensitivity was observed if mice were irradiated under either tribromoethanol or fentanyl-fluanisone-diazepam anesthesia. However, a small but significant degree of radioprotection was observed under chloral hydrate or pentobarbital anesthesia. Hypothermia or increased hypoxia are considered unlikely mechanisms for the protection, a direct chemical action being most probable. The preferred method for immobilizing the mice in order to locally irradiate the tumors was by simple physical restraint (with care taken tomore » minimize physiological stress). However, if anesthesia was a necessity, the present work suggests that for the MT tumor at least the nonprotecting tribromoethanol and fentanyl-fluanisone-diazepam are preferable to the protecting chloral hydrate and pentobarbital. Tribromoethanol is preferable to fetanyl-fluanisone-diazepam in that it produces a smaller drop in temperature. However, it is only a short-acting anesthetic, and prolongation of the state of anesthesia by repeated doses simply prolongs the temperature decline so that there may be no real benefit over fentanyl-fluanisone-diazepam.« less

Addition of low-dose ketamine to midazolam and low-dose bupivacaine improves hemodynamics and postoperative analgesia during spinal anesthesia for cesarean section

PubMed Central

Basuni, Ahmed Sobhy

2016-01-01

Background and Aims: Spinal anesthesia for cesarean section (CS) is associated with an incidence of hypotension of 60-94%. This study hypothesizes that intrathecal combination of low-dose ketamine, midazolam, and low-dose bupivacaine improves hemodynamics and postoperative analgesia compared with fentanyl and low-dose bupivacaine during CS. Material and Methods: Fifty parturients undergoing elective CS were randomized equally to receive ketamine (10 mg), midazolam (2 mg) and 0.5% hyperbaric bupivacaine (8 mg) in group ketamine-midazolam-bupivacaine (KMB) or fentanyl (25 μg) and 0.5% hyperbaric bupivacaine (8 mg) in group fentanyl-bupivacaine (FB). Heart rate (HR), mean arterial blood pressure (MAP), oxygen saturation, sensorimotor block characteristics, pain-free period, side-effects including: hypotension, bradycardia, nausea, vomiting, sedation, pruritus, respiratory depression and dissociative manifestations, Apgar score at 1 and 5 min, and patients' satisfaction visual analog scores (VAS) were recorded. Patients in group KMB were followed for 6 months in order to assess any neurological disorder. Results: Group KMB showed higher sensory level (P = 0.006), rapid sensory (P = 0.001) and motor (P = 0.005) onsets, prolonged sensory (P = 0.008) and motor (P = 0.002) blocks, and prolonged pain free period (P = 0.002). Ketamine-midazolam stabilized HR and MAP, and significantly reduced incidence of hypotension (P = 0.002), bradycardia (P = 0.013) and vomiting (P = 0.019). Apgar scores at 1 and 5 min were comparable in both groups (P = 0.699 and 0.646 respectively). Patients' satisfaction VAS scores were significantly higher in group KMB (P = 0.001). No patients in KMB group showed dissociative or neurotoxic manifestations. Conclusion: Intrathecal low-dose ketamine combined with midazolam and low-dose bupivacaine stabilizes hemodynamics and prolongs postoperative analgesia without significant side-effects in parturients undergoing CS. PMID:27006540

Pharmacologic Treatment Reduces Pressure Times Time Dose and Relative Duration of Intracranial Hypertension.

PubMed

Colton, Katharine; Yang, S; Hu, P F; Chen, H H; Bonds, B; Stansbury, L G; Scalea, T M; Stein, D M

2016-05-01

Past work has shown the importance of the "pressure times time dose" (PTD) of intracranial hypertension (intracranial pressure [ICP] > 19 mm Hg) in predicting outcome after severe traumatic brain injury. We used automated data collection to measure the effect of common medications on the duration and dose of intracranial hypertension. Patients >17 years old, admitted and requiring ICP monitoring between 2008 and 2010 at a single, large urban tertiary care facility, were retrospectively enrolled. Timing and dose of ICP-directed therapy were recorded from paper and electronic medical records. The ICP data were collected automatically at 6-second intervals and averaged over 5 minutes. The percentage of time of intracranial hypertension (PTI) and PTD (mm Hg h) were calculated. A total of 98 patients with 664 treatment instances were identified. Baseline PTD ranged from 27 (before administration of propofol and fentanyl) to 150 mm Hg h (before mannitol). A "small" dose of hypertonic saline (HTS; ≤250 mL 3%) reduced PTD by 38% in the first hour and 37% in the second hour and reduced the time with ICP >19 by 38% and 39% after 1 and 2 hours, respectively. A "large" dose of HTS reduced PTD by 40% in the first hour and 63% in the second (PTI reduction of 36% and 50%, respectively). An increased dose of propofol or fentanyl infusion failed to decrease PTD but reduced PTI between 14% (propofol alone) and 30% (combined increase in propofol and fentanyl, after 2 hours). Barbiturates failed to decrease PTD but decreased PTI by 30% up to 2 hours after administration. All reductions reported are significantly changed from baseline, P < .05. Baseline PTD values before drug administration reflects varied patient criticality, with much higher values seen before the use of mannitol or barbiturates. Treatment with HTS reduced PTD and PTI burden significantly more than escalation of sedation or pain management, and this effect remained significant at 2 hours after administration. © The Author(s) 2014.

Opioid analgesia in mechanically ventilated children: results from the multicenter Measuring Opioid Tolerance Induced by Fentanyl study.

PubMed

Anand, Kanwaljeet J S; Clark, Amy E; Willson, Douglas F; Berger, John; Meert, Kathleen L; Zimmerman, Jerry J; Harrison, Rick; Carcillo, Joseph A; Newth, Christopher J L; Bisping, Stephanie; Holubkov, Richard; Dean, J Michael; Nicholson, Carol E

2013-01-01

To examine the clinical factors associated with increased opioid dose among mechanically ventilated children in the pediatric intensive care unit. Prospective, observational study with 100% accrual of eligible patients. Seven pediatric intensive care units from tertiary-care children's hospitals in the Collaborative Pediatric Critical Care Research Network. Four hundred nineteen children treated with morphine or fentanyl infusions. None. Data on opioid use, concomitant therapy, demographic and explanatory variables were collected. Significant variability occurred in clinical practices, with up to 100-fold differences in baseline opioid doses, average daily or total doses, or peak infusion rates. Opioid exposure for 7 or 14 days required doubling of the daily opioid dose in 16% patients (95% confidence interval 12%-19%) and 20% patients (95% confidence interval 16%-24%), respectively. Among patients receiving opioids for longer than 3 days (n = 225), this occurred in 28% (95% confidence interval 22%-33%) and 35% (95% confidence interval 29%-41%) by 7 or 14 days, respectively. Doubling of the opioid dose was more likely to occur following opioid infusions for 7 days or longer (odds ratio 7.9, 95% confidence interval 4.3-14.3; p < 0.001) or co-therapy with midazolam (odds ratio 5.6, 95% confidence interval 2.4-12.9; p < 0.001), and it was less likely to occur if morphine was used as the primary opioid (vs. fentanyl) (odds ratio 0.48, 95% confidence interval 0.25-0.92; p = 0.03), for patients receiving higher initial doses (odds ratio 0.96, 95% confidence interval 0.95-0.98; p < 0.001), or if patients had prior pediatric intensive care unit admissions (odds ratio 0.37, 95% confidence interval 0.15-0.89; p = 0.03). Mechanically ventilated children require increasing opioid doses, often associated with prolonged opioid exposure or the need for additional sedation. Efforts to reduce prolonged opioid exposure and clinical practice variation may prevent the complications of opioid therapy.

Transversus Abdominis Plane Block Versus Wound Infiltration for Analgesia After Cesarean Delivery: A Randomized Controlled Trial.

PubMed

Tawfik, Mohamed Mohamed; Mohamed, Yaser Mohamed; Elbadrawi, Rania Elmohamadi; Abdelkhalek, Mostafa; Mogahed, Maiseloon Mostafa; Ezz, Hanaa Mohamed

2017-04-01

Transversus abdominis plane (TAP) block and local anesthetic wound infiltration provide analgesia after cesarean delivery. Studies comparing the 2 techniques are scarce, with conflicting results. This double-blind, randomized controlled trial aimed to compare bilateral ultrasound-guided TAP block with single-shot local anesthetic wound infiltration for analgesia after cesarean delivery performed under spinal anesthesia. We hypothesized that the TAP block would decrease postoperative cumulative fentanyl consumption at 24 hours. Eligible subjects were American Society of Anesthesiologists physical status II parturients with full-term singleton pregnancies undergoing elective cesarean delivery under spinal anesthesia. Exclusion criteria were: <19 years of age or >40 years of age; height <150 cm, weight <60 kg, body mass index ≥40 kg/m; contraindications to spinal anesthesia; history of recent opioid exposure; hypersensitivity to any of the drugs used in the study; significant cardiovascular, renal, or hepatic disease; and known fetal abnormalities. Eighty subjects were randomly allocated to 2 equal groups. In the infiltration group, participants received 15 mL of bupivacaine 0.25% in each side of the surgical wound (total 30 mL); and in the TAP group, participants received 20 mL of bupivacaine 0.25% bilaterally in the TAP block (total 40 mL). The TAP block and wound infiltration were performed by the primary investigator and the operating obstetrician, respectively. All participants received postoperative standard analgesia (ketorolac and paracetamol) and intravenous fentanyl via patient-controlled analgesia. Patients and outcome assessors were blinded to the study group. The primary outcome was the cumulative fentanyl consumption at 24 hours. Secondary outcomes were the time to the first postoperative fentanyl dose, cumulative fentanyl consumption at 2, 4, 6, and 12 hours, pain scores at rest and on movement at 2, 4, 6, 12, and 24 hours, the deepest level of sedation, the incidence of side effects (nausea and vomiting and pruritis), and patient satisfaction. Data from 78 patients (39 patients in each group) were analyzed. The mean ± SD of cumulative fentanyl consumption at 24 hours was 157.4 ± 63.4 μg in the infiltration group and 153.3 ± 68.3 μg in the TAP group (difference in means [95% confidence interval] is 4.1 [-25.6 to 33.8] μg; P = .8). There were no significant differences between the 2 groups in the time to the first postoperative fentanyl dose, cumulative fentanyl consumption at 2, 4, 6, and 12 hours, pain scores at rest and on movement at 2, 4, 6, 12, and 24 hours, the deepest level of sedation, and patient satisfaction. The incidence of side effects (nausea and vomiting and pruritis) was low in the 2 groups. TAP block and wound infiltration did not significantly differ regarding postoperative fentanyl consumption, pain scores, and patient satisfaction in parturients undergoing cesarean delivery under spinal anesthesia.

A Retrospective Observational Study of Anesthetic Induction Dosing Practices in Female Elderly Surgical Patients: Are We Overdosing Older Patients?

PubMed

Akhtar, Shamsuddin; Heng, Joseph; Dai, Feng; Schonberger, Robert B; Burg, Mathew M

2016-10-01

Despite guidelines suggesting a 25-50 % reduction in induction doses of intravenous anesthetic agents in the elderly (≥65 years), we hypothesized that practitioners were not sufficiently correcting drug administration for age, contributing to an increased incidence of hypotension in older patients undergoing general anesthesia. We conducted a retrospective, observational study in a tertiary-care academic hospital. The study included 768 female patients undergoing gynecologic surgeries who received propofol-based induction of general anesthesia. Weight-adjusted anesthetic induction dosing, age-associated differences in dosing by ASA-PS (American Society of Anesthesiology-Physical Status), and hemodynamic outcomes between younger (18-64 years, n = 537) and older (≥65 years, n = 231) female patients were analyzed. Older patients received lower doses of propofol and midazolam than younger patients (propofol: 2.037 ± 0.783 vs 2.322 ± 0.834 mg/kg, p < 0.001; midazolam: 0.013 ± 0.014 vs 0.023 ± 0.042 mg/kg, p < 0.001). However, practitioners still consistently exceeded the FDA recommended dose (1-1.5 mg/kg) of propofol for elderly patients. There was no significant difference in the doses of fentanyl administered between the two age groups (1.343 ± 0.744 vs 1.363 ± 0.763 μg/kg, p = 0.744), and doses of fentanyl in older patients exceeded the recommended dose (0.5-1.0 μg/kg). Corresponding to observed overdosing of induction agents, older patients experienced larger decreases in post-induction blood pressure and were more likely to receive vasopressor therapy. Anesthetic induction doses of fentanyl and propofol were not sufficiently corrected in older patients in accordance with recommendations. Significantly greater frequency of post-induction hypotension occurred amongst older patients. Quality improvement efforts may lead to improved outcomes in this vulnerable population.

Analgesic opioid dose is an important indicator of postoperative ileus following radical cystectomy with ileal conduit: experience in the robotic surgery era.

PubMed

Koo, Kyo Chul; Yoon, Young Eun; Chung, Byung Ha; Hong, Sung Joon; Rha, Koon Ho

2014-09-01

Postoperative ileus (POI) is common following bowel resection for radical cystectomy with ileal conduit (RCIC). We investigated perioperative factors associated with prolonged POI following RCIC, with specific focus on opioid-based analgesic dosage. From March 2007 to January 2013, 78 open RCICs and 26 robot-assisted RCICs performed for bladder carcinoma were identified with adjustment for age, gender, American Society of Anesthesiologists grade, and body mass index (BMI). Perioperative records including operative time, intraoperative fluid excess, estimated blood loss, lymph node yield, and opioid analgesic dose were obtained to assess their associations with time to passage of flatus, tolerable oral diet, and length of hospital stay (LOS). Prior to general anaesthesia, patients received epidural patient-controlled analgesia (PCA) consisted of fentanyl with its dose adjusted for BMI. Postoperatively, single intravenous injections of tramadol were applied according to patient desire. Multivariate analyses revealed cumulative dosages of both PCA fentanyl and tramadol injections as independent predictors of POI. According to surgical modality, linear regression analyses revealed cumulative dosages of PCA fentanyl and tramadol injections to be positively associated with time to first passage of flatus, tolerable diet, and LOS in the open RCIC group. In the robot-assisted RCIC group, only tramadol dose was associated with time to flatus and tolerable diet. Compared to open RCIC, robot-assisted RCIC yielded shorter days to diet and LOS; however, it failed to shorten days to first flatus. Reducing opioid-based analgesics shortens the duration of POI. The utilization of the robotic system may confer additional benefit.

Human Growth Hormone Delivery with a Microneedle Transdermal System: Preclinical Formulation, Stability, Delivery and PK of Therapeutically Relevant Doses

PubMed Central

Ameri, Mahmoud; Kadkhodayan, Miryam; Nguyen, Joe; Bravo, Joseph A.; Su, Rebeca; Chan, Kenneth; Samiee, Ahmad; Daddona, Peter E.

2014-01-01

This study evaluated the feasibility of coating formulated recombinant human growth hormone (rhGH) on a titanium microneedle transdermal delivery system, Zosano Pharma (ZP)-hGH, and assessed preclinical patch delivery performance. Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. rhGH liquid formulation was coated onto titanium microneedles by dip-coating and drying. The stability of coated rhGH was determined by size exclusion chromatography-high performance liquid chromatography (SEC-HPLC). Preclinical delivery and pharmacokinetic studies were conducted in female hairless guinea pigs (HGP) using rhGH coated microneedle patches at 0.5 and 1 mg doses and compared to Norditropin® a commercially approved rhGH subcutaneous injection. Studies demonstrated successful rhGH formulation development and coating on microneedle arrays. The ZP-hGH patches remained stable at 40 °C for six months with no significant change in % aggregates. Pharmacokinetic studies showed that the rhGH-coated microneedle patches, delivered with high efficiency and the doses delivered indicated linearity with average Tmax of 30 min. The absolute bioavailability of the microneedle rhGH patches was similar to subcutaneous Norditropin® injections. These results suggest that ZP-transdermal microneedle patch delivery of rhGH is feasible and may offer an effective and patient-friendly alternative to currently marketed rhGH injectables. PMID:24838219

Study protocol of a randomised controlled trial of intranasal ketamine compared with intranasal fentanyl for analgesia in children with suspected, isolated extremity fractures in the paediatric emergency department.

PubMed

Reynolds, Stacy L; Studnek, Jonathan R; Bryant, Kathleen; VanderHave, Kelly; Grossman, Eric; Moore, Charity G; Young, James; Hogg, Melanie; Runyon, Michael S

2016-09-08

Fentanyl is the most widely studied intranasal (IN) analgesic in children. IN subdissociative (INSD) ketamine may offer a safe and efficacious alternative to IN fentanyl and may decrease overall opioid use during the emergency department (ED) stay. This study examines the feasibility of a larger, multicentre clinical trial comparing the safety and efficacy of INSD ketamine to IN fentanyl and the potential role for INSD ketamine in reducing total opioid medication usage. This double-blind, randomised controlled, pilot trial will compare INSD ketamine (1 mg/kg) to IN fentanyl (1.5 μg/kg) for analgesia in 80 children aged 4-17 years with acute pain from a suspected, single extremity fracture. The primary safety outcome for this pilot trial will be the frequency of cumulative side effects and adverse events at 60 min after drug administration. The primary efficacy outcome will be exploratory and will be the mean reduction of pain scale scores at 20 min. The study is not powered to examine efficacy. Secondary outcome measures will include the total dose of opioid pain medication in morphine equivalents/kg/hour (excluding study drug) required during the ED stay, number and reason for screen failures, time to consent, and the number and type of protocol deviations. Patients may receive up to 2 doses of study drug. This study was approved by the US Food and Drug Administration, the local institutional review board and the study data safety monitoring board. This study data will be submitted for publication regardless of results and will be used to establish feasibility for a multicentre, non-inferiority trial. NCT02521415. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Dexmedetomidine in the Supratentorial Craniotomy

PubMed Central

Ilhan, Osman; Koruk, Senem; Serin, Gokcen; Erkutlu, Ibrahim; Oner, Unsal

2010-01-01

Objective: In this double-blind prospective clinical study, we investigated the effects of fentanyl and dexmedetomidine as adjuvant agents in supratentorial craniotomies on the following: hemodynamic changes during perioperative and recovery periods, brain edema perioperatively, recovery times and side effects, such as hypertension, shivering, nausea and vomiting. Materials and Methods: Thirty consenting ASA physical status I–II patients undergoing intracranial tumor surgery were randomly divided in two groups. In group D (n=15), dexmedetomidine was infused as a 1 μg/kg bolus dose 10 minutes before induction of anesthesia and maintained with 0.4–0.5 μg/kg/min during the operation. In group F (n=15), animals were given fentanyl 0.02 μg/kg/min as an infusion for anesthesia maintenance. At induction, fentanyl was given as a 2 μg/kg dose in group D and as a 4 μg/kg dose in group F. Hemodynamic changes, recovery times and postoperative side effects were recorded before induction, during the perioperative period and 24 hours postoperatively. Results: In group D; MAP and HR values after intubation, after skull clamp insertion and after extubation were lower than in group F (p<0.05). In group D, cerebral relaxation scores were also significantly lower. Recovery times were found to be shorter in group D as compared to group F; the same trend was observed for the supplemental opioid requirement. During the postoperative period, there was no shivering, nausea or vomiting in group D, but in group F, 3 patients complained of shivering, and 2 patients experienced nausea and vomiting. Conclusion: In our study, we found that dexmedetomidine controlled the hemodynamic changes better than fentanyl perioperatively, after extubation and during the early postoperative period. Our results suggest that that dexmedetomidine is safer and more effective in controlling hemodynamic changes during surgical stimulation than the standard agents used in neuroanesthesia. PMID:25610125

Identification of Unique Metabolites of the Designer Opioid Furanyl Fentanyl.

PubMed

Goggin, Melissa M; Nguyen, An; Janis, Gregory C

2017-06-01

The illicit drug market has seen an increase in designer opioids, including fentanyl and methadone analogs, and other structurally unrelated opioid agonists. The designer opioid, furanyl fentanyl, is one of many fentanyl analogs clandestinely synthesized for recreational use and contributing to the fentanyl and opioid crisis. A method has been developed and validated for the analysis of furanyl fentanyl and furanyl norfentanyl in urine specimens from pain management programs. Approximately 10% of samples from a set of 500 presumptive heroin-positive urine specimens were found to contain furanyl fentanyl, with an average concentration of 33.8 ng/mL, and ranging from 0.26 to 390 ng/mL. Little to no furanyl norfentanyl was observed; therefore, the furanyl fentanyl specimens were further analyzed by untargeted high-resolution mass spectrometry to identify other metabolites. Multiple metabolites, including a dihydrodiol metabolite, 4-anilino-N-phenethyl-piperidine (4-ANPP) and a sulfate metabolite were identified. The aim of the presented study was to identify the major metabolite(s) of furanyl fentanyl and estimate their concentrations for the purpose of toxicological monitoring. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

[Eighty cases of monitored anesthesia care (MAC) for inguinal hernia repairs using tumescent local anesthesia (TLA)].

PubMed

Adachi, Koko; Kameyama, Eri; Yamada, Masahiro; Nakamura, Tadaho; Uchida, Kentaroh; Hayasaka, Tomoko

2011-10-01

This paper discusses the efficacy and difficulty of the management of monitored anesthesia care (MAC) for inguinal hernia repairs using tumescent local anesthesia(TLA). Eighty patients were retrospectively divided into four groups (all n = 20) according to the drugs used; group P (propofol), group PF (propofol and fentanyl), group PFM (propofol, fentanyl and midazolam), group PR (propofol and remifentanyl). The four groups were analyzed in terms of the applied dose, airway use, wake-up test to determine whether hernia was repaired, postoperative pain and nausea. More propofol was administered in group P than in group PFM and PR. Although, airway was used for nine patients, there was no difference between the four groups. Postoperative pain and nausea also do not differ between the groups. One patient in group P showed unsuccessful repair with wake-up test. MAC shows a beneficial effect on inguinal hernia repairs under TLA. The rate of airway use was as high as eleven percent, and maintenance of the patients' airway requires attention. In terms of wake-up test, propofol combined with opioid administration may be more effective than propofol administration alone. There was no significant difference between the groups in pain and nausea, regardless at the use of fentanyl or remifentanil.

Qualitative Identification of Fentanyl Analogs and Other Opioids in Postmortem Cases by UHPLC-Ion Trap-MSn.

PubMed

Shoff, Elisa N; Zaney, M Elizabeth; Kahl, Joseph H; Hime, George W; Boland, Diane M

2017-07-01

Since 2013, the Miami-Dade County Medical Examiner Department has experienced an increase in the number of opioid-related deaths. The majority of cases coincided with the introduction of fentanyl into the local heroin supply. From 2014 to 2015, Miami-Dade County experienced a near 600% increase in fentanyl-related deaths, followed by an additional 200% increase in 2016. In 2015, two novel fentanyl analogs were identified in medical examiner cases: beta-hydroxythiofentanyl and acetyl fentanyl. In 2016, four additional fentanyl analogs emerged: para-fluoroisobutyryl fentanyl, butyryl fentanyl, furanyl fentanyl and carfentanil, as well as the synthetic opioid U-47700. In order to address this epidemic, a method was developed and validated to identify 44 opioid-related and analgesic compounds in postmortem samples using ultra high performance liquid chromatography ion trap mass spectrometry with MSn capabilities. The limit of detection for all compounds ranged from 0.1 to 5 ng/mL, with a majority having MS3 spectral fragmentation. Blood, urine, liver or brain specimens from ~500 postmortem cases were submitted for analysis based on case history and/or initial screening results. Of those cases, 375 were positive for illicit fentanyl and/or one or more fentanyl analogs. Due to the potency of these compounds, they were almost always included in the cause of death. Worth emphasizing and extremely alarming is the detection of carfentanil in 134 cases, 104 of which were initially missed by gas chromatography mass spectrometry. By incorporating this sensitive, highly specific, and evolving screening procedure into the workflow, the toxicology laboratory continues to effectively assist the medical examiners in determining the cause and manner of death of decedents in Miami-Dade County. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Continuous spinal labor analgesia for two deliveries in a parturient with severe subvalvular aortic stenosis.

PubMed

Hyuga, Shunsuke; Okutomi, Toshiyuki; Kato, Rie; Hosokawa, Yuki

2016-12-01

Various degrees of left ventricular outflow tract (LVOT) obstruction have been seen in patients with subvalvular aortic stenosis (SAS). Regional analgesia during labor for parturients with SAS is relatively contraindicated because it has a potential risk for hemodynamic instability due to sympathetic blockade as a result of vasodilation by local anesthetics. We thought continuous spinal analgesia (CSA) using an opioid and minimal doses of local anesthetic could provide more stable hemodynamic status. We demonstrate the management of a 28-year-old pregnant patient with SAS who received CSA for her two deliveries. For her first delivery (peak pressure gradient (∆P) between LV and aorta was approximately 55 mmHg), intrathecal fentanyl was used as a basal infusion, but we needed a small amount of bupivacaine to provide supplemental intrathecal analgesia as labor progressed. Although there were mild fluctuations in hemodynamics, she was asymptomatic. For her second delivery (∆P between LV and aorta was approximately 90 mmHg), minimal doses of continuous bupivacaine were used as a basal infusion. For her additional analgesic requests, bolus co-administration of fentanyl was effective. There were no fluctuations in her hemodynamics. Although her SAS in her second pregnancy was more severe than in the first, her hemodynamics exhibited less fluctuation during the second delivery with this method. In conclusion, CSA using fentanyl combined with minimal doses of bupivacaine provided satisfactory analgesia and stable hemodynamics in parturient with severe SAS.

Fentanyl novel derivative-related deaths.

PubMed

Giorgetti, Arianna; Centola, Carmela; Giorgetti, Raffaele

2017-05-01

Fentanyl (FEN) is a potent, synthetic narcotic used as an anaesthetic and a pain reliever, but also illegally manufactured. For diversion purpose, it is being steadily modified to produce new analogous compounds and derivatives (FENS), categorised as novel psychoactive substances. While potential FEN abuse is already known, even in the absence of a clear lethal dosage, there is still a shortage of data on its derivatives. A literature review of FENS-related deaths was performed, to better understand potential damage and future perspectives of FEN congeners. Epidemiological data, pathological findings, administration routes, average concentrations and lethal doses, toxicological issues, trends in misuses, comparison among FENS, and possible explanation for FENS abuse are reviewed and discussed in depth. This study provides a medical-legal and toxicological assessment of this phenomenon in order to understand the role of illegal fentanyl and its congeners in deaths from FENS overdose. Copyright © 2017 John Wiley & Sons, Ltd.

An open-label, two-period comparative study on pharmacokinetics and safety of a combined ethinylestradiol/gestodene transdermal contraceptive patch.

PubMed

Zhang, Chao; Li, Haiyan; Xiong, Xin; Zhai, Suodi; Wei, Yudong; Zhang, Shuang; Zhang, Yuanyuan; Xu, Lin; Liu, Li

2017-01-01

We investigated the pharmacokinetics and safety profiles of a newly developed combined ethinylestradiol (EE)/gestodene (GSD) transdermal contraceptive patch after a single-dose administration and compared with the market available tablet formulation in healthy adult subjects. An open-label, two-period comparative study was conducted in 12 healthy women volunteers. A single dose of the study combined EE/GE transdermal contraceptive patch and oral tablet (Milunet ® ) were administered. Blood samples at different time points after dose were collected, and concentrations were analyzed. A reliable, highly sensitive and accurate high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS) assay method was developed in this study to determine the plasma concentrations of EE and GSD. Compared to the tablet, the study patch had a significantly decreased maximum plasma concentration ( C max ), extended time to reach the C max and half-life, as well as increased clearance and apparent volume of distribution. The half-lives of EE and GSD of the patch were 3.3 and 2.2 times, respectively, than the half-life of the tablet. The areas under the plasma concentration-time curve (AUCs) of EE and GSD of the patch were 8.0 and 16.2 times, respectively, than the AUC of the tablet. No severe adverse event was observed during the whole study, and the general safety was acceptable. In conclusion, compared to the oral tablet Milunet, the study contraceptive patch was well tolerated and showed potent drug exposure, significant extended half-life and stable drug concentrations.

Exposure to fentanyl-contaminated heroin and overdose risk among illicit opioid users in Rhode Island: A mixed methods study.

PubMed

Carroll, Jennifer J; Marshall, Brandon D L; Rich, Josiah D; Green, Traci C

2017-08-01

Illicit fentanyl use has become wide spread in the US, causing high rates of overdose deaths among people who use drugs. This study describes patterns and perceptions of fentanyl exposure among opioid users in Rhode Island. A mixed methods study was conducted via questionnaire with a convenience sample of 149 individuals using illicit opioids or misusing prescription opioids in Rhode Island between January and November 2016. Of these, 121 knew of fentanyl and reported known or suspected exposure to fentanyl in the past year. Semi-structured interviews were conducted with the first 47 participants. Study participants were predominantly male (64%) and white (61%). Demographic variables were similar across sample strata. Heroin was the most frequently reported drug of choice (72%). Self-reported exposure to illicit fentanyl in the past year was common (50.4%, n=61). In multivariate models, regular (at least weekly) heroin use was independently associated with known or suspected fentanyl exposure in the past year (adjusted prevalence ratio (APR)=4.07, 95% CI: 1.24-13.3, p=0.020). In interviews, users described fentanyl as unpleasant, potentially deadly, and to be avoided. Participants reporting fentanyl exposure routinely experienced or encountered non-fatal overdose. Heroin users reported limited ability to identify fentanyl in their drugs. Harm reduction strategies used to protect themselves from fentanyl exposure and overdose, included test hits, seeking prescription opioids in lieu of heroin, and seeking treatment with combination buprenorphine/naloxone. Participants were often unsuccessful in accessing structured treatment programs. Among illicit opioid users in Rhode Island, known or suspected fentanyl exposure is common, yet demand for fentanyl is low. Fentanyl-contaminated drugs are generating user interest in effective risk mitigation strategies, including treatment. Responses to the fentanyl epidemic should be informed by the perceptions and experiences of local users. The rapid scale-up of buprenorphine/naloxone provision may slow the rate of fentanyl-involved overdose deaths. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Analgesic Opioid Dose Is an Important Indicator of Postoperative Ileus Following Radical Cystectomy with Ileal Conduit: Experience in the Robotic Surgery Era

PubMed Central

Koo, Kyo Chul; Yoon, Young Eun; Chung, Byung Ha; Hong, Sung Joon

2014-01-01

Purpose Postoperative ileus (POI) is common following bowel resection for radical cystectomy with ileal conduit (RCIC). We investigated perioperative factors associated with prolonged POI following RCIC, with specific focus on opioid-based analgesic dosage. Materials and Methods From March 2007 to January 2013, 78 open RCICs and 26 robot-assisted RCICs performed for bladder carcinoma were identified with adjustment for age, gender, American Society of Anesthesiologists grade, and body mass index (BMI). Perioperative records including operative time, intraoperative fluid excess, estimated blood loss, lymph node yield, and opioid analgesic dose were obtained to assess their associations with time to passage of flatus, tolerable oral diet, and length of hospital stay (LOS). Prior to general anaesthesia, patients received epidural patient-controlled analgesia (PCA) consisted of fentanyl with its dose adjusted for BMI. Postoperatively, single intravenous injections of tramadol were applied according to patient desire. Results Multivariate analyses revealed cumulative dosages of both PCA fentanyl and tramadol injections as independent predictors of POI. According to surgical modality, linear regression analyses revealed cumulative dosages of PCA fentanyl and tramadol injections to be positively associated with time to first passage of flatus, tolerable diet, and LOS in the open RCIC group. In the robot-assisted RCIC group, only tramadol dose was associated with time to flatus and tolerable diet. Compared to open RCIC, robot-assisted RCIC yielded shorter days to diet and LOS; however, it failed to shorten days to first flatus. Conclusion Reducing opioid-based analgesics shortens the duration of POI. The utilization of the robotic system may confer additional benefit. PMID:25048497

Pharmacokinetics of Memantine after a Single and Multiple Dose of Oral and Patch Administration in Rats.

PubMed

Lee, Soo-Han; Kim, Seung-Hyun; Noh, Yook-Hwan; Choi, Byung-Moon; Noh, Gyu-Jeong; Park, Woo-Dae; Kim, Eun-Jung; Cho, Ik-Hyun; Bae, Chun-Sik

2016-02-01

Memantine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist used to treat Alzheimer's disease. We investigated memantine pharmacokinetics after oral, IV and patch administration in rats, and compared memantine pharmacokinetics after multiple- or single-dose oral and transdermal administration. Venous blood was collected at preset intervals in single- and multiple-dose studies. Non-compartmental pharmacokinetics was analysed for all formulations. The oral, IV and patch memantine doses were 10 mg/kg, 2 mg/kg and 8.21 ± 0.89 mg/kg, respectively. The maximum plasma concentration was lower and the half-life longer after patch administration than oral and IV administration. Memantine bioavailability was 41 and 63% for oral and patch administration, respectively. Steady state was achieved around 24 hr for oral and patch administration. The mean AUC increased after oral or patch administration from single to multiple dose. The memantine patch formulation displayed a longer duration of action and lower peak plasma concentration. However, drug exposure was similar to the oral formulation at each dose. Additionally, the memantine patch formulation displayed a smaller interindividual variability and lower accumulation than the oral formulation. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Comparison of Dexmedetomidine and Fentanyl as an Adjuvant to Ropivacaine for Postoperative Epidural Analgesia in Pediatric Orthopedic Surgery.

PubMed

Park, Sang Jun; Shin, Seokyung; Kim, Shin Hyung; Kim, Hyun Woo; Kim, Seung Hyun; Do, Hae Yoon; Choi, Yong Seon

2017-05-01

Opioids are commonly used as an epidural adjuvant to local anesthetics, but are associated with potentially serious side effects, such as respiratory depression. The aim of this study was to compare the efficacy and safety of dexmedetomidine with that of fentanyl as an adjuvant to epidural ropivacaine in pediatric orthopedic surgery. This study enrolled 60 children (3-12 years old) scheduled for orthopedic surgery of the lower extremities and lumbar epidural patient-controlled analgesia (PCA). Children received either dexmedetomidine (1 μg/kg) or fentanyl (1 μg/kg) along with 0.2% ropivacaine (0.2 mL/kg) via an epidural catheter at 30 minutes before the end of surgery. Postoperatively, the children were observed for ropivacaine consumption via epidural PCA, postoperative pain intensity, need for rescue analgesics, emergence agitation, and other adverse effects. The mean dose of bolus epidural ropivacaine was significantly lower within the first 6 h after surgery in the dexmedetomidine group, compared with the fentanyl group (0.029±0.030 mg/kg/h vs. 0.053±0.039 mg/kg/h, p=0.012). The median pain score at postoperative 6 h was also lower in the dexmedetomidine group, compared to the fentanyl group [0 (0-1.0) vs. 1.0 (0-3.0), p=0.039]. However, there was no difference in the need for rescue analgesia throughout the study period between groups. The use of dexmedetomidine as an epidural adjuvant had a significantly greater analgesic and local anesthetic-sparing effect, compared to fentanyl, in the early postoperative period in children undergoing major orthopedic lower extremity surgery. © Copyright: Yonsei University College of Medicine 2017

Comparison of Dexmedetomidine and Fentanyl as an Adjuvant to Ropivacaine for Postoperative Epidural Analgesia in Pediatric Orthopedic Surgery

PubMed Central

Park, Sang Jun; Shin, Seokyung; Kim, Shin Hyung; Kim, Hyun Woo; Kim, Seung Hyun; Do, Hae Yoon

2017-01-01

Purpose Opioids are commonly used as an epidural adjuvant to local anesthetics, but are associated with potentially serious side effects, such as respiratory depression. The aim of this study was to compare the efficacy and safety of dexmedetomidine with that of fentanyl as an adjuvant to epidural ropivacaine in pediatric orthopedic surgery. Materials and Methods This study enrolled 60 children (3–12 years old) scheduled for orthopedic surgery of the lower extremities and lumbar epidural patient-controlled analgesia (PCA). Children received either dexmedetomidine (1 µg/kg) or fentanyl (1 µg/kg) along with 0.2% ropivacaine (0.2 mL/kg) via an epidural catheter at 30 minutes before the end of surgery. Postoperatively, the children were observed for ropivacaine consumption via epidural PCA, postoperative pain intensity, need for rescue analgesics, emergence agitation, and other adverse effects. Results The mean dose of bolus epidural ropivacaine was significantly lower within the first 6 h after surgery in the dexmedetomidine group, compared with the fentanyl group (0.029±0.030 mg/kg/h vs. 0.053±0.039 mg/kg/h, p=0.012). The median pain score at postoperative 6 h was also lower in the dexmedetomidine group, compared to the fentanyl group [0 (0–1.0) vs. 1.0 (0–3.0), p=0.039]. However, there was no difference in the need for rescue analgesia throughout the study period between groups. Conclusion The use of dexmedetomidine as an epidural adjuvant had a significantly greater analgesic and local anesthetic-sparing effect, compared to fentanyl, in the early postoperative period in children undergoing major orthopedic lower extremity surgery. PMID:28332374

A Novel Oral Fluid Assay (LC-QTOF-MS) for the Detection of Fentanyl and Clandestine Opioids in Oral Fluid After Reported Heroin Overdose.

PubMed

Griswold, Matthew K; Chai, Peter R; Krotulski, Alex J; Friscia, Melissa; Chapman, Brittany P; Varma, Neha; Boyer, Edward W; Logan, Barry K; Babu, Kavita M

2017-12-01

The adulteration of heroin with non-pharmaceutical fentanyl and other high-potency opioids is one of the factors contributing to striking increases in overdose deaths. To fully understand the magnitude of this problem, accurate detection methods for fentanyl and other novel opioid adulterant exposures are urgently required. The objective of this work was to compare the detection of fentanyl in oral fluid and urine specimens using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) in a population of heroin users presenting to the Emergency Department after overdose. This was a prospective observational study of adult Emergency Department patients who presented after a reported heroin overdose requiring naloxone administration. Participants provided paired oral fluid and urine specimens, which were prepared, extracted, and analyzed using a dual LC-QTOF-MS workflow for the identification of traditional and emerging drugs of abuse. Analytical instrumentation included SCIEX TripleTOF® 5600+ and Waters Xevo® G2-S QTOF systems. Thirty participants (N = 30) were enrolled during the study period. Twenty-nine participants had fentanyl detected in their urine, while 27 had fentanyl identified in their oral fluid (overall agreement 93.3%, positive percent agreement 93.1%). Cohen's Kappa (k) was calculated and demonstrated moderately, significant agreement (k = 0.47; p value 0.002) in fentanyl detection between oral fluid and urine using this LC-QTOF-MS methodology. Additional novel opioids and metabolites, including norfentanyl, acetylfentanyl, and U-47700, were detected during this study. In this study of individuals presenting to the ED after reported heroin overdose, a strikingly high proportion had a detectable fentanyl exposure. Using LC-QTOF-MS, the agreement between paired oral fluid and urine testing for fentanyl detection indicates a role for oral fluid testing in surveillance for nonpharmaceutical fentanyl. Additionally, the use of LC-QTOF-MS allowed for the detection of other clandestine opioids (acetylfentanyl and U-47700) in oral fluid.

Antinociceptive Interactions between the Imidazoline I2 Receptor Agonist 2-BFI and Opioids in Rats: Role of Efficacy at the μ-Opioid Receptor

PubMed Central

Siemian, Justin N.; Obeng, Samuel; Zhang, Yan; Zhang, Yanan

2016-01-01

Although μ-opioids have been reported to interact favorably with imidazoline I2 receptor (I2R) ligands in animal models of chronic pain, the dependence on the μ-opioid receptor ligand efficacy on these interactions had not been previously investigated. This study systematically examined the interactions between the selective I2 receptor ligand 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI) and three μ-opioid receptor ligands of varying efficacies: fentanyl (high efficacy), buprenorphine (medium-low efficacy), and 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[(3′-isoquinolyl) acetamido] morphine (NAQ; very low efficacy). The von Frey test of mechanical nociception and Hargreaves test of thermal nociception were used to examine the antihyperalgesic effects of drug combinations in complete Freund’s adjuvant–induced inflammatory pain in rats. Food-reinforced schedule-controlled responding was used to examine the rate-suppressing effects of each drug combination. Dose-addition and isobolographical analyses were used to characterize the nature of drug-drug interactions in each assay. 2-BFI and fentanyl fully reversed both mechanical and thermal nociception, whereas buprenorphine significantly reversed thermal but only slightly reversed mechanical nociception. NAQ was ineffective in both nociception assays. When studied in combination with fentanyl, NAQ acted as a competitive antagonist (apparent pA2 value: 6.19). 2-BFI/fentanyl mixtures produced additive to infra-additive analgesic interactions, 2-BFI/buprenorphine mixtures produced supra-additive to infra-additive interactions, and 2-BFI/NAQ mixtures produced supra-additive to additive interactions in the nociception assays. The effects of all combinations on schedule-controlled responding were generally additive. Results consistent with these were found in experiments using female rats. These findings indicate that lower-efficacy μ-opioid receptor agonists may interact more favorably with I2R ligands than high-efficacy μ-opioid receptor agonists. PMID:27056847

Naloxone reversal of an overdose of a novel, long-acting transdermal fentanyl solution in laboratory Beagles.

PubMed

Freise, K J; Newbound, G C; Tudan, C; Clark, T P

2012-08-01

Opioid overdose in dogs is manifested by clinical signs such as excessive sedation, bradycardia, and hypothermia. The ability of two different intramuscular (i.m.) naloxone reversal regimens to reverse the opioid-induced effects of a fivefold overdose of long-acting transdermal fentanyl solution was evaluated in dogs. Twenty-four healthy Beagles were administered a single 13 mg/kg dose (fivefold overdose) of transdermal fentanyl solution and randomized to two naloxone reversal regimen treatment groups, hourly administration for 8 h of 40 (n = 8) or 160 μg/kg i.m. (n = 16). All dogs were sedated and had reduced body temperatures and heart rates (HRs) prior to naloxone administration. Both dosage regimens significantly reduced sedation (P < 0.001), and the 160 μg/kg naloxone regimen resulted in a nearly threefold lower odds of sedation than that of the 40 μg/kg i.m. naloxone regimen (P < 0.05). Additionally, naloxone significantly increased the mean body temperatures and HR (P < 0.001), although the 160 μg/kg regimen increased body temperature and HR more (P < 0.05). However, the narcotic side effects of fentanyl returned within 1-3 h following termination of the naloxone dosage regimens. The opioid-induced effects of an overdose of transdermal fentanyl solution can be safely and effectively reversed by either 40 or 160 μg/kg i.m. naloxone administered at hourly intervals. © 2012 Blackwell Publishing Ltd.

Opioid Concentrations in Oral Fluid and Plasma in Cancer Patients With Pain.

PubMed

Heiskanen, Tarja; Langel, Kaarina; Gunnar, Teemu; Lillsunde, Pirjo; Kalso, Eija A

2015-10-01

Measuring opioid concentrations in pain treatment is warranted in situations where optimal opioid analgesia is difficult to reach. To assess the usefulness of oral fluid (OFL) as an alternative to plasma in opioid concentration monitoring in cancer patients on chronic opioid therapy. We collected OFL and plasma samples from 64 cancer patients on controlled-release (CR) oral morphine, CR oral oxycodone, or transdermal (TD) fentanyl for pain. Samples were obtained on up to five separate days. A total of 213 OFL and plasma samples were evaluable. All patients had detectable amounts of the CR or TD opioid in both plasma and OFL samples. The plasma concentrations of oxycodone and fentanyl (determination coefficient R(2) = 0.628 and 0.700, respectively), but not morphine (R(2) = 0.292), were moderately well correlated to the daily opioid doses. In contrast to morphine and fentanyl (mean OFL/plasma ratio 2.0 and 3.0, respectively), the OFL oxycodone concentrations were significantly higher than the respective plasma concentrations (mean OFL/plasma ratio 14.9). An active transporter could explain the much higher OFL vs. plasma concentrations of oxycodone compared with morphine and fentanyl. OFL analysis is well suited for detecting the studied opioids. For morphine and fentanyl, an approximation of the plasma opioid concentrations is obtainable, whereas for oxycodone, the OFL/plasma concentration relationship is too variable for reliable approximation results. Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

SU-D-213-07: Initial Characterization of a Gel Patch Dosimeter for in Vivo Dosimetry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matrosic, C; Culberson, W; Rosen, B

Purpose: In vivo dosimetry, despite being the most direct method for monitoring the dose delivered during radiation therapy and being recommended by several national and international organizations (AAPM, ICRU, NACP), is underutilized in the clinic due to issues associated with dose sensitivity, feasibility, and cost. Given the increasing complexity of radiation therapy modern treatments, there is a compelling need for a robust, affordable in vivo dosimetry option. In this work we present the initial characterization of a novel gel patch in vivo dosimeter. Methods: DEFGEL (6%T) was used to make 1-cm thick small cylindrical patch dosimeters. The optical density ofmore » each dosimeter was read before and after irradiation by an in-house laser densitometer. The dosimeters were irradiated using a Varian Clinac EX linac. Three separate batches of gel patches were used to create dose response curves and evaluate repeatability. The development time of the dosimeter was also evaluated. Results: The dose response of the dosimeter was found to be linear from a range of approximately 1-Gy to 20-Gy, which is a larger window of linearity compared to other in vivo dosimeters. At doses below 1-Gy, the cumulative uncertainties were on the order of the measured data. When compared, the three batches demonstrated repeatability from 1-Gy to approximately 13-Gy, with some variation at higher doses. For doses of >8-Gy, the dosimeter reached full optical density after 4-hours, whereas low doses developed within an hour. Conclusion: Initial results indicate that the gel patch dosimeter is a reliable and simple way to measure a large range of doses, including high doses such as those delivered during hypofractionated treatments (e.g. SBRT or MR-guided radiotherapy). The simple fabrication method for the dosimeter and the use of a laser densitometer would allow for the dosimeter to used and read in-house, cheaply and easily.« less

Evaluating high-dose rivastigmine patch in severe Alzheimer's disease: analyses with concomitant memantine usage as a factor.

PubMed

Grossberg, George T; Farlow, Martin R; Meng, Xiangyi; Velting, Drew M

2015-01-01

ACTION, a 24-week, prospective, randomized, parallel-group, double-blind study in patients with severe Alzheimer's disease (AD), demonstrated significant efficacy of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch on the Severe Impairment Battery (SIB) and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV). Overall, 61% of the study population received at least 1 dose of concomitant memantine, regardless of dose or duration. This retrospective analysis investigated the effects of concomitant memantine on the efficacy, safety and tolerability of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch. Patients were stratified according to whether or not they received at least one dose of concomitant memantine during the double-blind phase. Changes from baseline on the SIB and ADCS-ADL-SIV were compared using analysis of covariance (ANCOVA) with treatment, pooled center, memantine usage and treatment-by-memantine as factors, and baseline as a covariate. Safety and tolerability were assessed. Memantine-treated patients were younger than those not receiving memantine (mean 75.9 and 78.8 years, respectively), with a lower screening Mini-Mental State Examination (8.6 and 9.2, respectively). ANCOVA confirmed there was no significant interaction (p>0.1) between study treatment and memantine use on the SIB or ADCS-ADL-SIV. The incidence of adverse events was: 71.4%, 13.3 mg/24 h patch with memantine; 79.7%, 13.3 mg/24 h patch alone; 74.7%, 4.6 mg/24 h patch with memantine; and 71.1%, 4.6 mg/24 h patch alone. These data suggest benefit of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch, regardless of concomitant memantine use. The incidence of adverse events with highdose patch was similar in memantine-treated patients and those not receiving memantine.

Illicit Fentanyl-Related Fatalities in Florida: Toxicological Findings.

PubMed

Lee, Dayong; Chronister, Chris W; Broussard, Wilson A; Utley-Bobak, Suzanne R; Schultz, Daniel L; Vega, Russell S; Goldberger, Bruce A

2016-10-01

Fentanyl induces pharmacological effects and abuse liability comparable to other prescription opioids and heroin. A surge in fentanyl-related fatalities has been periodically reported throughout the USA. The University of Florida Forensic Toxicology Laboratory observed a significant increase in fentanyl-related deaths starting in mid-2014. The present report evaluated toxicological findings, demographics of the decedents and circumstances of death in the postmortem cases that were submitted to the laboratory for toxicological analysis from July 2014 to January 2015 and that were tested for fentanyl in biological specimens. The cases originated from 6 of the 24 Florida Medical Examiner Districts, with the majority from District 12 (Desoto, Manatee and Sarasota counties). The specimens were analyzed for fentanyl by gas chromatography-mass spectrometry; the limit of detection (LOD) was 0.62 ng/mL and the limit of quantification (LOQ) was 2.5 ng/mL. During the 7-month period, the laboratory tested 143 postmortem cases for fentanyl and 50% had quantifiable fentanyl in postmortem blood. Fentanyl concentrations ranged from 2.5 to 68 ng/mL (n = 66; median: 9.8 ng/mL); six cases were positive for fentanyl >LOD but

Effect of high-dose nicotine patch on craving and negative affect leading up to lapse episodes.

PubMed

Ferguson, Stuart G; Shiffman, Saul

2014-07-01

Nicotine patches have been reliably demonstrated to improve smoking cessation outcomes but most users still lapse, and then relapse, during treatment. While patch has been shown to alleviate background cravings, its effects on cue-induced cravings - which have been linked to the occurrence of lapse events - are poorly understood. Here we investigate the effect of nicotine patch on the intensity of craving and negative affect experienced during the hours immediately preceding lapse episodes. Participants were 185 smokers who had quit in the context of a randomized, double-blind trial of high-dose (35 mg) nicotine patch and who lapsed at least once during the first 5 weeks of treatment. Participants used electronic diaries to monitor their smoking, affect, and craving during their cessation attempt. The data suggest that developments on the lapse day - either external events or changes in internal states - caused craving and negative affect to rise, cumulating in the lapse. Nicotine is known to lower background craving and negative affect, but the difference between patch and placebo appeared to dissipate in the hours immediately preceding lapse episodes. Understanding the process by which these symptoms "spike" prior to a lapse - and developing treatments to counter it - are worthy research endeavors.

Pharmacokinetics of a Novel, Transdermal Fentanyl Solution in Rhesus Macaques (Macaca mulatta)

PubMed Central

Salyards, Gregory W; Lemoy, Marie-Josee; Knych, Heather K; Hill, Ashley E; Christe, Kari L

2017-01-01

Rhesus macaques (Macaca mulatta) are the most commonly used NHP biomedical model and experience both research and clinical procedures requiring analgesia. Opioids are a mainstay of analgesic therapy. A novel, transdermal fentanyl solution (TFS) has been developed as a long-acting, single-administration topical opioid and was reported to provide at least 4 d of effective plasma concentrations in beagles (Canis familiaris). To evaluate the pharmacokinetic profile of TFS in healthy adult rhesus macaques, we used a 2-period, 2-treatment crossover study of a single topical administration of 1.3 (25) and 2.6 mg/kg (50 μL/kg) TFS. TFS was applied to the clipped dorsal skin of adult rhesus macaques (n = 6; 3 male, 3 female) under ketamine sedation (10 mg/kg IM). We hypothesized that TFS in rhesus macaques would provide at least 4 d of effective plasma concentrations (assumed to be ≥ 0.2 ng/mL, based on human studies). Plasma fentanyl concentrations were determined by liquid chromatography–tandem mass spectrometry before drug administration and at 0, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, 60, 72, 96, 120, 144, 168, 240, 336, 408, and 504 h afterward. Noncompartmental pharmacokinetic analysis was performed. For each dose (1.3 and 2.6 mg/kg), respectively, the maximal plasma concentration was 1.95 ± 0.40 and 4.19 ± 0.69 ng/mL, occurring at 21.3 ± 4.1 and 30.7 ± 8.7 h; the AUC was 227.3 ± 31.7 and 447.0 ± 49.1 h/ng/mL, and the terminal elimination half-life was 93.7 ± 7.1 and 98.8 ± 5.4 h. No adverse effects were noted after drug administration at either dose. Macaques maintained plasma fentanyl concentrations of 0.2 ng/mL or greater for at least 7 d after 1.3 mg/kg and at least 10 d after 2.6 mg/kg topical administration of TFS. A single TFS dose may provide efficacious analgesia to rhesus macaques and reduce stress, discomfort, and risk to animals and personnel. PMID:28724494

Analysis of Oxygen Saturations Recorded During Dental Intravenous Sedations: A Retrospective Quality Assurance of 3500 Cases

PubMed Central

Viljoen, Andre; Byth, Karen; Coombs, Malcolm; Mahoney, Greg; Stewart, Douglas

2011-01-01

The death of a patient under sedation in New South Wales, Australia, in 2002 has again raised the question of the safety of dental sedation. This study sought answers to 2 questions: Can safe oxygen saturation levels (≥94%) be consistently maintained by a single operator/sedationist? Does the additional use of propofol, in subanesthetic doses, increase the risk of exposure to hypoxemia? Three thousand five hundred cases generated between 1996 and 2006 were randomly examined and divided into 2 subcohorts: 1750 patients were sedated with midazolam and fentanyl, and 1750 patients received propofol, in subanesthetic increments, in addition to midazolam and fentanyl. Initial sedation was established using midazolam and fentanyl in both subcohorts. The second subcohort received propofol during times of noxious stimulation. Patient exposure to 2 or more oxygen desaturations below 94% was uncommon. The variables that were significantly associated with low saturations were age, gender, and weight. Neither the dose of midazolam nor the additional use of propofol was a significant risk factor. ASA classification (I or II) was not a determinant of risk. The data, within the limitations of the study, showed that a single operator/sedationist, supported by a well-trained team of nurses, can consistently maintain safe oxygen saturation levels. The additional use of propofol did not increase exposure to hypoxemia. PMID:21882986

Randomized Controlled Feasibility Trial of Intranasal Ketamine Compared to Intranasal Fentanyl for Analgesia in Children with Suspected Extremity Fractures.

PubMed

Reynolds, Stacy L; Bryant, Kathleen K; Studnek, Jonathan R; Hogg, Melanie; Dunn, Connell; Templin, Megan A; Moore, Charity G; Young, James R; Walker, Katherine Rivera; Runyon, Michael S

2017-12-01

We compared the tolerability and efficacy of intranasal subdissociative ketamine to intranasal fentanyl for analgesia of children with acute traumatic pain and investigated the feasibility of a larger noninferiority trial that could investigate the potential opioid-sparing effects of intranasal ketamine. This randomized controlled trial compared 1 mg/kg intranasal ketamine to 1.5 μg/kg intranasal fentanyl in children 4 to 17 years old with acute pain from suspected isolated extremity fractures presenting to an urban Level II pediatric trauma center from December 2015 to November 2016. Patients, parents, treating physicians, and outcome assessors were blinded to group allocation. The primary outcome, a tolerability measure, was the frequency of cumulative side effects and adverse events within 60 minutes of drug administration. The secondary outcomes included the difference in mean pain score reduction at 20 minutes, the proportion of patients achieving a clinically significant reduction in pain in 20 minutes, total dose of opioid pain medication in morphine equivalents/kg/hour (excluding study drug) required during the emergency department (ED) stay, and the feasibility of enrolling children presenting to the ED in acute pain into a randomized trial conducted under U.S. regulations. All patients were monitored until 6 hours after their last dose of study drug or until admission to the hospital ward or operating room. Of 629 patients screened, 87 received the study drug and 82 had complete data for the primary outcome (41 patients in each group). The median (interquartile range) age was 8 (6-11) years and 62% were male. Baseline pain scores were similar among patients randomized to receive ketamine (73 ± 26) and fentanyl (69 ± 26; mean difference [95% CI] = 4 [-7 to 15]). The cumulative number of side effects was 2.2 times higher in the ketamine group, but there were no serious adverse events and no patients in either group required intervention. The most common side effects of ketamine were bad taste in the mouth (37; 90.2%), dizziness (30; 73.2%), and sleepiness (19; 46.3%). The most common side effects of fentanyl were sleepiness (15; 36.6%), bad taste in the mouth (9; 22%), and itchy nose (9; 22%). No patients experienced respiratory side effects. At 20 minutes, the mean pain scale score reduction was 44 ± 36 for ketamine and 35 ± 29 for fentanyl (mean difference = 9 [95% CI = -4 to 23]). Procedural sedation with ketamine occurred in 28 ketamine patients (65%) and 25 fentanyl patients (57%) prior to completing the study. Intranasal ketamine was associated with more minor side effects than intranasal fentanyl. Pain relief at 20 minutes was similar between groups. Our data support the feasibility of a larger, noninferiority trial to more rigorously evaluate the safety, efficacy, and potential opioid-sparing benefits of intranasal ketamine analgesia for children with acute pain. © 2017 by the Society for Academic Emergency Medicine.

Comparison of the Haemodynamic Effects of Three Different Methods at the Induction of Anaesthesia

PubMed Central

Uygur, Mehmet Levent; Ersoy, Ayşın; Altan, Aysel; Ervatan, Zekeriya; Kamalı, Sedat

2014-01-01

Objective Haemodynamic variations are inevitable during induction of anaesthetic drugs. The present study investigates the haemodynamic variations of three different drugs (thiopental, propofol, and etomidate) used for induction of general anaesthesia together with fentanyl. Methods In a randomized, double-blind study, 45 patients were assigned to one of three groups (n=15 each). Fentanyl 1 μg kg−1 was injected over 60 sec followed by propofol 2 mg kg−1 (Group P), thiopentone 6 mg kg−1 (Group T), or etomidate 0.3 mg kg−1 (Group E). Noninvasive measurements of systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), and heart rate (HR) was performed on admittance, immediately before the induction of anaesthesia, and 1, 3, and 5 min thereafter. Cardiac output (CO) values were recorded before induction, immediately after the injection of the drug, and at 1 min after the intubation. Results In all groups, during the study period, SAP, DAP, MAP, and CO values decreased with respect to time before induction. Following the administration of the induction dose of propofol (Group P), a significantly greater decrease of systolic and diastolic blood pressure was observed with etomidate (Group E) or thiopentone (Group T). Decrease in CO was also more marked with propofol (Group P) than with etomidate (Group E) or thiopentone (Group T). Conclusion It’s concluded that, in this study, the combination of fentanyl-etomidate is safer than both the groups of fentanyl-propofol and fentanyl-thiopental in terms of providing haemodynamic stability. PMID:27366443

[Analgesia and sedation in neonatal-pediatric intensive care].

PubMed

Schlünder, C; Houben, F; Hartwig, S; Theisohn, M; Roth, B

1991-01-01

In pediatric intensive care, analgesia and sedation has become increasingly important for newborns as well as prematures in recent years. However, its importance is frequently not well recognized and sedation is confounded with analgesia. In our intensive-care unit (ICU), fentanyl and midazolam have proved to be useful. In newborn and premature infants, fentanyl alone has been sufficient because of its analgesic and sedative action. In a study on 20 newborns and prematures suffering from severe respiratory problems as compared with a historical group that did not receive fentanyl, we could show that in subjects receiving fentanyl, considerably less treatment with sedatives and other analgesics was necessary. Cardiopulmonary tolerance was satisfactory. The highest bilirubin values were reached about 1 day earlier and were slightly higher than those measured in the control group, but oral nutrition could be initiated sooner. In small infants, additional midazolam was given after cardiac surgery. During the first 72 h, we found a correlation between serum levels of midazolam and the depth of sedation; however, after 72 h of medication, the dose had to be raised because of an increase in metabolic clearance. During the concomitant administration of midazolam and fentanyl, significantly less midazolam was needed to achieve appropriate analog-sedation. Prior to the administration of analgesics and sedatives, care should be taken to ensure that circulatory conditions are stable and that there is no hypovolemia, and the drugs must be given slowly during several minutes. Especially in a pediatric ICU, light and noise should be diminished and contact between the parents and the child should be encouraged, even when the child is undergoing mechanical ventilation.

NeuroD modulates opioid agonist-selective regulation of adult neurogenesis and contextual memory extinction.

PubMed

Zheng, Hui; Zhang, Yue; Li, Wen; Loh, Horace H; Law, Ping-Yee

2013-04-01

Addictive drugs, including opioids, modulate adult neurogenesis. In order to delineate the probable implications of neurogenesis on contextual memory associated with addiction, we investigated opioid agonist-selective regulation of neurogenic differentiation 1 (NeuroD) activities under the conditioned place preference (CPP) paradigm. Training mice with equivalent doses of morphine and fentanyl produced different CPP extinction rates without measurable differences in the CPP acquisition rate or magnitude. Fentanyl-induced CPP required much longer time for extinction than morphine-induced CPP. We observed a parallel decrease in NeuroD activities and neurogenesis after morphine-induced CPP, but not after fentanyl-induced CPP. Increasing NeuroD activities with NeuroD-lentivirus (nd-vir) injection at the dentate gyrus before CPP training reversed morphine-induced decreases in NeuroD activities and neurogenesis, and prolonged the time required for extinction of morphine-induced CPP. On the other hand, decreasing NeuroD activities via injection of miRNA-190-virus (190-vir) reversed the fentanyl effect on NeuroD and neurogenesis and shortened the time required for extinction of fentanyl-induced CPP. Another contextual memory task, the Morris Water Maze (MWM), was affected similarly by alteration of NeuroD activities. The reduction in NeuroD activities either by morphine treatment or 190-vir injection decreased MWM task retention, while the increase in NeuroD activities by nd-vir prolonged MWM task retention. Thus, by controlling NeuroD activities, opioid agonists differentially regulate adult neurogenesis and subsequent contextual memory retention. Such drug-related memory regulation could have implications in eventual context-associated relapse.

Maximum tolerated dose of nalmefene in patients receiving epidural fentanyl and dilute bupivacaine for postoperative analgesia.

PubMed

Dougherty, T B; Porche, V H; Thall, P F

2000-04-01

This study investigated the ability of the modified continual reassessment method (MCRM) to determine the maximum tolerated dose of the opioid antagonist nalmefene, which does not reverse analgesia in an acceptable number of postoperative patients receiving epidural fentanyl in 0.075% bupivacaine. In the postanesthetic care unit, patients received a single intravenous dose of 0.25, 0.50, 0.75, or 1.00 microg/kg nalmefene. Reversal of analgesia was defined as an increase in pain score of two or more integers above baseline on a visual analog scale from 0 through 10 after nalmefene administration. Patients were treated in cohorts of one, starting with the lowest dose. The maximum tolerated dose of nalmefene was defined as that dose, among the four studied, with a final mean probability of reversal of anesthesia (PROA) closest to 0.20 (ie., a 20% chance of causing reversal). The modified continual reassessment method is an iterative Bayesian statistical procedure that, in this study, selected the dose for each successive cohort as that having a mean PROA closest to the preselected target PROA of 0.20. The modified continual reassessment method repeatedly updated the PROA of each dose level as successive patients were observed for presence or absence of ROA. After 25 patients, the maximum tolerated dose of nalmefene was selected as 0.50 microg/kg (final mean PROA = 0.18). The 1.00-microg/kg dose was never tried because its projected PROA was far above 0.20. The modified continual reassessment method facilitated determination of the maximum tolerated dose ofnalmefene . Operating characteristics of the modified continual reassessment method suggest it may be an effective statistical tool for dose-finding in trials of selected analgesic or anesthetic agents.

Topical fentanyl stimulates healing of ischemic wounds in diabetic rats

PubMed Central

FAROOQUI, Mariya; ERICSON, Marna E; GUPTA, Kalpna

2016-01-01

Background Topically applied opioids promote angiogenesis and healing of ischemic wounds in rats. We examined if topical fentanyl stimulates wound healing in diabetic rats by stimulating growth-promoting signaling, angiogenesis, lymphangiogenesis and nerve regeneration. Methods We used Zucker diabetic fatty rats that develop obesity and diabetes on a high fat diet due to a mutation in the Leptin receptor. Fentanyl blended with hydrocream was applied topically on ischemic wounds twice daily, and wound closure was analyzed regularly. Wound histology was analyzed by hematoxylin and eosin staining. Angiogenesis, lymphangiogenesis, nerve fibers and phospho-PDGFR-β were visualized by CD31-, lymphatic vessel endothelium-1, protein gene product 9.5- and anti-phospho PDGFR-β-immunoreactivity, respectively. Nitric oxide synthase (NOS) and PDGFR-β signaling were analyzed using Western immunoblotting. Results Fentanyl significantly promoted wound closure as compared to PBS. Histology scores were significantly higher in fentanyl-treated wounds, indicative of increased granulation tissue formation, reduced edema and inflammation, and increased matrix deposition. Fentanyl treatment resulted in increased wound angiogenesis, lymphatic vasculature, nerve fibers, nitric oxide, NOS and PDGFR-β signaling as compared to PBS. Phospho PDGFR-β co-localized with CD31 co-staining for vasculature. Conclusions Topically applied fentanyl promotes closure of ischemic wounds in diabetic rats. Increased angiogenesis, lymphangiogenesis, peripheral nerve regeneration, NO and PDGFR-β signaling are associated with fentanyl-induced tissue remodeling and wound healing. PMID:25266258

Stability of Fentanyl Citrate in Polyolefin Bags.

PubMed

Donnelly, Ronald F

2016-01-01

Fentanyl is used to manage pain because it is a potent lipophilic opiate agonist. The stability of fentanyl in polyolefin bags when diluted to either 10 µg/mL or 50 µg/mL with sodium chloride 0.9% has not been studied. The chemical stability of fentanyl 50 µg/mL packaged in polyvinyl chloride bags has been studied, however, the stability in polyolefin bags is lacking. Polyolefin bags were aseptically filled with either 10-µg/mL or 50-µg/mL fentanyl solution. Containers were then stored at either 5°C and protected from light or 22°C and exposed to light for 93 days. Fentanyl peaks were monitored using a stability-indicatin high-performance liquid chromatographic method. Changes to color, clarity, and pH were also monitored. There were no signs of chemical degradation of fentanyl packaged in polyolefin bags at either 5°C or 22°C after storage for 93 days. Over the course of the study, all solutions remained colorless and clear. The pH showed a slight decrease during the 93 days of storage. The stability of both undiluted (50-µg/mL) and diluted (10-µg/mL) fentanyl solutions when packaged in polyolefin bags was 93 days when stored at either 5°C or 22°C. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Influence of fentanyl and morphine on intestinal circulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tverskoy, M.; Gelman, S.; Fowler, K.C.

The influence of fentanyl and morphine on the intestinal circulation was evaluated in an isolated loop preparation in 37 dogs anesthetized with pentobarbital intravenously. Selected intestinal segments were pumped with aortic blood at a constant pressure of 100 mm Hg. A mixture of /sup 86/Rb and 9-micron spheres labeled with /sup 141/Ce was injected into the arterial cannula supplying the intestinal loop, while mesenteric venous blood was collected for activity counting. A strong correlation was found between the clearances of rubidium and microspheres (r = 0.97, P less than 0.0001), suggesting that the shunting of 9-micron spheres through the intestinesmore » reflects the shunting of blood through nonnutritive vessels. Intravenous fentanyl decreased oxygen uptake (O/sub 2/up), and vascular resistance (VR), and increased blood flow (BF), rubidium and microsphere clearances (Cl-Rb, Cl-Sph, respectively), and permeability--surface area product (PS) in a dose-related fashion. Intravenous morphine in a dose of 1 mg X kg-1 increased Cl-Rb (nutritive BF) without changes in total (nutritive and nonnutritive) BF. This increase in nutritive BF is probably related to morphine-induced histamine release. Morphine in a dose of 5 mg X kg-1 was accompanied by vasoconstriction that was completely abolished by alpha-adrenoceptor blockade. The data suggest that morphine-induced intestinal vasoconstriction is mediated via a release of epinephrine, apparently from the adrenal medulla. It is concluded that changes in the intestinal circulation during anesthesia with narcotics might play a certain role in the cardiovascular homeostasis during anesthesia and surgery. An increase in oxygen content in portal venous blood, resulting from a decrease in intestinal oxygen uptake, should facilitate hepatic oxygenation.« less

Efficacy of rivastigmine tartrate, transdermal system, in Alzheimer's disease.

PubMed

Nieto, Rachel A; Deardorff, William James; Grossberg, George T

2016-01-01

As the most common major neurocognitive disorder, Alzheimer's disease (AD) will play an increasingly important role both socially and financially as the population ages. Approved treatments for AD are symptomatic in nature and show modest improvements in cognition and global functioning among patients with AD. This article focuses on the pharmacokinetics, pharmacodynamics, efficacy, and safety of the transdermal patch form of the cholinesterase inhibitor rivastigmine. The rivastigmine transdermal system is approved for the treatment of patients with mild, moderate, and severe AD. Three randomized trials have shown the rivastigmine patch to be efficacious and tolerable across all stages of AD. The rivastigmine patch offers several advantages over the capsule form, including decreased peak to trough plasma fluctuations, reduced rates of nausea and vomiting, better treatment adherence, higher probability of reaching the target dose, ease of administration, and greater satisfaction among caregivers. These factors may be especially important in patients with severe AD, in which patients are more vulnerable to adverse side effects from higher doses. While the patch is more expensive than generic therapies, patient populations that may benefit from the patch include those that are particularly sensitive to GI side effects, have chronic gastrointestinal problems, have difficulty swallowing medications, or have failed to respond with high doses of other generic options.

Reinforcement of subarachnoid block by epidural volume effect in lower abdominal surgery: A comparison between fentanyl and tramadol for efficacy and block properties

PubMed Central

Mohan, Atiharsh; Singh, Preet Mohinder; Malviya, Deepak; Arya, Sunil Kumar; Singh, Dinesh Kumar

2012-01-01

Background: Epidural volume extension (EVE) is claimed to increase the block height and decrease the dose requirement for intrathecal drug. However, almost all studies have been done in obstetric population and none actually compares the effect of additional drugs added to epidural volume. Materials and Methods: Seventy-five (ASA I and II) patients scheduled for lower abdominal surgery were randomly divided into three groups. All groups received intrathecal 10 mg bupivacaine; two groups received additional 10 ml of normal saline epidurally with 25 mg tramadol or 25 mg of fentanyl. Groups were than compared for maximal block height, rate of sensory block regression to T10, and motor block regression to Bromage scale of 0. Time to first analgesia and adverse effects were also compared among the three groups. Materials and Methods: Seventy-five (ASA I and II) patients scheduled for lower abdominal surgery were randomly divided into three groups. All groups received intrathecal 10 mg bupivacaine; two groups received additional 10 ml of normal saline epidurally with 25 mg tramadol or 25 mg of fentanyl. Groups were than compared for maximal block height, rate of sensory block regression to T10, and motor block regression to Bromage scale of 0. Time to first analgesia and adverse effects were also compared among the three groups. Results: Groups with EVE had statistically significant higher block height, with a significant faster regression that the control group. However, both fentanyl and tramadol groups were inseparable in respect to motor or sensory block regression. Fentanyl group had maximal time to first analgesia, followed by tramadol and control groups. Hemodynamic alterations were also more common in EVE groups. Conclusion: EVE can increase the block height significantly, but it seems to be limited only to the physical property of additional volume in epidural space and fentanyl or tramadol do not seem to differ in their ability to alter block properties. PMID:25885615

Hot and Cold Drugs: National Park Service Medication Stability at the Extremes of Temperature.

PubMed

Armenian, Patil; Campagne, Danielle; Stroh, Geoff; Ives Tallman, Crystal; Zeng, William Z D; Lin, Thomas; Gerona, Roy R

2017-01-01

National Park Service (NPS) Parkmedics provide medical care in austere environments. The objective of this study was to evaluate the stability of specific medications used by Parkmedics at extremes of temperatures likely to be faced in the field. This is a bench research study conducted in the laboratory setting over a 4-week period. Parenteral medications were separated into 4 temperature exposure groups: A) 45°C (hot); B) -20°C (cold); C) hot then cold temperatures alternating weekly; and D) cold then hot temperatures alternating weekly. At study start and the end of each week, three aliquots from each group were sampled to determine the remaining drug concentration through liquid chromatography-quadrupole time-of-flight mass spectrometry (Agilent LC 1260- QTOF/MS 6550). Quantitative analysis was done using Agilent MassHunter Quantitative Analysis software. The mean drug concentration from triplicate aliquots was expressed as percentage of its baseline concentration to monitor the drug's stability during storage. Eight medications were analyzed (atropine, diphenhydramine, fentanyl, hydromorphone, midazolam, morphine, naloxone, ondansetron). Hydromorphone, morphine, and ondansetron showed the greatest stability, at above 90% of original concentration in all study arms. Diphenhydramine, fentanyl and midazolam showed heat independent degradation, degrading the same way regardless of heat exposure. By the end of the study period, 51-56% midazolam remained in all groups. Atropine and naloxone showed heat dependent degradation, degrading more when exposed to heat. Atropine had the most degradation, being undetectable after 4 weeks of heat exposure. We recommend that EMS providers replace atropine, naloxone, diphenhydramine, fentanyl, and midazolam frequently if they are practicing in low call volume or high-temperature environments. Further studies will be needed to determine if re-dosing midazolam, naloxone, and atropine is the appropriate clinical strategy in this setting if adequate clinical effect is not reached with a single dose.

Crystallographic and theoretical studies of an inclusion complex of β-cyclodextrin with fentanyl.

PubMed

Ogawa, Noriko; Nagase, Hiromasa; Loftsson, Thorsteinn; Endo, Tomohiro; Takahashi, Chisato; Kawashima, Yoshiaki; Ueda, Haruhisa; Yamamoto, Hiromitsu

2017-10-15

The crystal structure of an inclusion complex of β-cyclodextrin (β-CD) with fentanyl was determined by single crystal X-ray diffraction analysis. The crystal belongs to the triclinic space group P1 and the complex comprises one fentanyl, two β-CD, and several water molecules. β-CD and fentanyl form a host-guest inclusion complex at a ratio of 2:1 and the asymmetric unit of the complex contains two host molecules (β-CDs) in a head-to-head arrangement that form dimers through hydrogen bonds between the secondary hydroxyl groups of β-CD and one guest molecule. Fentanyl is totally contained within the β-CD cavity and the structure of the phenylethyl part of fentanyl inside the dimeric cavity of the complex is disordered. Furthermore, theoretical molecular conformational calculations were conducted to clarify the mobility of the guest molecule in the β-CD cavity using CONFLEX software. Crystal optimization and crystal energy calculations were also conducted. The results of the theoretical calculations confirmed that the conformation of disorder part 1, which was high in occupancy by crystal structure analysis, was more stable. The phenylethyl part of fentanyl existed in several stable conformations. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of a Low-Dose Contraceptive Patch on Efficacy, Bleeding Pattern, and Safety

PubMed Central

Wiegratz, Inka; Bassol, Susana; Weisberg, Edith; Mellinger, Uwe

2014-01-01

This Phase III, uncontrolled, open-label, multicenter study was conducted to investigate the contraceptive efficacy, bleeding pattern, and cycle control of a novel once-a-week contraceptive patch, delivering low-dose ethinyl estradiol (EE) and gestodene (GSD) at the same systemic exposure seen after oral administration of a combined oral contraceptive containing 0.02 mg EE/0.06 mg GSD. Participants were women aged 18 to 35 years, all of whom received the EE/GSD patch for 13 cycles each of 21 treatment days (one patch per week for 3 weeks) followed by a 7-day, patch-free interval. The primary efficacy variable was the occurrence of unintended pregnancies during the study period as assessed by life table analysis and the Pearl Index. Secondary efficacy variables were days with bleeding during four 90-day reference periods and during 1 treatment year, bleeding pattern, and cycle control. The Kaplan-Meier probability of contraceptive protection after 364 treatment days was 98.8% and the adjusted Pearl Index was 0.81. The percentage of participants with intracyclic bleeding/spotting decreased over time, from 11.4% to 6.8% in cycles 1 and 12, respectively. Almost all participants (range: 90.8%-97.6%) experienced withdrawal bleeding across the study period. Compliance was very high (mean: 97.9%; median: 100%). The most frequent adverse events were headache (9.5%) and application site reaction (8.5%); no clinically significant safety concerns were observed. Results suggest the EE/GSD patch is highly effective in preventing pregnancy. Menstrual bleeding pattern was favorable and within the ranges expected of a healthy female population. The patch was well tolerated and treatment compliance was high. PMID:24784719

Optimization of the radioimmunoassays for measuring fentanyl and alfentanil in human serum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schuettler, J.; White, P.F.

Measurement of serum fentanyl and alfentanil concentrations by radioimmunoassay (RIA) may result in significant errors and high variability when the technique described in the available fentanyl and alfentanil RIA kits is used. The authors found a 29-94% overestimation of measured fentanyl and alfentanil serum levels when 3H-fentanyl or 3H-alfentanil was added lastly to the mixture of antiserum and sample. This finding is related to a reduction in binding sites for the labeled compounds after preincubation of sample and antiserum. If this sequence is used, it becomes necessary to extend the incubation period up to 6 h for fentanyl and upmore » to 10 h for alfentanil in order to achieve equilibration between unlabeled and labeled drug with respect to antiserum binding. However, when antiserum is added lastly to the mixture of sample and labeled drug, measurement accuracy and precision for fentanyl and alfentanil serum concentrations are enhanced markedly. In addition, it is important to perform the calibration curves and sample measurements using the same medium (i.e., serum alone or a serum/buffer dilution). In summary, to optimize the RIA for fentanyl and alfentanil, the authors recommend the following: 1) adding the antiserum lastly to the mixture of sample and labeled drug; 2) performing calibration curves using patient's blank serum when possible; 3) carefully examining and standardizing each step of the RIA procedure to reduce variability, and, finally; 4) comparing results with those of other established RIA laboratories.« less

[Continued Use of Rotigotine Transdermal Patches for Parkinson Disease].

PubMed

Yasutaka, Yuki; Fujioka, Shinsuke; Shibaguchi, Hirotomo; Imakyure, Osamu; Washiyama, Atsushi; Tsuboi, Yoshio; Futagami, Koujiro

2016-06-01

Transdermal patches containing rotigotine, a dopamine agonist (DA) for treatment of Parkinson disease, continuously exert stable effects when applied once daily. Therefore, they are expected to reduce the patient burdens due to complications such as wearing-off and dysphagia. However, dosing is occasionally reduced or discontinued after application because of several reasons such as skin reactions or unsatisfactory efficacy. To identify the risk factors involved in the reduced or discontinued use of rotigotine patches, a retrospective study was conducted with reference to the medical records of patients with Parkinson disease who received rotigotine patches in our hospital. 85 patients were involved in this study. Dosing of rotigotine was reduced or discontinued in 53 patients during the study period. The factors associated with charges in treatment included combination therapy with clonazepam and oral administration of another DA before the application of rotigotine. The reduction or discontinuation rate of rotigotine patches in patients who reduced the equivalent dose of DA on the introduction of rotigotine patches was 94.7%, showing a significantly higher rate compared with 61.3% in the increased dose group. To improve adherence to rotigotine patch therapy, physicians need to carefully consider concomitant drugs and total dose of DAs. (Received December 7, 2015; Accepted February 22, 2016; Published June 1, 2016).

A review: Fentanyl and non-pharmaceutical fentanyls.

PubMed

Suzuki, Joji; El-Haddad, Saria

2017-02-01

Fentanyl and non-pharmaceutical fentanyls (NPFs) have been responsible for numerous outbreaks of overdoses all over the United States since the 1970s. However, there has been a growing concern in recent years that NPFs are contributing to an alarming rise in the number of opioid-related overdoses. The authors conducted a narrative review of the published and grey literature on fentanyl and NPFs in PubMed, Google Scholar, and Google using the following search terms: "fentanyl", "non-pharmaceutical fentanyl", "fentanyl analogs", "fentanyl laced heroin" and "fentanyl overdose". References from relevant publications and grey literature were also reviewed to identify additional citations for inclusion. The article reviews the emergence and misuse of fentanyl and NPFs, their clinical pharmacology, and the clinical management and prevention of fentanyl-related overdoses. Fentanyl and NPFs may be contributing to the recent rise in overdose deaths in the United States. There is an urgent need to educate clinicians, researchers, and patients about this public health threat. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Hydroxyisohexyl 3-cyclohexene carboxaldehyde allergy: relationship between patch test and repeated open application test thresholds.

PubMed

Fischer, L A; Menné, T; Avnstorp, C; Kasting, G B; Johansen, J D

2009-09-01

Hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) is a synthetic fragrance ingredient. Case reports of allergy to HICC appeared in the 1980s, and HICC has recently been included in the European baseline series. Human elicitation dose-response studies performed with different allergens have shown a significant relationship between the patch-test threshold and the repeated open application test (ROAT) threshold, which mimics some real-life exposure situations. Fragrance ingredients are special as significant amounts of allergen may evaporate from the skin. The study aimed to investigate the relationship between elicitation threshold doses at the patch test and the ROAT, using HICC as the allergen. The expected evaporation rate was calculated. Seventeen HICC-allergic persons were tested with a dilution series of HICC in a patch test and a ROAT (duration up to 21 days). Seventeen persons with no HICC allergy were included as control group for the ROAT. Results The response frequency to the ROAT (in microg HICC cm(-2) per application) was significantly higher than the response frequency to the patch test at one of the tested doses. Furthermore the response rate to the accumulated ROAT dose was significantly lower at half of the doses compared with the patch test. The evaporation rate of HICC was calculated to be 72% over a 24-h period. The ROAT threshold in dose per area per application is lower than the patch test threshold; furthermore the accumulated ROAT threshold is higher than the patch test threshold, which can probably be explained by the evaporation of HICC from the skin in the open test.

Fentanyl Ameliorates Severe Acute Pancreatitis-Induced Myocardial Injury in Rats by Regulating NF-κB Signaling Pathway

PubMed Central

Wang, Yayun; Chen, Manhua

2017-01-01

Background Acute pancreatitis (AP) is a sudden inflammation of the pancreas. It results in multiple, severe complications, and 15–20% of patients develop severe acute pancreatitis (SAP) with mortality as high as 30%. Consequently, it is imperative to develop an effective therapy for SAP. Material/Methods We used 30 adult male Sprague Dawley (SD) rats. Rats were randomly divided into 3 groups – sham, SAP, and fentanyl+SAP – with 10 rats in each group. An automatic biochemical analyzer was used to analyze the concentration of creatine kinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH). Terminal-deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay was applied to assess the cell apoptosis rate. Pathological changes in pancreas/heart were detected with hematoxylin and eosin (HE) staining. Western immunoblot assay was used to analyze protein levels of interleukin (IL)-1β, IL-6, and IκB. Results Fentanyl pre-treatment inhibits SAP-induced elevation of CK-MB/LDH concentrations in serum. Compared with the sham group, SAP generates a higher brown/yellow staining rate, which is abated by fentanyl. In the pancreas, SAP generated more serious interstitial edema/hemorrhage and fat necrosis than in the sham group, which are attenuated by fentanyl. Likewise, compared to the sham group, SAP generates swelled/disordered myocardial fibers and congested blood vessels in myocardium, which are ameliorated by fentanyl. In the sham group, there was little IL-1β/IL-6, and fentanyl significantly inhibited SAP-induced up-regulation of IL-1β/IL-6 levels. Compared with the sham group, SAP significantly reduced IκB level, which was rescued by fentanyl. Conclusions Fentanyl effectively alleviates SAP-induced pancreas and heart injuries through regulating the nuclear factor-κB (NF-κB) signaling pathway. PMID:28680032

[Neurotoxic effects of levobupivacaine and fentanyl on rat spinal cord].

PubMed

Abut, Yesim Cokay; Turkmen, Asli Zengin; Midi, Ahmet; Eren, Burak; Yener, Nese; Nurten, Asiye

2015-01-01

The purpose of the study was to compare the neurotoxic effects of intrathecally administered levobupivacaine, fentanyl and their mixture on rat spinal cord. In experiment, there were four groups with medication and a control group. Rats were injected 15μL saline or fentanyl 0.0005μg/15μL, levobupivacaine 0.25%/15μL and fentanyl 0.0005μg+levobupivacaine 0.25%/15μL intrathecally for four days. Hot plate test was performed to assess neurologic function after each injection at 5th, 30th and 60th min. Five days after last lumbal injection, spinal cord sections between the T5 and T6 vertebral levels were obtained for histologic analysis. A score based on subjective assessment of number of eosinophilic neurons - Red neuron - which means irreversible neuronal degeneration. They reflect the approximate number of degenerating neurons present in the affected neuroanatomic areas as follows: 1, none; 2, 1-20%; 3, 21-40%; 4, 41-60%; and 5, 61-100% dead neurons. An overall neuropathologic score was calculated for each rat by summating the pathologic scores for all spinal cord areas examined. In the results of HPT, comparing the control group, analgesic latency statistically prolonged for all four groups. In neuropathologic investment, the fentanyl and fentanyl+levobupivacaine groups have statistically significant high degenerative neuron counts than control and saline groups. These results suggest that, when administered intrathecally in rats, fentanyl and levobupivacaine behave similar for analgesic action, but fentanyl may be neurotoxic for spinal cord. There was no significant degeneration with levobupivacaine, but fentanyl group has had significant degeneration. Copyright © 2013 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

Ovarian activity in obese and nonobese women treated with three transdermal contraceptive patches delivering three different doses of ethinyl estradiol and levonorgestrel.

PubMed

Foegh, Marie; Archer, David F; Stanczyk, Frank Z; Rubin, Arkady; Mishell, Daniel R

2013-02-01

The effect of obesity on ovarian follicular suppression in women using low-estrogen dose contraceptive patches has not been determined. A Phase II, parallel-group, multicenter, three-cycle study evaluated three patches containing different ethinyl estradiol (EE) and levonorgestrel (LNG) doses. Serum levels of EE, LNG, sex hormone-binding globulin and progesterone were compared in 41 obese [body mass index (BMI) ≥30] and 75 nonobese (BMI <30) women. Suppression of ovulation during the luteal phase was dose dependent, with the highest dose (AG200-15) preventing progesterone increases in all women (cycles 2-3). In the follicular phase, the lowest-dose patch had the highest rate of increased progesterone in nonobese subjects. Progesterone levels ≥3.0 ng/mL in the follicular phase were more common in obese than nonobese women. AG200-15 suppresses ovulation in obese and nonobese women. All three patches found increased progesterone in the follicular phase, albeit more in obese versus nonobese women. Copyright © 2013 Elsevier Inc. All rights reserved.

Analyzing Milestones in Smoking Cessation: Illustration in a Nicotine Patch Trial in Adult Smokers

ERIC Educational Resources Information Center

Shiffman, Saul; Scharf, Deborah M.; Shadel, William G.; Gwaltney, Chad J.; Dang, Qianyu; Paton, Stephanie M.; Clark, Duncan B.

2006-01-01

Tests of addiction treatments seldom reveal where treatment exercises its effect (i.e., promoting initial abstinence, preventing lapses, and/or impeding progression from lapse to relapse). The authors illustrate analyses distinguishing effects on these milestones in a randomized trial of high-dose nicotine patch (35 mg; n = 188) versus placebo (n…

Multiple Fentanyl Overdoses - New Haven, Connecticut, June 23, 2016.

PubMed

Tomassoni, Anthony J; Hawk, Kathryn F; Jubanyik, Karen; Nogee, Daniel P; Durant, Thomas; Lynch, Kara L; Patel, Rushaben; Dinh, David; Ulrich, Andrew; D'Onofrio, Gail

2017-02-03

On the evening of June 23, 2016, a white powder advertised as cocaine was purchased off the streets from multiple sources and used by an unknown number of persons in New Haven, Connecticut. During a period of less than 8 hours, 12 patients were brought to the emergency department (ED) at Yale New Haven Hospital, experiencing signs and symptoms consistent with opioid overdose. The route of intoxication was not known, but presumed to be insufflation ("snorting") in most cases. Some patients required doses of the opioid antidote naloxone exceeding 4 mg (usual initial dose = 0.1-0.2 mg intravenously), and several patients who were alert after receiving naloxone subsequently developed respiratory failure. Nine patients were admitted to the hospital, including four to the intensive care unit (ICU); three required endotracheal intubation, and one required continuous naloxone infusion. Three patients died. The white powder was determined to be fentanyl, a drug 50 times more potent than heroin, and it included trace amounts of cocaine. The episode triggered rapid notification of public health and law enforcement agencies, interviews of patients and their family members to trace and limit further use or distribution of the fentanyl, immediate naloxone resupply and augmentation for emergency medical services (EMS) crews, public health alerts, and plans to accelerate naloxone distribution to opioid users and their friends and families. Effective communication and timely, coordinated, collaborative actions of community partners reduced the harm caused by this event and prevented potential subsequent episodes.

Two syringe spinal anesthesia technique for cesarean section: A controlled randomized study of a simple way to achieve more satisfactory block and less hypotension.

PubMed

Keera, Amr Aly Ismail; Elnabtity, Ali Mohamed Ali

2016-01-01

Multiple trials have been tried to prevent hypotension during spinal anesthesia. However, the drug choice and mode of administration is still a matter of debate. To compare the outcome of spinal injection of hyperbaric bupivacaine and fentanyl separately to standard injection of mixed fentanyl with hyperbaric bupivacaine. A randomized, controlled clinical trial. One hundred twenty-four parturient scheduled for elective cesarean section were randomly allocated into two groups, each 62 parturient: Group M received spinal anesthesia using 10 mg bupivacaine 0.5% premixed with 25 μg fentanyl in the same syringe and Group S received 25 μg fentanyl in one syringe and 10 mg bupivacaine 0.5% without barbotage in a second syringe. Patients with intraoperative pain that was controllable without the need for a shift to general anesthesia was significantly lower in Group S (3.2%) than in Group M (16.1%). The frequency of hypotension was significantly lower in Group S compared to Group M (P < 0.05). Time till the onset of sensory block was nonsignificantly shorter with nonsignificantly higher mean level of maximal sensory block in Group S compared to Group M (P > 0.05). There was no significant difference in the time till occurrence of hypotension, duration of hypotension, mean dose of ephedrine used for the treatment of hypotension and frequency of patients developed itching between the groups (P > 0.05). Separate intrathecal injection of fentanyl and hyperbaric bupivacaine provided a significant improvement in the quality of sensory block and significant reduction of the frequency of hypotension compared to injection of mixed medications.

An Efficient, Optimized Synthesis of Fentanyl and Related Analogs

DOE PAGES

Valdez, Carlos A.; Leif, Roald N.; Mayer, Brian P.; ...

2014-09-18

The alternate and optimized syntheses of the parent opioid fentanyl and its analogs are described. The routes presented exhibit high-yielding transformations leading to these powerful analgesics after optimization studies were carried out for each synthetic step. The general three-step strategy produced a panel of four fentanyls in excellent yields (73–78%) along with their more commonly encountered hydrochloride and citric acid salts. In conclusion, the following strategy offers the opportunity for the gram-scale, efficient production of this interesting class of opioid alkaloids.

An Efficient, Optimized Synthesis of Fentanyl and Related Analogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Valdez, Carlos A.; Leif, Roald N.; Mayer, Brian P.

The alternate and optimized syntheses of the parent opioid fentanyl and its analogs are described. The routes presented exhibit high-yielding transformations leading to these powerful analgesics after optimization studies were carried out for each synthetic step. The general three-step strategy produced a panel of four fentanyls in excellent yields (73–78%) along with their more commonly encountered hydrochloride and citric acid salts. In conclusion, the following strategy offers the opportunity for the gram-scale, efficient production of this interesting class of opioid alkaloids.

Sex Differences and the Effects of Stress on Subsequent Opioid Consumption in Adult Rats Following Adolescent Nicotine Exposure: A Psychopharmacologic Examination of the Gateway Hypothesis

DTIC Science & Technology

1997-07-18

sign of fentanyl addiction is death by drug overdose (David Hester, personal communication, 1996). The addiction and abuse liability offentanyl is high...rats, not exposed to stress, died of apparent fentanyl overdose . These two rats also had been exposed to 12 mg nicotinelkglday and died despite lower...nicotinelkglday) during adolescence was related to increased, subsequent fentanyl self-administration in non-stressed male rats. Exposure to immobilization stress

Acute Opioid-Induced Myoclonic Reaction after Use of Fentanyl as an Anesthetic Drug for an Emergency Cesarean Section.

PubMed

Almedallah, Dana Khaled; Alshamlan, Dana Yousef; Shariff, Erum Mubbashir

2018-01-01

Myoclonus is an abnormal involuntary movement that has been previously reported with administration of high doses of opioids for prolonged periods of time. In this case, however, we report an acute myoclonic reaction and review the literature on the possible causative pathophysiology. We report the case of a 24-year-old woman who was admitted for postdated cesarean section. She started to have abnormal involuntary movements after administration of an epidural anesthesia containing 700 μg of fentanyl with 115 mL (0.5) bupivacaine and 40 mL (2%) lidocaine. Upon examination, the patient was conscious, alert, and oriented. Her vital signs were stable. Her movements can be described as generalized, sudden, involuntary, jerking movements, involving the upper limbs, head, torso as well as the lower limbs. The frequency of these jerks was about every 1-2 min lasting for 10 s. There was no change in level of consciousness during these abnormal movements. The rest of the neurological examination was normal. Laboratory values showed normoglycemia and normal serum biochemistry. A routine electroencephalogram showed no epileptiform activity. Brain imaging was normal. Based on history, examination, and laboratory findings, we made the diagnosis of drug-induced myoclonus, which in this clinical scenario was secondary to fentanyl. We discontinued fentanyl and, gradually, the intensity and frequency of the abnormal movements decreased and disappeared after a few hours. A clear definitive explanation of the acute effect of opioids is still to be reached. It involves an interaction of complex neuroanatomical pathways and neurophysiological receptors. Nonetheless, a unanimous effort is needed to raise awareness about the role of opioids in the development of abnormal movements and their clinical management, to insure that they do not go unnoticed in the clinical scenarios, and to further add more scientific content that could help in reaching an explanatory theory.

Flow characterization and patch clamp dose responses using jet microfluidics in a tubeless microfluidic device.

PubMed

Resto, Pedro J; Bhat, Abhishek; Stava, Eric; Lor, Chong; Merriam, Elliot; Diaz-Rivera, Ruben E; Pearce, Robert; Blick, Robert; Williams, Justin C

2017-11-01

Surface tension passive pumping is a way to actuate flow without the need for pumps, tubing or valves by using the pressure inside small drop to move liquid via a microfluidic channel. These types of tubeless devices have typically been used in cell biology. Herein we present the use of tubeless devices as a fluid exchange platform for patch clamp electrophysiology. Inertia from high-speed droplets and jets is used to create flow and perform on-the-fly mixing of solutions. These are then flowed over GABA transfected HEK cells under patch in order to perform a dose response analysis. TIRF imaging and electrical recordings are used to study the fluid exchange properties of the microfluidic device, resulting in 0-90% fluid exchange times of hundreds of milliseconds. COMSOL is used to model flow and fluid exchange within the device. Patch-clamping experiments show the ability to use high-speed passive pumping and its derivatives for studying peak dose responses, but not for studying ion channel kinetics. Our system results in fluid exchange times slower than when using a standard 12-barrel application system and is not as stable as traditional methods, but it offers a new platform with added functionality. Surface tension passive pumping and tubeless devices can be used in a limited fashion for electrophysiology. Users may obtain peak dose responses but the system, in its current form, is not capable of fluid exchange fast enough to study the kinetics of most ion channels. Copyright © 2017 Elsevier B.V. All rights reserved.

Compliance and patching and atropine amblyopia treatments.

PubMed

Wang, Jingyun

2015-09-01

In the past 20 years, there has been a great advancement in knowledge pertaining to compliance with amblyopia treatments. The occlusion dose monitor introduced quantitative monitoring methods in patching, which sparked our initial understanding of the dose-response relationship for patching amblyopia treatment. This review focuses on current compliance knowledge and the impact it has on patching and atropine amblyopia treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Postmortem Toxicology Findings of Acetyl Fentanyl, Fentanyl, and Morphine in Heroin Fatalities in Tampa, Florida

PubMed Central

Pearson, Julia; Poklis, Justin; Poklis, Alphonse; Wolf, Carl; Mainland, Mary; Hair, Laura; Devers, Kelly; Chrostowski, Leszek; Arbefeville, Elise; Merves, Michele

2017-01-01

In the last two years, an epidemic of 40 fatal heroin overdose cases has occurred in the Tampa area of Florida. Of these cases, 14 involved fentanyl and acetyl fentanyl. Victim demographics, case histories, toxicology findings, and causes and manners of death for all 40 deaths are presented. In 26 deaths in which acetyl fentanyl or fentanyl were not involved, free and total peripheral blood morphine concentrations were consistent with fatal heroin intoxications, averaging 0.16 mg/L and 0.35 mg/L, respectively. In the heroin cases with fentanyl present (n=7), the average free morphine concentration was 0.040 mg/L, the average total morphine concentration was 0.080 mg/L, and the average fentanyl concentration was 0.012 mg/L. In the cases with heroin, fentanyl, and acetyl fentanyl (n=3), the average free morphine concentration was 0.010 mg/L, the average total morphine concentration was 0.030 mg/L, the average fentanyl concentration was 0.018 mg/L, and the average acetyl fentanyl concentration was 0.008 mg/L. In the cases involving only acetyl fentanyl (without heroin or fentanyl, n=4), the average acetyl fentanyl concentration was 0.47 mg/L and the average acetyl norfentanyl concentration was 0.053 mg/L. The presented cases, with associated drug concentrations, case histories, demographics, and causes and manners of death may help provide assistance with the interpretation of the postmortem findings. Based on case circumstances, autopsy results, and toxicology results, it is evident that fentanyl and/or acetyl fentanyl, when present, contributed to the cause of death. PMID:29034049

Postmortem Tissue Distribution of Acetyl Fentanyl, Fentanyl and their Respective Nor-Metabolites Analyzed by Ultrahigh Performance Liquid Chromatography with Tandem Mass Spectrometry

PubMed Central

Poklis, Justin; Poklis, Alphonse; Wolf, Carl; Mainland, Mary; Hair, Laura; Devers, Kelly; Chrostowski, Leszek; Arbefeville, Elise; Merves, Michele; Pearson, Julia

2015-01-01

In the last two years, an epidemic of fatal narcotic overdose cases has occurred in the Tampa area of Florida. Fourteen of these deaths involved fentanyl and/or the new designer drug, acetyl fentanyl. Victim demographics, case histories, toxicology findings and causes and manners of death, as well as, disposition of fentanyl derivatives and their nor-metabolites in postmortem heart blood, peripheral blood, bile, brain, liver, urine and vitreous humor are presented. In the cases involving only acetyl fentanyl (without fentanyl, n=4), the average peripheral blood acetyl fentanyl concentration was 0.467 mg/L (range 0.31 to .60 mg/L) and average acetyl norfentanyl concentration was 0.053 mg/L (range 0.002 to 0.086 mg/L). In the cases involving fentanyl (without acetyl fentanyl, n=7), the average peripheral blood fentanyl concentration was 0.012 mg/L (range 0.004 to 0.027 mg/L) and average norfentanyl blood concentration was 0.001 mg/L (range 0.0002 to 0.003 mg/L). In the cases involving both acetyl fentanyl and fentanyl (n=3), the average peripheral blood acetyl fentanyl concentration was 0.008 mg/L (range 0.006 to 0.012 mg/L), the average peripheral blood acetyl norfentanyl concentration was 0.001 mg/L (range 0.001 to 0.002 mg/L), the average peripheral blood fentanyl concentration was 0.018 mg/L (range 0.015 to 0.021 mg/L) and the average peripheral blood norfentanyl concentration was 0.002 mg/L (range 0.001 mg/L to 0.003 mg/L). Based on the toxicology results, it is evident that when fentanyl and/or acetyl fentanyl were present, they contributed to the cause of death. A novel ultrahigh performance liquid chromatography (UPLC) tandem mass spectrometry (MS/MS) method to identify and quantify acetyl fentanyl, acetyl norfentanyl, fentanyl and norfentanyl in postmortem fluids and tissues is also presented. PMID:26583960

Effects of acupuncture and transcutaneous stimulation analgesia on plasma hormone levels during and after major abdominal surgery.

PubMed

Kho, H G; Kloppenborg, P W; van Egmond, J

1993-05-01

The effects of acupuncture and transcutaneous electrical stimulation (TES) on plasma adrenaline (A) and noradrenaline (NA), adrenocorticotropic hormone (ACTH), beta-endorphin (beta E), anti-diuretic hormone (ADH) and hydrocortisone (cortisol) were evaluated during and, for four days after surgery in 42 male patients submitted to a standardized major abdominal operation in a comparative study of three different anaesthetic techniques. Group 1 received acupuncture and transcutaneous stimulation as the main non-pharmacological analgesic during surgery. Group 2 received moderate-dose fentanyl (initial bolus of 10 micrograms kg-1 followed by continuous infusion of 5 micrograms kg-1 h-1 for the first hour, and then 4 micrograms kg-1 h-1. Group 3 received a combination of both methods. In all three groups analgesia was supplemented, if necessary, by small bolus injections of 50 micrograms fentanyl. Anaesthesia was induced in all groups with thiopentone 5 mg kg-1 and vecuronium 0.1 mg kg-1 and patients were ventilated (N2O:O2 = 2:1) to achieve normocapnia without the use of a halogenated agent. Pre-operatively acupuncture plus TES in Groups 1 and 3 led to a rise in beta E (P < 0.05) without changes of haemodynamics. After intubation beta E did not increase further. Intubation in Group 2 led to an increase of beta E (P < 0.05) also, and to a rise in pulse rate and blood pressure (P < 0.05) in all three groups. Per-operatively acupuncture plus TES in Group 1 showed a response of circulating NA and cortisol similar to that in Groups 2 and 3, whereas the responses of the circulating A, ACTH, beta E and ADH in Group 1 were more pronounced (P < 0.01). Post-operatively no differences in the hormonal profiles could be discerned between the groups with or without acupuncture plus TES (Group 2 vs. Group 3) nor between those with or without moderate-dose fentanyl anaesthesia (Group 1 vs. Group 3). It is concluded that acupuncture and TES have no effect on the cardiovascular response to laryngoscopy and intubation. They can replace moderate-dose fentanyl anaesthesia in major abdominal surgery at the cost of a more enhanced per-operative neuroendocrine stress response, which does not, however, influence the postoperative hormonal profiles nor the rapidity of return to pre-operative values.

Pharmacological Consequence of the A118G Mu Opioid Receptor Polymorphism on Morphine- and Fentanyl-mediated Modulation of Ca2+ Channels in Humanized Mouse Sensory Neurons

PubMed Central

Mahmoud, Saifeldin; Thorsell, Annika; Sommer, Wolfgang H.; Heilig, Markus; Holgate, Joan K.; Bartlett, Selena E.; Ruiz-Velasco, Victor

2011-01-01

Background The most common functional single nucleotide polymorphism of the human OPRM1 gene, A118G, has been shown to be associated with inter-individual differences in opioid analgesic requirements, particularly with morphine, in patients with acute postoperative pain. The purpose of the present study was to examine whether this polymorphism would modulate the morphine and fentanyl pharmacological profile of sensory neurons isolated from a humanized mouse model homozygous for either the 118A or 118G allele. Methods The coupling of wild-type and mutant mu opioid receptors to voltage-gated Ca2+ channels after exposure to either ligand was examined by employing the whole-cell variant of the patch-clamp technique in acutely dissociated trigeminal ganglion neurons. Morphine-mediated antinociception was measured in mice carrying either the 118AA or 118GG allele. Results The biophysical parameters (cell size, current density, and peak current amplitude potential) measured from both groups of sensory neurons were not significantly different. In 118GG neurons, morphine was approximately 5-fold less potent and 26% less efficacious than that observed in 118AA neurons. On the other hand, the potency and efficacy of fentanyl were similar for both groups of neurons. Morphine-mediated analgesia in 118GG mice was significantly reduced compared to the 118AA mice. Conclusions This study provides evidence to suggest that the diminished clinical effect observed with morphine in 118G carriers results from an alteration of the receptor’s pharmacology in sensory neurons. Additionally, the impaired analgesic response with morphine may explain why carriers of this receptor variant have an increased susceptibility to become addicted to opioids. PMID:21926562

Increases in Fentanyl-Related Overdose Deaths - Florida and Ohio, 2013-2015.

PubMed

Peterson, Alexis B; Gladden, R Matthew; Delcher, Chris; Spies, Erica; Garcia-Williams, Amanda; Wang, Yanning; Halpin, John; Zibbell, Jon; McCarty, Carolyn Lullo; DeFiore-Hyrmer, Jolene; DiOrio, Mary; Goldberger, Bruce A

2016-08-26

In March and October 2015, the Drug Enforcement Administration (DEA) and CDC issued nationwide alerts identifying fentanyl, particularly illicitly manufactured fentanyl (IMF), as a threat to public health and safety (1,2). IMF is pharmacologically similar to pharmaceutical fentanyl (PF), but is unlawfully produced in clandestine laboratories, obtained via illicit drug markets, and includes fentanyl analogs. Fentanyl is a synthetic opioid 50-100 times more potent than morphine and approved for the management of surgical/postoperative pain, severe chronic pain, and breakthrough cancer pain.* DEA's National Forensic Laboratory Information System (NFLIS) collects drug identification results from drug cases analyzed by federal, state, and local forensic laboratories throughout the United States.(†) In 2014, 80% of fentanyl submissions (i.e., drug products obtained by law enforcement that tested positive for fentanyl) in NFLIS were identified from 10 states, including Florida and Ohio (2), and seven of these 10 states reported sharp increases in fentanyl-related overdose deaths (fentanyl deaths) (3). This report presents findings of increased fentanyl deaths during 2013-2015 from investigations conducted by the University of Florida and the Ohio Department of Public Health, in collaboration with CDC. Analyses examined the association between trends in fentanyl-related law enforcement submissions and fentanyl deaths and describes groups at risk for fentanyl death using medical examiner and coroner reports. The marked increases in fentanyl death in Florida and Ohio during 2013-2015 were closely associated with parallel increases in fentanyl submissions, with the largest impact on persons who use heroin, consistent with reports that IMF is commonly mixed with or sold as heroin (1,4). In Ohio, circumstances associated with fentanyl deaths included a current diagnosed mental health disorder(§) and recent release from an institution such as a jail, rehabilitation facility, or hospital.

Comparison of abuse, suspected suicidal intent, and fatalities related to the 7-day buprenorphine transdermal patch versus other opioid analgesics in the National Poison Data System.

PubMed

Coplan, Paul M; Sessler, Nelson E; Harikrishnan, Venkatesh; Singh, Richa; Perkel, Charles

2017-01-01

Prescription opioid related abuse, suicide and death are significant public health problems. This study compares rates of poison center calls categorized as intentional abuse, suspected suicidal intent or fatality for the 7-day buprenorphine transdermal system/patch (BTDS) with other extended-release and long-acting (ER/LA) opioids indicated for chronic pain. Retrospective 24-month cohort study using National Poison Data System data from July 2012 through June 2014. BTDS was introduced in the United States in January 2011. Numbers and rates of calls of intentional abuse, suspected suicidal intent and fatalities were evaluated for BTDS, ER morphine, ER oxycodone, fentanyl patch, ER oxymorphone and methadone tablets/capsules, using prescription adjustment to account for community availability. Rate ratios (RR) and 95% confidence intervals (CI) were calculated. Absolute numbers and prescription-adjusted rates of intentional abuse and suspected suicidal intent with BTDS were significantly lower (p < .0001) than for all other ER/LA opioid analgesics examined. No fatalities associated with BTDS exposure were reported. This post-marketing evaluation of BTDS indicates infrequent poison center calls for intentional abuse and suspected suicidal intent events, suggesting lower rates of these risks with BTDS compared to other ER/LA opioids.

Optimal intrathecal hyperbaric bupivacaine dose with opioids for cesarean delivery: a prospective double-blinded randomized trial.

PubMed

Onishi, Eiko; Murakami, Mamoru; Hashimoto, Keiji; Kaneko, Miho

2017-05-01

Single-shot spinal anesthesia is commonly used for cesarean delivery. Achieving adequate anesthesia throughout surgery needs to be balanced with associated complications. We investigated the optimal dose of intrathecal hyperbaric bupivacaine, co-administered with opioids, for anesthesia for cesarean delivery. This prospective, randomized, double-blinded, dose-ranging trial included parturients scheduled to undergo cesarean delivery under spinal anesthesia. An epidural catheter was first inserted at the T11-12 vertebral interspace, followed by spinal anesthesia at the L2-3 or L3-4 vertebral interspace. Subjects were randomly assigned to one of seven doses of intrathecal hyperbaric bupivacaine 0.5% (6, 7, 8, 9, 10, 11 or 12mg), with added 15μg fentanyl and 75μg morphine. Successful induction of anesthesia (success ind ) was defined as achievement of bilateral sensory loss to cold at the T6 dermatome or higher, within 10 minutes. Successful maintenance of anesthesia (success main ) was defined by no epidural supplementation within 60 minutes of intrathecal injection. The effective doses for 50% (ED 50 ) and 95% (ED 95 ) of patients were estimated using logistic regression analysis. The ED 50 and ED 95 for success main were 6.0mg (95% CI: 4.5 to 7.5mg) and 12.6mg (95% CI: 7.9 to 17.2mg), respectively. The incidence of respiratory discomfort and maternal satisfaction scores did not differ significantly between dose groups. Phenylephrine dose and nausea/vomiting incidence increased with increasing doses of bupivacaine. Under study conditions, our results suggest that 12.6mg of intrathecal bupivacaine, administered with fentanyl and morphine, is required to achieve adequate intraoperative analgesia without the need for epidural supplemention. Copyright © 2017 Elsevier Ltd. All rights reserved.

Index to Drug-Specific Information

MedlinePlus

... Factive (gemifloxacin) Felbamate Felbatol (felbamate) Fentanyl buccal soluble film Fentanyl buccal tablets Fentanyl nasal spray Fentanyl sublingual ... Onfi (clobazam) Onglyza (saxagliptin) Onsolis (fentanyl buccal soluble film) OptimarkM (gasoversetamide) Optison (perflutren protein-type A microspheres) ...

A toxicology-based review of fentanyl-related deaths in New Mexico (1986-2007).

PubMed

Krinsky, Clarissa S; Lathrop, Sarah L; Crossey, Michael; Baker, Ginger; Zumwalt, Ross

2011-12-01

Since its approval in the United States, fentanyl has become increasingly popular for the medical management of pain and as a substance of abuse. Fentanyl is unique among the opioids in its widespread use with a transdermal delivery system, which contributes to its unique pharmacokinetics and abuse potential. We examined the demographics of deaths with fentanyl identified on toxicologic analysis and reviewed specific challenges in the laboratory detection of postmortem fentanyl levels. The New Mexico Office of the Medical Investigator database was searched for all cases from January 1986 through December 2007 with fentanyl reported as present or quantified. Those deaths with a cause of death identified as drug overdose were then analyzed separately. From 1986 to 2007, 154 cases were identified with fentanyl present in postmortem samples, with 96 of the cases identified as fentanyl-related drug overdoses. The number of fentanyl-related deaths has increased over the past 20 years, corresponding to both statewide increases in the medical use of fentanyl and the abuse of prescription opioids. The demographics of these fentanyl-related overdoses showed that subjects were more likely to be female, white non-Hispanic, and older than those in previously described overdose deaths. Several cases were identified with central and peripheral blood samples and antemortem and postmortem samples available for fentanyl quantification. Given the uncharacteristic demographics of fentanyl-related deaths and the complexity of the laboratory analysis of fentanyl, forensic scientists must use caution in both the detection and interpretation of fentanyl concentrations.

Initial Characterization of a Gel Patch Dosimeter for In Vivo Dosimetry

PubMed Central

Matrosic, C; Culberson, W; Rosen, B; Madsen, E; Frank, G; Bednarz, B

2016-01-01

In vivo dosimetry is a greatly underutilized tool for patient safety in clinical external beam radiotherapy treatments, despite being recommended by several national and international organizations (AAPM, ICRU, IAEA, NACP). The reasons for this underutilization mostly relate to the feasibility and cost of in vivo dosimetry methods. Due to the increase in the number of beam angles and dose per fraction in modern treatments, there is a compelling need for a novel dosimeter that is robust and affordable while able to operate properly in these complex conditions. This work presents a gel patch dosimeter as a novel method of in vivo dosimetry. DEFGEL, a 6%T normoxic polyacrylamide gel, was injected into 1-cm thick acrylic molds to create 1-cm thick small cylindrical patch dosimeters. To evaluate the change in optical density due to radiation induced polymerization, dosimeters were scanned before and after irradiation using an in-house developed laser densitometer. The dose-responses of three separate batches of gel were evaluated and compared to check for linearity and repeatability. The response development time was evaluated to ensure that the patch dosimeter could be high throughput. Additionally, the potential of this system to be used as an in vivo dosimeter was tested with a clinically relevant end-to-end in vivo phantom test. All irradiations were performed with a Varian Clinac 21EX at the University of Wisconsin Medical Radiation Research Center (UWMRRC). The dose response of all three batches of gel was found to be linear within the range of 2–20 Gy. At doses below 0.5 Gy the statistical uncertainties were prohibitively large to make quantitative assessments of the results. The three batches demonstrated good repeatability in the range of 2 Gy to up to 10 Gy, with only slight variations in response at higher doses. For low doses the dosimeter fully developed within an hour while at higher doses they fully developed within four hours. During the in vivo phantom test the predicted patch absorbed dose was 4.23 Gy while the readout dose was evaluated to be 4.37 Gy, which corresponds to a 3.2% discrepancy. The dosimeter and densitometer pairing shows promise as an in vivo dosimetry system, especially for hypofractionated or MRI-guided radiotherapy treatments where higher doses are prescribed. PMID:27088207

Initial characterization of a gel patch dosimeter for in vivo dosimetry

NASA Astrophysics Data System (ADS)

Matrosic, C.; Culberson, W.; Rosen, B.; Madsen, E.; Frank, G.; Bednarz, B.

2016-05-01

In vivo dosimetry is a greatly underutilized tool for patient safety in clinical external beam radiotherapy treatments, despite being recommended by several national and international organizations (AAPM, ICRU, IAEA, NACP). The reasons for this underutilization mostly relate to the feasibility and cost of in vivo dosimetry methods. Due to the increase in the number of beam angles and dose per fraction in modern treatments, there is a compelling need for a novel dosimeter that is robust and affordable while able to operate properly in these complex conditions. This work presents a gel patch dosimeter as a novel method of in vivo dosimetry. DEFGEL, a 6% T normoxic polyacrylamide gel, was injected into 1 cm thick acrylic molds to create 1 cm thick small cylindrical patch dosimeters. To evaluate the change in optical density due to radiation induced polymerization, dosimeters were scanned before and after irradiation using an in-house developed laser densitometer. The dose-responses of three separate batches of gel were evaluated and compared to check for linearity and repeatability. The response development time was evaluated to ensure that the patch dosimeter could be high throughput. Additionally, the potential of this system to be used as an in vivo dosimeter was tested with a clinically relevant end-to-end in vivo phantom test. All irradiations were performed with a Varian Clinac 21EX at the University of Wisconsin Medical Radiation Research Center (UWMRRC). The dose-response of all three batches of gel was found to be linear within the range of 2-20 Gy. At doses below 0.5 Gy the statistical uncertainties were prohibitively large to make quantitative assessments of the results. The three batches demonstrated good repeatability in the range of 2 Gy to up to 10 Gy, with only slight variations in response at higher doses. For low doses the dosimeter fully developed within an hour while at higher doses they fully developed within four hours. During the in vivo phantom test the predicted patch absorbed dose was 4.23 Gy while the readout dose was evaluated to be 4.37 Gy, which corresponds to a 3.2% discrepancy. The dosimeter and densitometer pairing shows promise as an in vivo dosimetry system, especially for hypofractionated or MRI-guided radiotherapy treatments where higher doses are prescribed.

High-dose buprenorphine: perioperative precautions and management strategies.

PubMed

Roberts, D M; Meyer-Witting, M

2005-02-01

Buprenorphine has been in clinical use in anaesthesia for several decades. Recently, the high-dose sublingual formulation (Subutex, Reckitt Benckiser, Slough, U.K.) has been increasingly used as maintenance therapy in opioid dependence, as an alternative to methadone and other pharmacological therapies. Buprenorphine has unique pharmacological properties making it well suited for use as a maintenance therapy in opioid dependence. However, these same properties may cause difficulty in the perioperative management of pain. Buprenorphine is a partial opioid agonist, attenuating the effects of supplemental illicit or therapeutic opioid agonists. As a result of its high receptor affinity, supplemental opioids do not readily displace buprenorphine from the opioid receptor in standard doses. High-dose buprenorphine has an extended duration of action that prolongs both of these effects. The perioperative management of patients stabilized on high-dose buprenorphine and undergoing surgery requires consideration of the likely analgesic requirements. Where possible the buprenorphine should be continued. Pain management should focus on maximizing non-opioid analgesia, local anaesthesia and non-pharmacological techniques. Where pain may not be adequately relieved by these methods, the addition of a full opioid agonist such as fentanyl or morphine at appropriate doses should be considered, accompanied by close monitoring in a high dependency unit. In situations where this regimen is unlikely to be effective, preoperative conversion to morphine or methadone may be an option. Where available, liaison with a hospital-based alcohol and drug service should always be considered.

Geographic differences in perioperative opioid administration in children

PubMed Central

Rabbitts, Jennifer A.; Groenewald, Cornelius B.; Räsänen, Jukka

2012-01-01

Objectives To investigate whether geographic differences exist in perioperative opioid administration to children. Aim To investigate whether perioperative fentanyl use for cleft lip and palate surgery varies between children of three different geographic regions. Background Differences have been found in perioperative opioid administration to children of differing ethnicity in the U.S.A. Whether similar differences exist in perioperative opioid administration to children residing in different geographic regions is unknown. Methods/materials We retrospectively reviewed the medical records of ASA I children who underwent surgery under standardized general anesthesia between January 2010 and April 2011 during SMILE Network International mission trips to Africa, India and Central and South America. Perioperative administration of fentanyl was compared between these three locations. Results We analyzed data from 79 children who underwent surgery in Africa, 76 in India and 153 in Central and South America. Children in Central and South America were given less than 50% of the intraoperative amount of fentanyl (2.0 ± 1.2 mcg/kg) administered to children in Africa (4.1 ± 2.4 mcg/kg; p<0.001) and children in India (4.3 ± 2.2 mcg/kg; p < 0.001). Postoperatively, fentanyl was administered in equivalent doses to all groups. Conclusions Children in Central and South America received less opioid intraoperatively than African and Indian children, under standardized anesthesia for cleft surgeries. Further research is necessary to elucidate the mechanisms underlying these group differences. PMID:22324378

Nebulized fentanyl vs intravenous morphine for ED patients with acute abdominal pain: a randomized double-blinded, placebo-controlled clinical trial.

PubMed

Deaton, Travis; Auten, Jonathan D; Darracq, Michael A

2015-06-01

Patients with acute abdominal pain commonly present to emergency departments. The safe and effective relief of discomfort is a concern to patients and physicians. Intravenous opioids are the traditional method used to provide pain relief in this setting, but intravenous access is time consuming and not always achievable. Alternative methods of pain control may therefore be necessary for the acute management of painful conditions without adding to the overall physical or psychological discomfort. The purpose of this study was to evaluate the feasibility of nebulized fentanyl (NF) in the alleviation of acute and undifferentiated abdominal pain. We also sought to compare NF with intravenous morphine (IVM) and to assess patient and provider satisfaction with NF. Nebulized fentanyl (2 μg/kg) was compared to IVM (0.1 mg/kg) at 10, 20, 30, and 40 minutes; and patient and physician satisfaction was recorded. The NF group experienced more rapid pain relief and more sustained and clinically significant pain relief over the 40-minute study interval. There were no adverse effects noted in the NF group. Both patient and physician satisfaction scores were higher in the NF group. Fentanyl citrate at a dose of 2 μg/kg through a breath-actuated nebulizer appears to be a feasible and safe alternative to IVM (0.1 mg/kg) in the treatment of acute abdominal pain. Copyright © 2015 Elsevier Inc. All rights reserved.

Comparison of bupivacaine and ropivacaine in combination with fentanyl used for walking epidural anesthesia in labor

PubMed Central

Gündüz, Şükrü; Eriş Yalçın, Serenat; Karakoç, Gökhan; Akkurt, Mehmet Özgür; Yalçın, Yakup; Yavuz, And

2017-01-01

Objective: Effective pain relief during labor is essential to reduce maternal and perinatal morbidity arising due to pain-induced maternal sympathetic activation, and to avoid unnecessary cesarean sections performed due to maternal anxiety. Walking epidural analgesia on labor reveals lower pain scores, leading to higher maternal satisfaction with better cardiovascular and pulmonary physiology. Despite the extensive use and relative safety of bupivacaine, newer drugs such as ropivacaine have been developed as alternative agents to decrease the risk for cardiac and central nervous system toxicity. Materials and Methods: One hundred women who requested epidural analgesia in active labor were randomly allocated into two groups; one group received 20 mL of ropivacaine 0.125% with fentanyl 50 µg and the other received 20 mL of bupivacaine 0.125% with fentanyl 50 µg. The efficacy of analgesia, adverse effects, and obstetric and neonatal outcomes of both groups were compared. Results: There were no differences between the two study groups in the measured obstetric and neonatal outcomes. The onset time, duration of analgesia, and sensory levels were similar between the groups. Visual analog pain scale scores did not differ between the groups before analgesia or at any of the subsequent evaluation periods. Conclusion: Both ropivacaine and bupivacaine provide equivalent labor analgesia with high maternal satisfaction and tolerable adverse effects in the clinically used dose range. No adverse obstetric or neonatal outcomes were observed in either group. Therefore, either drug is a reasonable choice for labor analgesia and can be used without jeopardizing the safety of the mother and fetus. PMID:29085707

Pretreatment with remifentanil, fentanyl, or lidocaine to prevent withdrawal after rocuronium using venous occlusion technique in children and adolescents: a prospective randomized placebo-controlled double-blind study.

PubMed

Abu-Halaweh, S A; Aloweidi, A K; Qudaisat, I Y; Al-Hussami, M O; Al Zaben, K R; Abu-Halaweh, A S

2014-12-01

Pain caused by intravenous injection of the muscle relaxant rocuronium bromide is common in children and adolescents. The cause of this unwanted effect is still unclear, and different pretreatment drugs have been administered in attempts to alleviate this side effect, with varying degrees of success. This study used a 60-s venous occlusion technique to evaluate the effectiveness of pretreatment with lidocaine, fentanyl, or remifentanil in preventing pain-induced withdrawal caused by intravenous injection of rocuronium bromide during the induction of general anesthesia. One hundred and one child and adolescent patients, ASA Ι-II, requiring various surgical procedures under general anesthesia with muscle relaxation and mechanical ventilation, were enrolled. Patients were allocated randomly using computer-generated randomization into one of four pretreatment groups: a remifentanil group (1 µg/kg, n = 25), fentanyl group (1 µg/kg, n = 26), lidocaine 1% group (0.5 mg/kg, n = 25), and normal saline group (n = 25). Drug doses were prepared in normal saline to a total volume of 5 ml. Venous occlusion was applied 10 cm above the venous access site. Pretreatment drugs were injected and retained for 60 s at the site of injection by an anesthetist blinded to group allocation. After release of the tourniquet, rocuronium (0.5 mg/kg) was then injected over 5 s, and withdrawal was recorded by another anesthetist blinded to group allocation. Descriptive statistics, analysis of variance, and a chi-squared test were used to statistically analyze the results as appropriate. Compared to normal saline, all other pretreatment groups scored a significantly lower mean of withdrawal response (P < 0.001). Lidocaine was superior to both remifentanil (P < 0.05) and fentanyl (P < 0.05) in suppressing the withdrawal response to rocuronium injection. Remifentanil was superior to fentanyl in suppressing the withdrawal response caused by rocuronium injection (P < 0.001). Using a venous occlusion technique for 60 s, lidocaine was found to be most effective in preventing the withdrawal effect caused by rocuronium injection in children and adolescents. Lidocaine was superior to remifentanil which, in turn, was more effective than fentanyl.

Fentanyl Enhances Hepatotoxicity of Paclitaxel via Inhibition of CYP3A4 and ABCB1 Transport Activity in Mice

PubMed Central

Pan, Jia-Hao; Bi, Bing-Tian; Feng, Kun-Yao; Huang, Wan; Zeng, Wei-An

2015-01-01

Fentanyl, a potent opioid analgesic that is used to treat cancer pain, is commonly administered with paclitaxel in advanced tumors. However, the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanism of action is not well studied. The purpose of this study was to investigate the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanisms of action. Pharmacokinetic parameters of paclitaxel were tested using reversed phase high-performance liquid chromatography (RP-HPLC). Aspartate transaminase (AST), alanine aminotransferase (ALT), and mouse liver histopathology were examined. Moreover, the cytotoxicity of anti-carcinogens was examined using 1-(4, 5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), and the intracellular accumulation of doxorubicin and rhodamine 123 was detected by flow cytometry. Furthermore, the expression of ABCB1 and the activity of ABCB1 ATPase and CYP3A4 were also examined. In this study, the co-administration of fentanyl and paclitaxel prolonged the half-life (t1/2) of paclitaxel from 1.455 hours to 2.344 hours and decreased the clearance (CL) from 10.997 ml/h to 7.014 ml/h in mice. Fentanyl significantly increased the levels of ALT in mice to 88.2 U/L, which is more than 2-fold higher than the level detected in the control group, and it increased the histological damage in mouse livers. Furthermore, fentanyl enhanced the cytotoxicity of anti-carcinogens that are ABCB1 substrates and increased the accumulation of doxorubicin and rhodamine 123. Additionally, fentanyl stimulated ABCB1 ATPase activity and inhibited CYP3A4 activity in the liver microsomes of mice. Our study indicates that the obvious hepatotoxicity during this co-administration was due to the inhibition of CYP3A4 activity and ABCB1 transport activity. These findings suggested that the accumulation-induced hepatotoxicity of paclitaxel when it is combined with fentanyl should be avoided. PMID:26633878

Steady-state plasma concentration profile of transdermal rotigotine: an integrated analysis of three, open-label, randomized, phase I multiple dose studies.

PubMed

Elshoff, Jan-Peer; Braun, Marina; Andreas, Jens-Otto; Middle, Michelle; Cawello, Willi

2012-04-01

The dopamine agonist rotigotine is formulated in a transdermal delivery system (patch) for once-daily application. It has been reported as efficacious in the treatment of idiopathic Parkinson's disease (PD) and restless legs syndrome. This article summarizes the results of 3 clinical studies conducted to characterize the 24-hour pharmacokinetic profile of rotigotine in steady state and the effect of different patch application sites on this profile. In addition, the relative bioavailability of a single, large patch versus 2 smaller patches was assessed. One Phase I study (SP871) assessed the steady-state pharmacokinetic properties at different application sites at a rotigotine maintenance dose of 3 mg/24 hours in healthy participants. Due to tolerability issues, the steady-state pharmacokinetic properties of rotigotine at higher doses (8 mg/24 hours) was assessed in 2 Phase I studies (SP630, SP651) in early-stage PD patients. Relative rotigotine bioavailability from a 40 cm(2) patch versus 2 × 20 cm(2) patches (SP651) and from a 15 cm(2) patch versus 1 × 5 cm(2) + 1 × 10 cm(2) patches (SP871) was also evaluated. Rotigotine concentrations in plasma were analyzed using a validated LC-MS/MS method. The pharmacokinetic variables were calculated using standard noncompartmental analysis. Release of rotigotine to the skin was 31% to 62% of total drug content in the patch. Variability of rotigotine exposure was low within participants (15%) compared with the variability observed between participants (54%). Rotigotine exposure increased proportionally in the therapeutic dose range of 2 mg/24 hours to 8 mg/24 hours. Plasma concentrations at steady state were stable over the 24-hour patch-on period. Delivery via a single, large patch compared with a combination of smaller patches did not appear to influence exposure to rotigotine. Bioavailability showed some variability depending on patch application site (hip, shoulder, abdomen, flank, thigh, upper arm); the respective mean ratios for AUC ranged between 0.87 (abdomen vs flank) and 1.46 (shoulder vs thigh). Continuous rotigotine delivery via a once-daily transdermal patch generated stable mean steady-state 24-hour plasma concentrations in healthy participants as well as patients with early-stage PD. Doses were achieved either by application of 1 large patch or a combination of smaller patches, resulting in the same total surface area. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Deaths Involving Fentanyl, Fentanyl Analogs, and U-47700 - 10 States, July-December 2016.

PubMed

O'Donnell, Julie K; Halpin, John; Mattson, Christine L; Goldberger, Bruce A; Gladden, R Matthew

2017-11-03

Preliminary estimates of U.S. drug overdose deaths exceeded 60,000 in 2016 and were partially driven by a fivefold increase in overdose deaths involving synthetic opioids (excluding methadone), from 3,105 in 2013 to approximately 20,000 in 2016 (1,2). Illicitly manufactured fentanyl, a synthetic opioid 50-100 times more potent than morphine, is primarily responsible for this rapid increase (3,4). In addition, fentanyl analogs such as acetylfentanyl, furanylfentanyl, and carfentanil are being detected increasingly in overdose deaths (5,6) and the illicit opioid drug supply (7). Carfentanil is estimated to be 10,000 times more potent than morphine (8). Estimates of the potency of acetylfentanyl and furanylfentanyl vary but suggest that they are less potent than fentanyl (9). Estimates of relative potency have some uncertainty because illicit fentanyl analog potency has not been evaluated in humans. This report describes opioid overdose deaths during July-December 2016 that tested positive for fentanyl, fentanyl analogs, or U-47700, an illicit synthetic opioid, in 10 states participating in CDC's Enhanced State Opioid Overdose Surveillance (ESOOS) program.* Fentanyl analogs are similar in chemical structure to fentanyl but not routinely detected because specialized toxicology testing is required. Fentanyl was detected in at least half of opioid overdose deaths in seven of 10 states, and 57% of fentanyl-involved deaths also tested positive for other illicit drugs, such as heroin. Fentanyl analogs were present in >10% of opioid overdose deaths in four states, with carfentanil, furanylfentanyl, and acetylfentanyl identified most frequently. Expanded surveillance for opioid overdoses, including testing for fentanyl and fentanyl analogs, assists in tracking the rapidly changing illicit opioid market and informing innovative interventions designed to reduce opioid overdose deaths.

The dose-response relationship between the patch test and ROAT and the potential use for regulatory purposes.

PubMed

Fischer, Louise Arup; Voelund, Aage; Andersen, Klaus Ejner; Menné, Torkil; Johansen, Jeanne Duus

2009-10-01

Allergic contact dermatitis is common and can be prevented. The relationship between thresholds for patch tests and the repeated open application test (ROAT) is unclear. It would be desirable if patch test and ROAT data from already sensitized individuals could be used in prevention. The aim was to develop an equation that could predict the response to an allergen in a ROAT based on the dose-response curve derived by patch testing. Results from two human experimental elicitation studies with non-volatile allergens, nickel and the preservative methyldibromo glutaronitrile (MDBGN), were analysed by logistic dose-response statistics. The relation for volatile compounds was investigated using the results from experiments with the fragrance chemicals hydroxyisohexyl 3-cyclohexene carboxaldehyde and isoeugenol. For non-volatile compounds, the outcome of a ROAT can be estimated from the patch test by: ED(xx)(ROAT) = 0.0296 ED(xx)(patch test). For volatile compounds, the equation predicts that the response in the ROAT is more severe than the patch test response, but it overestimates the response. This equation may be used for non-volatile compounds other than nickel and MDBGN, after further validation. The relationship between the patch test and the ROAT can be used for prevention, to set safe levels of allergen exposure based on patch test data.

Lactic Acid Bacteria Improves Peyer's Patch Cell-Mediated Immunoglobulin A and Tight-Junction Expression in a Destructed Gut Microbial Environment.

PubMed

Kim, Sung Hwan; Jeung, Woonhee; Choi, Il-Dong; Jeong, Ji-Woong; Lee, Dong Eun; Huh, Chul-Sung; Kim, Geun-Bae; Hong, Seong Soo; Shim, Jae-Jung; Lee, Jung Lyoul; Sim, Jae-Hun; Ahn, Young-Tae

2016-06-28

To evaluate the effects of lactic acid bacteria (LAB) on Peyer's patch cells, mice were treated with a high dose of kanamycin to disturb the gut microbial environment. The overarching goal was to explore the potential of LAB for use as a dietary probiotic that buffers the negative consequences of antibiotic treatment. In vitro, LAB stimulated the production of immunoglobulin A (IgA) from isolated Peyer's patch cells. Inflammation-related genes (TNF-α, IL-1β, and IL-8) were up-regulated in Caco-2 cells stimulated with lipopolysaccharide (LPS), while tight-junction-related genes (ZO-1 and occludin) were down-regulated; the effects of LPS on inflammatory gene and tight-junction gene expression were reversed by treatment with LAB. Mice treated with a high dose of kanamycin showed increased serum IgE levels and decreases in serum IgA and fecal IgA levels; the number of Peyer's patch cells decreased with kanamycin treatment. However, subsequent LAB treatment was effective in reducing the serum IgE level and recovering the serum IgA and fecal IgA levels, as well as the number of Peyer's patch cells. In addition, ZO-1 and occludin mRNA levels were up-regulated in the ileum tissues of mice receiving LAB treatment. Lactic acid bacteria can enhance the intestinal immune system by improving the integrity of the intestinal barrier and increasing the production of IgA in Peyer's patches. Lactic acid bacteria should be considered a potential probiotic candidate for improving intestinal immunity, particularly in mitigating the negative consequences of antibiotic use.

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

PubMed

Smith, C; McEwan, A I; Jhaveri, R; Wilkinson, M; Goodman, D; Smith, L R; Canada, A T; Glass, P S

1994-10-01

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. 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. 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. 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.

Computational design of environmental sensors for the potent opioid fentanyl

DOE PAGES

Bick, Matthew J.; Greisen, Per J.; Morey, Kevin J.; ...

2017-09-19

Here, we describe the computational design of proteins that bind the potent analgesic fentanyl. Our approach employs a fast docking algorithm to find shape complementary ligand placement in protein scaffolds, followed by design of the surrounding residues to optimize binding affinity. Co-crystal structures of the highest affinity binder reveal a highly preorganized binding site, and an overall architecture and ligand placement in close agreement with the design model. We also use the designs to generate plant sensors for fentanyl by coupling ligand binding to design stability. The method should be generally useful for detecting toxic hydrophobic compounds in the environment.

Computational design of environmental sensors for the potent opioid fentanyl

PubMed Central

Morey, Kevin J; Antunes, Mauricio S; La, David; Sankaran, Banumathi; Reymond, Luc; Johnsson, Kai; Medford, June I

2017-01-01

We describe the computational design of proteins that bind the potent analgesic fentanyl. Our approach employs a fast docking algorithm to find shape complementary ligand placement in protein scaffolds, followed by design of the surrounding residues to optimize binding affinity. Co-crystal structures of the highest affinity binder reveal a highly preorganized binding site, and an overall architecture and ligand placement in close agreement with the design model. We use the designs to generate plant sensors for fentanyl by coupling ligand binding to design stability. The method should be generally useful for detecting toxic hydrophobic compounds in the environment. PMID:28925919

Computational design of environmental sensors for the potent opioid fentanyl

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bick, Matthew J.; Greisen, Per J.; Morey, Kevin J.

Here, we describe the computational design of proteins that bind the potent analgesic fentanyl. Our approach employs a fast docking algorithm to find shape complementary ligand placement in protein scaffolds, followed by design of the surrounding residues to optimize binding affinity. Co-crystal structures of the highest affinity binder reveal a highly preorganized binding site, and an overall architecture and ligand placement in close agreement with the design model. We also use the designs to generate plant sensors for fentanyl by coupling ligand binding to design stability. The method should be generally useful for detecting toxic hydrophobic compounds in the environment.

21 CFR 522.800 - Droperidol and fentanyl citrate injection.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Droperidol and fentanyl citrate injection. 522.800... § 522.800 Droperidol and fentanyl citrate injection. (a) Specifications. Droperidol and fentanyl citrate injection is a sterile solution containing 20 milligrams of droperidol and 0.4 milligram of fentanyl citrate...

21 CFR 522.800 - Droperidol and fentanyl citrate injection.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Droperidol and fentanyl citrate injection. 522.800... § 522.800 Droperidol and fentanyl citrate injection. (a) Specifications. Droperidol and fentanyl citrate injection is a sterile solution containing 20 milligrams of droperidol and 0.4 milligram of fentanyl citrate...

21 CFR 522.800 - Droperidol and fentanyl citrate injection.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Droperidol and fentanyl citrate injection. 522.800... § 522.800 Droperidol and fentanyl citrate injection. (a) Specifications. Droperidol and fentanyl citrate injection is a sterile solution containing 20 milligrams of droperidol and 0.4 milligram of fentanyl citrate...

Acetyl fentanyl overdose fatalities--Rhode Island, March-May 2013.

PubMed

2013-08-30

In May 2013, the Rhode Island State Health Laboratories noticed an unusual pattern of toxicology results among 10 overdose deaths of suspected illicit drug users that had occurred during March 7-April 11, 2013. An enzyme-linked immunosorbent assay (ELISA) for fentanyl in blood was positive for fentanyl in all 10 cases, but confirmatory gas chromatography/mass spectrometry (GC/MS) did not detect fentanyl. The mass spectrum was instead consistent with acetyl fentanyl, a fentanyl analog. Acetyl fentanyl, a synthetic opioid, has not been documented in illicit drug use or overdose deaths, and is not available as a prescription drug anywhere. Animal studies suggest that acetyl fentanyl is up to five times more potent than heroin as an analgesic.

Prolonging the duration of single-shot intrathecal labour analgesia with morphine: A systematic review.

PubMed

Al-Kazwini, Hadeel; Sandven, Irene; Dahl, Vegard; Rosseland, Leiv Arne

2016-10-01

Single-shot spinal with bupivacaine plus fentanyl or sufentanil is commonly used as analgesia during labour, but the short duration limits the clinical feasibility. Different drugs have been added to prolong the analgesic duration. The additional effect of intra-thecal morphine has been studied during labour pain as well as after surgery. We assessed whether adding morphine to intra-thecal bupivacaine+fentanyl or sufentanil prolongs pain relief during labour. Meta-analysis of placebo-controlled randomized clinical trials of analgesia prolongation after single-shot intrathecal morphine ≤250μg during labour when given in combination with bupivacaine+fentanyl or sufentanil. After identifying 461 references, 24 eligible studies were evaluated after excluding duplicate publications, case reports, studies of analgesia after caesarean delivery, and epidural labour analgesia. Mean duration in minutes was the primary outcome measure and was included in the calculation of the standardized mean difference. Duration was defined as the time between a single shot spinal until patient request of rescue analgesia. All reported side effects were registered. Results of individual trials were combined using a random effect model. Cochrane tool was used to assess risk of bias. Five randomized placebo-controlled clinical trials (286 patients) were included in the meta-analysis. A dose of 50-250μg intrathecal morphine prolonged labour analgesia by a mean of 60.6min (range 3-155min). Adding morphine demonstrated a medium beneficial effect as we found a pooled effect of standardized mean difference=0.57 (95% CI: -0.10 to 1.24) with high heterogeneity (I 2 =88.1%). However, the beneficial effect was statistically non-significant (z=1.66, p=0.096). The lower-bias trials showed a small statistically non-significant beneficial effect with lower heterogeneity. In influential analysis, that excluded one study at a time from the meta-analysis, the effect size appears unstable and the results indicate no robustness of effect. Omitting the study with highest effects size reduces the pooled effect markedly and that study suffers from inadequate concealment of treatment allocation and blinding. Trial quality was generally low, and there were too few trials to explore sources of heterogeneity in meta-regression and stratified analyses. In general, performing meta-analyses on a small number of trials are possible and may be helpful if one is aware of the limitations. As few as one more placebo-controlled trial would increase the reliability greatly. Evidence from this systematic review suggests a possible beneficial prolonging effect of adding morphine to spinal analgesia with bupivacaine+fentanyl or +sufentanil during labour. The study quality was low and heterogeneity high. No severe side effects were reported. More adequately-powered randomized trials with low bias are needed to determine the benefits and harms of adding morphine to spinal local anaesthetic analgesia during labour. Epidural analgesia is documented as the most effective method for providing pain relief during labour, but from a global perspective most women in labour have no access to epidural analgesia. Adding morphine to single shot spinal injection of low dose bupivacaine, fentanyl or sufentanil may be efficacious but needs to be investigated. Copyright © 2016 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Subcutaneous administration of fentanyl in childbirth: an observational study on the clinical effectiveness of fentanyl for mother and neonate.

PubMed

Fleet, Julie; Jones, Meril; Belan, Ingrid

2014-01-01

to explore the maternal and neonatal effects of fentanyl administered subcutaneously to women during labour. two methods were used: (1) A retrospective audit of the birth register and maternal and neonatal records for the period from January 2000 to December 2007. (2) A pilot study was also conducted on a convenience sample of women between July 2008 and October 2008. this study was conducted within a maternity unit at a rural South Australian hospital where approximately 350 babies are birthed each year. audit participants included women who had uncomplicated pregnancies and birthed at term (37-42 weeks gestation). Women in the experimental group consisted of those who had utilised only subcutaneous fentanyl for pain relief (n=75), or nitrous oxide and oxygen prior to being administered subcutaneous fentanyl (n=196). Stratified random selection based on parity and age was used to determine the control group, which consisted of women who used no pharmacological pain relief (n=196). The pilot study involved a convenience sample of women (n=10) assessed to have an uncomplicated pregnancy and labour occurring at term (≥37 weeks gestation). audit variables examined included the women's age, parity, labour duration, mode of birth (spontaneous or assisted), analgesia used, total dosage, time administered prior to birth, time of birth, neonatal Apgar scores, time to establish breathing, naloxone use, days spent in hospital post-birth and breast-feeding outcomes upon discharge. The pilot study explored maternal effects assessed pre- and 30 minutes post-administration of subcutaneously administered fentanyl by observing pain scores, vital signs, sedation levels, nausea/vomiting scores and anti-emetic use. To assess possible adverse effects in the neonate Apgar scores, time to establish respiration, naloxone use, transfer to neonatal nursery and breast-feeding outcomes upon discharge were recorded. women in the experimental groups were more likely to be induced, experienced a longer duration of labour and had an increased likelihood of an assisted vaginal birth. The average total dose of fentanyl administered was 250 μg. Neonatal outcomes were comparable between groups when examining Apgar scores <7 at 1 and 5 minutes and time to establish breathing. There was, however, a significant difference with naloxone administration between the groups. There was no significant difference between groups in hospital stay or breast-feeding on discharge. The pilot study identified a clinically significant reduction in pain scores for 78% of women following the administration of subcutaneous fentanyl, with the average pain score decreasing from 8.4 (±1.4) to 7.2 (±1.1) (paired t-test, p=0.017). Vital signs were not affected, no anti-emetics were required and all women remained alert with no sedation noted. the audit identified fentanyl use was associated with a longer length of labour, but this may be explained by more women in the experimental groups requiring induction of labour than those in the control group. However, length of hospital stay, breast-feeding rates and neonatal outcomes were comparable amongst the three groups. Results of the pilot study are consistent with those of the audit in relation to the effects on mother and neonate. In addition, the pilot study begins to provide evidence that fentanyl is efficacious in providing pain relief. results of this study are the first to explore the effects of fentanyl administered subcutaneously to women during labour. This method of analgesia offers women an additional choice of pain relief during childbirth and may be particularly beneficial in remote and rural settings where resources are often limited and access to specialist services difficult. Further research, however, is required to be able to generalise the outcomes and provide further data to support the clinical effectiveness of this route of administration of fentanyl. Copyright © 2013 Elsevier Ltd. All rights reserved.

Is a larger refuge always better? Dispersal and dose in pesticide resistance evolution

PubMed Central

Takahashi, Daisuke; Yamanaka, Takehiko; Sudo, Masaaki; Andow, David A.

2017-01-01

The evolution of resistance against pesticides is an important problem of modern agriculture. The high‐dose/refuge strategy, which divides the landscape into treated and nontreated (refuge) patches, has proven effective at delaying resistance evolution. However, theoretical understanding is still incomplete, especially for combinations of limited dispersal and partially recessive resistance. We reformulate a two‐patch model based on the Comins model and derive a simple quadratic approximation to analyze the effects of limited dispersal, refuge size, and dominance for high efficacy treatments on the rate of evolution. When a small but substantial number of heterozygotes can survive in the treated patch, a larger refuge always reduces the rate of resistance evolution. However, when dominance is small enough, the evolutionary dynamics in the refuge population, which is indirectly driven by migrants from the treated patch, mainly describes the resistance evolution in the landscape. In this case, for small refuges, increasing the refuge size will increase the rate of resistance evolution. Our analysis distils major driving forces from the model, and can provide a framework for understanding directional selection in source‐sink environments. PMID:28422284

The usefulness of interpectoral block as an analgesic technique in breast cancer surgery.

PubMed

Ortiz de la Tabla González, R; Gómez Reja, P; Moreno Rey, D; Pérez Naranjo, C; Sánchez Martín, I; Echevarría Moreno, M

2018-04-01

To compare the analgesic efficacy of continuous interpectoral block (CIPB) compared to intravenous analgesia (IV) after breast surgery. A prospective, comparative and randomised study of women aged from 18-75years, ASAI-III, operated for breast cancer. In group1 (CIPB) after general anaesthetic, an ultrasound-guided interpectoral catheter was placed and 30mL of 0.5% ropivacaine was administered through it. In the event of an increase in heart rate and blood pressure >15% after the surgical incision, intravenous fentanyl 1μg·kg -1 was administered, repeating the dose as necessary. In the postoperative period, perfusion of ropivacaine 0.2% 5mL·h -1 ; with PCA bolus 5mL/30minutes was administered through the catheter for 24hours and rescue analgesia prescribed with 5mg subcutaneous morphine chloride. In group2 (IV), after induction of general anaesthesia, intravenous fentanyl was administered in the same way as in the other group. The patients received metamizole 2g with dexketoprofen 50mg and ondansetron 4mg postoperatively followed by perfusion of metamizole 4%, tramadol 0.2% and ondansetron 0.08% 2ml·h -1 ; with PCA bolus 2mL/20min for 24hours. The same rescue analgesia was prescribed. The principal variables recorded were pain at rest and during movement, according to a simple verbal scale (VAS 0-10) and the rescue analgesia required on discharge from recovery, at 12 and at 24hours. 137 patients were included: 81 in group1 (59.12%) and 56 in group2 (40.87%). No significant differences were observed in the analgesia between either group, but differences were observed in the dose of intraoperative fentanyl (P<.05). Differences that were not significant were observed in the rescue analgesia required on recovery (10% fewer on group1). Both techniques provided effective postoperative analgesia, but the CIPB group required significantly less intraoperative fentanyl. Copyright © 2017 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

Is a larger refuge always better? Dispersal and dose in pesticide resistance evolution.

PubMed

Takahashi, Daisuke; Yamanaka, Takehiko; Sudo, Masaaki; Andow, David A

2017-06-01

The evolution of resistance against pesticides is an important problem of modern agriculture. The high-dose/refuge strategy, which divides the landscape into treated and nontreated (refuge) patches, has proven effective at delaying resistance evolution. However, theoretical understanding is still incomplete, especially for combinations of limited dispersal and partially recessive resistance. We reformulate a two-patch model based on the Comins model and derive a simple quadratic approximation to analyze the effects of limited dispersal, refuge size, and dominance for high efficacy treatments on the rate of evolution. When a small but substantial number of heterozygotes can survive in the treated patch, a larger refuge always reduces the rate of resistance evolution. However, when dominance is small enough, the evolutionary dynamics in the refuge population, which is indirectly driven by migrants from the treated patch, mainly describes the resistance evolution in the landscape. In this case, for small refuges, increasing the refuge size will increase the rate of resistance evolution. Our analysis distils major driving forces from the model, and can provide a framework for understanding directional selection in source-sink environments. © 2017 The Author(s). Evolution published by Wiley Periodicals, Inc. on behalf of The Society for the Study of Evolution.

The analgesic efficacy of oxycodone hydrochloride versus fentanyl during outpatient artificial abortion operation: A randomized trial.

PubMed

Xie, Kangjie; Zhang, Wen; Fang, Wumei; Lian, Yanhong; Lin, Sufeng; Fang, Jun

2017-06-01

Problems like body movement, respiratory depression, and complained of pain are still common phenomenon in outpatient artificial abortion general anesthesia. Oxycodone hydrochloride is a semisynthetic opioid and has a good therapeutic effect on visceral pain. We hypothesize that oxycodone hydrochloride would be superior to fentanyl in outpatient artificial abortion surgery. In this clinical trial 149 American Society of Anesthesiologists (ASA) I or II female outpatients scheduled for elective artificial abortion surgeries under general anesthesia were randomly divided into 3 groups: oxycodone hydrochloride 0.06 mg/kg group (group A), oxycodone hydrochloride 0.08 mg/kg group (group B), and control group fentanyl 2 ug/kg (group C). The primary outcome was level body movement and respiratory depression during the surgery, the second outcome included the visual analogue scale (VAS) score 30 minutes after waking. A total of 120 participants completed the study, n = 40 in each group. There was no significant difference in patients' age, body mass index (BMI), preoperative heart rate, mean arterial blood pressure, consumption dose of propofol, intraoperative body movement type and times, and duration of surgery among the 3 groups (P > .05). Comparing the incidence of intraoperative respiratory depression and SPO2 < 90% among the 3 groups, group C's was significantly higher than those of groups A and B, and the difference was statistically significant (P < .05). Group A had no difference compared with group B. In VAS score 30minutes after waking, group C was the highest, followed by group A, with group B as the lowest. The difference among the 3 groups was statistically significant (P < .05), but a difference delta less than 1 on the VAS scale is not clinically significant. The analgesic effect of oxycodone hydrochloride at 0.06 mg/kg applied to painless artificial abortion surgery is not superior than that of fentanyl, but the incidence of intraoperative respiratory depression and hypoxemia is significantly lower than fentanyl.

Evaluation of the Coat-A-Count sup 125 I fentanyl RIA: Comparison of sup 12 5I RIA and GC/MS-SIM for quantification of fentanyl in case urine specimens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watts, V.W.; Caplan, Y.H.

The Coat-A-Count solid phase {sup 125}I Fentanyl Radioimmunoassay was evaluated with respect to linearity and precision using equine urine fortified with fentanyl and then compared with a gas chromatographic/mass spectrometric method for quantification of fentanyl in urine. The RIA assay was found to be linear over the urine fentanyl concentration range of 0.25 to 7.5 ng/mL and precise with coefficients of variation (CV) ranging from 9.6 to 19.3%. The RIA calibrators, ranging in fentanyl concentrations from 0.25 to 7.5 ng/mL, and controls, at mean fentanyl concentrations of 0.46 and 1.32 ng/mL, were compared by both the RIA and GC/MS methods.more » The cross-reactivity with the {sup 125}I RIA test was determined for the fentanyl metabolites, norfentanyl and hydroxyfentanyl, and found to be 5% and 35%, respectively. The illicit fentanyl analogs were found to show significant cross-reactivity, ranging from 20 to 100%. The {sup 125}I RIA was compared to GC/MS quantifications of fentanyl in 35 positive and 20 negative case urine specimens.« less

High Body Mass Index and Use of Fentanyl Iontophoretic Transdermal System in Postoperative Pain Management: Results of a Pooled Analysis of Six Phase 3/3B Trials.

PubMed

Viscusi, Eugene R; Ding, Li; Phipps, J Bradley; Itri, Loretta M; Schauer, Philip R

2017-06-01

Postoperative pain management can be challenging in patients with a high body mass index (BMI) especially as a result of poor venous access and delayed ambulation that can result in serious complications. Fentanyl iontophoretic transdermal system (ITS) is a needle-free, patient-controlled analgesic method available for use in acute postoperative pain. The primary objective of these analyses was to determine if there were any differences between patients with high BMI (>40 kg/m 2 ) and lower BMIs (<30 kg/m 2 and 35-40 kg/m 2 ) in terms of efficacy or safety. Data from three registration, placebo-controlled trials and three active-comparator trials using fentanyl ITS (IONSYS ® , The Medicines Company, Parsippany, NJ) for the management of postoperative pain were analyzed using BMI categories of <35 kg/m 2 , 35-40 kg/m 2 , and >40 kg/m 2 . The majority of patients had lower abdominal or orthopedic surgery. For these analyses, the primary efficacy variables were assessed via patient global assessment of pain control (PGA) at 24 h and investigator global assessment (IGA) at study discharge. PGA and IGA are categorical 4-point scales (excellent, good, fair, or poor) with treatment "success" defined as either excellent or good. Safety was evaluated via treatment emergent adverse events (TEAEs). There were 1403 patients randomly assigned and treated with fentanyl ITS for at least 3 h (BMI <35 kg/m 2 : 1180; 35-40 kg/m 2 : 136, BMI >40 kg/m 2 : 85; and 2 missing). PGA treatment success, which evaluates the method of pain control, at 24 h was consistent in the high and low BMI groups in patients treated with fentanyl ITS (<35 kg/m 2 : 946/1180 [80.2%]; 35-40 kg/m 2 : 103/136 [75.7%]; and >40 kg/m 2 : 65/85 [76.5%]). The IGA results at study discharge were similar to the PGA. Safety appeared similar with fentanyl ITS across the BMI groups. In these analyses, fentanyl ITS was as efficacious, as assessed by the PGA ratings of treatment "success", in patients with high BMI (>40 kg/m 2 ) as it was for those with lower BMIs (<35 kg/m 2 or 35-40 kg/m 2 ) and was generally well tolerated across all BMI categories.

Urushiol Patch Test Using the T.R.U.E. TEST System.

PubMed

Kim, Yesul; Longenecker, Amy; ElSohly, Mahmoud A; Gul, Waseem; Hage, Raymond J; Hamann, Curtis P; Marks, James G

Poison ivy, poison oak, and poison sumac are the most common causes of allergic contact dermatitis in North America. Although extensive efforts have been made to develop therapies that prevent and treat allergic contact dermatitis to these plants, there lacks an entirely effective method, besides complete avoidance. Efforts to develop a more effective preventive therapy, such as a vaccine, are ongoing. To accurately evaluate the efficacy of these new therapies, an appropriate assessment tool is needed. The aim of this study was to evaluate the safety and appropriate doses of urushiol required for a patch test based on the hydrogel delivery system of the Thin-Layer Rapid Use Epicutaneous Patch Test. Nine subjects were patch tested with various doses of urushiol and a negative control on day 0. Patch test sites were inspected for any local reaction on days 2, 4, 7, 14, and 21 after the initial exposure and graded by standard morphology. All 9 subjects did not have any significant adverse effects. The urushiol patch test using the hydrogel delivery method demonstrated urushiol sensitivity. All doses of urushiol resulted in a local reaction, and severity of reactions was correlated with dosage of urushiol used in the patch test.

Isoflurane minimum alveolar concentration reduction by fentanyl.

PubMed

McEwan, A I; Smith, C; Dyar, O; Goodman, D; Smith, L R; Glass, P S

1993-05-01

Isoflurane is commonly combined with fentanyl during anesthesia. Because of hysteresis between plasma and effect site, bolus administration of fentanyl does not accurately describe the interaction between these drugs. The purpose of this study was to determine the MAC reduction of isoflurane by fentanyl when both drugs had reached steady biophase concentrations. Seventy-seven patients were randomly allocated to receive either no fentanyl or fentanyl at several predetermined plasma concentrations. Fentanyl was administered using a computer-assisted continuous infusion device. Patients were also randomly allocated to receive a predetermined steady state end-tidal concentration of isoflurane. Blood samples for fentanyl concentration were taken at 10 min after initiation of the infusion and before and immediately after skin incision. A minimum of 20 min was allowed between the start of the fentanyl infusion and skin incision. The reduction in the MAC of isoflurane by the measured fentanyl concentration was calculated using a maximum likelihood solution to a logistic regression model. There was an initial steep reduction in the MAC of isoflurane by fentanyl, with 3 ng/ml resulting in a 63% MAC reduction. A ceiling effect was observed with 10 ng/ml providing only a further 19% reduction in MAC. A 50% decrease in MAC was produced by a fentanyl concentration of 1.67 ng/ml. Defining the MAC reduction of isoflurane by all the opioids allows their more rational administration with inhalational anesthetics and provides a comparison of their relative anesthetic potencies.

Isoflurane exerts neuroprotective actions at or near the time of severe traumatic brain injury.

PubMed

Statler, Kimberly D; Alexander, Henry; Vagni, Vincent; Holubkov, Richard; Dixon, C Edward; Clark, Robert S B; Jenkins, Larry; Kochanek, Patrick M

2006-03-03

Isoflurane improves outcome vs. fentanyl anesthesia, in experimental traumatic brain injury (TBI). We assessed the temporal profile of isoflurane neuroprotection and tested whether isoflurane confers benefit at the time of TBI. Adult, male rats were randomized to isoflurane (1%) or fentanyl (10 mcg/kg iv bolus then 50 mcg/kg/h) for 30 min pre-TBI. Anesthesia was discontinued, rats recovered to tail pinch, and TBI was delivered by controlled cortical impact. Immediately post-TBI, rats were randomized to 1 h of isoflurane, fentanyl, or no additional anesthesia, creating 6 anesthetic groups (isoflurane:isoflurane, isoflurane:fentanyl, isoflurane:none, fentanyl:isoflurane, fentanyl:fentanyl, fentanyl:none). Beam balance, beam walking, and Morris water maze (MWM) performances were assessed over post-trauma d1-20. Contusion volume and hippocampal survival were assessed on d21. Rats receiving isoflurane pre- and post-TBI exhibited better beam walking and MWM performances than rats treated with fentanyl pre- and any treatment post-TBI. All rats pretreated with isoflurane had better CA3 neuronal survival than rats receiving fentanyl pre- and post-TBI. In rats pretreated with fentanyl, post-traumatic isoflurane failed to affect function but improved CA3 neuronal survival vs. rats given fentanyl pre- and post-TBI. Post-traumatic isoflurane did not alter histopathological outcomes in rats pretreated with isoflurane. Rats receiving fentanyl pre- and post-TBI had the worst CA1 neuronal survival of all groups. Our data support isoflurane neuroprotection, even when used at the lowest feasible level before TBI (i.e., when discontinued with recovery to tail pinch immediately before injury). Investigators using isoflurane must consider its beneficial effects in the design and interpretation of experimental TBI research.

The Metabolites of Fentanyl and its Derivatives

DTIC Science & Technology

1988-09-01

TECHNIQUES ..... ........... 22 4.1 Stable Isotopes .... ............... .... 22 4.2 Radioisotope Tracers ... ............. .... 23 4.3 Radioimmunoassay...50 (relative to morphine).1 These properties have occasioned its popularity in surgical analgesia, especially when combined with a powerful ...studies by Janssen and coworkers, 5 carfentanil is one of the most powerful , achiral fentanyls. In addition to high potency, cis-3-methylfentanyl,5

Evaluating Response to High-Dose 13.3 mg/24 h Rivastigmine Patch in Patients with Severe Alzheimer's Disease.

PubMed

Farlow, Martin R; Sadowsky, Carl H; Velting, Drew M; Meng, Xiangyi; Islam, M Zahur

2015-06-01

To identify factors predicting improvement/stabilization on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and investigate whether early treatment responses can predict long-term outcomes, during a trial of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch in patients with severe Alzheimer's disease (AD). Logistic regression was used to relate Week 24 ADCS-CGIC score to potential baseline predictors. Additional analyses based on receiver-operating characteristic curves were performed using Week 8/16 ADCS-CGIC scores to predict response (13.3 mg/24 h patch) at Week 24. ADCS-CGIC score of (1) 1-3 = "improvement," (2) 1-4 = "improvement or no change". "Treatment" (13.3 mg/24 h patch) and increased age were significant predictors of "improvement" (P = 0.01 and P = 0.003, respectively), and "treatment" (P = 0.001), increased age (P = 0.002), and prior AD treatment (P = 0.03) for "improvement or no change". At Week 8 and 16, ADCS-CGIC scores of 4 and 5 were optimal thresholds in predicting "improvement," and "improvement or no change," respectively, at Week 24. A significant therapeutic effect of high-dose rivastigmine patch on ADCS-CGIC response was observed. The 13.3 mg/24 h patch was identified as a predictor of "improvement" or "improvement or no change". Patients with minimal worsening/improvement/no change after treatment initiation may be more likely to respond following long-term therapy. © 2015 John Wiley & Sons Ltd.

Comparison of propofol with pentobarbital/midazolam/fentanyl sedation for magnetic resonance imaging of the brain in children.

PubMed

Pershad, Jay; Wan, Jim; Anghelescu, Doralina L

2007-09-01

Propofol and pentobarbital, alone or combined with other agents, are frequently used to induce deep sedation in children for MRI. However, we are unaware of a previous comparison of these 2 agents as part of a randomized, controlled trial. We compared the recovery time of children after deep sedation with single-agent propofol with a pentobarbital-based regimen for MRI and considered additional variables of safety and efficacy. This prospective, randomized trial at a tertiary children's hospital enrolled 60 patients 1 to 17 years old who required intravenous sedation for elective cranial MRI. Patients were assigned randomly to receive a loading dose of propofol followed by continuous intravenous infusion of propofol or to receive sequential doses of midazolam, pentobarbital, and fentanyl until a modified Ramsay score of >4 was attained. A nurse who was blind to group assignment assessed discharge readiness (Aldrete score > 8) and administered a follow-up questionnaire. We compared recovery time, time to induction of sedation, total sedation time, quality of imaging, number of repeat-image sequences, adverse events, caregiver satisfaction, and time to return to presedation functional status. The groups were similar in age, gender, race, American Society of Anesthesiology physical status class, and frequency of cognitive impairment. No sedation failure or significant adverse events were observed. Propofol offered significantly shorter sedation induction time, recovery time, total sedation time, and time to return to baseline functional status. Caregiver satisfaction scores were also significantly higher in the patients in the propofol group. Propofol permits faster onset and recovery than, and comparable efficacy to, a pentobarbital/midazolam/fentanyl regimen for sedation of children for MRI.

Volatility of fragrance chemicals: patch testing implications.

PubMed

Gilpin, Sarah J; Hui, Xiaoying; Maibach, Howard I

2009-01-01

Diagnostic and predictive patch testing to determine contact allergy due to fragrance materials requires applying a fixed dose of material to the skin. This dose can be affected by the volatile nature of fragrances; little data exist on how the loss of fragrance dose due to volatility affects patch testing. (1) To evaluate pH dependence and evaporation rates of two fragrance chemicals, geraniol, citronellol, and a common fragrance solvent, diethyl phthalate (DEP) and (2) Assess implications for predictive patch-testing methods for fragrances. pH analysis of each material at 1% for three values (4.0, 5.0, 7.0) was done over 40 hours. Volatility experiments for each material, nonradiolabeled and radiolabeled, were conducted over a 24-hour period, taking readings at six time points (5 minutes, 15 minutes, 40 minutes, 1 hour, 3 hours, and 24 hours). Evaporation rates were not sensitive to pH shifts from 4.0 to 7.0. Evaporation rates for nonradiolabeled materials were low: after 24 hours, geraniol lost 8.9%, citronellol 27.0% and DEP 14.5%. The volatility data for radiolabeled materials demonstrated that geraniol loses up to 39% of its dose, citronellol loses up to 26%, and DEP up to 14% within 40 minutes. The tendency of fragrance materials to evaporate can impact the dose being applied to the patch and therefore the result of the patch and ultimately the decision-making process regarding that fragrance material's safety. These data, developed with DEP, utilized in a predictive sensitization assay cannot be generalized.

Can exposure limitations for well-known contact allergens be simplified? An analysis of dose-response patch test data.

PubMed

Fischer, Louise Arup; Menné, Torkil; Voelund, Aage; Johansen, Jeanne Duus

2011-06-01

Allergic contact dermatitis is triggered by chemicals in the environment. Primary prevention is aimed at minimizing the risk of induction, whereas secondary and tertiary prevention are aimed at reducing elicitation. To identify the elicitation doses that will elicit an allergic reaction in 10% of allergic individuals under patch test conditions (ED(10) patch test) for different allergens, and to compare the results with those for different allergens and with animal data indicating sensitizing potency from the literature. The literature was searched for patch test elicitation studies that fulfilled six selected criteria. The elicitation doses were calculated, and fitted dose-response curves were drawn. Sixteen studies with eight different allergens-methylchloroisothiazolinone/ methylisothiazolinone, formaldehyde, nickel, cobalt, chromium, isoeugenol, hydroxyiso hexyl 3-cyclohexene carboxaldehyde, and methyldibromo glutaronitrile-were selected. The median ED(10) value was 0.835 µg/cm(2). The ED(10) patch test values were all within a factor of 7 from the lowest to the highest value, leaving out three outliers. No obvious patterns between the sensitization and elicitation doses for the allergens were found. We found a rather small variation in the ED(10) patch test between the allergens, and no clear relationship between induction potency and elicitation threshold of a range of allergens. This knowledge may stimulate thoughts on introducing a generic approach for limitations in exposure to well-known allergens. © 2011 John Wiley & Sons A/S.

Comprehensive study of the intestinal stage of listeriosis in a rat ligated ileal loop system.

PubMed

Pron, B; Boumaila, C; Jaubert, F; Sarnacki, S; Monnet, J P; Berche, P; Gaillard, J L

1998-02-01

The intestinal stage of listeriosis was studied in a rat ligated ileal loop system. Listeria monocytogenes translocated to deep organs with similar efficiencies after inoculation of loops with or without Peyer's patches. Bacterial seeding of deep organs was demonstrated as early as 15 min after inoculation. It was dose dependent and nonspecific, as the delta inlAB, the delta hly, and the delta actA L. monocytogenes mutants and the nonpathogenic species, Listeria innocua, translocated similarly to wild-type L. monocytogenes strains. The levels of uptake of listeriae by Peyer's patches and villous intestine were similar and low, 50 to 250 CFU per cm2 of tissue. No listeria cells crossing the epithelial sheet of Peyer's patches and villous intestine were observed by transmission electron microscopy. The lack of significant interaction of listeriae and the follicle-associated epithelium of Peyer's patches was confirmed by scanning electron microscopy. The follicular tissue of Peyer's patches was a preferential site of Listeria replication. With all doses tested, the rate of bacterial growth was 10 to 20 times higher in Peyer's patches than in villous intestine. At early stages of Peyer's patch infection, listeriae were observed inside mononuclear cells of the dome area. Listeriae then disseminated throughout the follicular tissue except for the germinal center. The virulence determinants hly and, to a lesser extent, actA, but not inlAB, were required for the completion of this process. This study suggests that Peyer's patches are preferential sites for replication rather than for entry of L. monocytogenes, due to the presence of highly permissive mononuclear cells whose nature remains to be defined.

Comprehensive Study of the Intestinal Stage of Listeriosis in a Rat Ligated Ileal Loop System

PubMed Central

Pron, Benedicte; Boumaila, Claire; Jaubert, Francis; Sarnacki, Sabine; Monnet, Jean-Paul; Berche, Patrick; Gaillard, Jean-Louis

1998-01-01

The intestinal stage of listeriosis was studied in a rat ligated ileal loop system. Listeria monocytogenes translocated to deep organs with similar efficiencies after inoculation of loops with or without Peyer’s patches. Bacterial seeding of deep organs was demonstrated as early as 15 min after inoculation. It was dose dependent and nonspecific, as the ΔinlAB, the Δhly, and the ΔactA L. monocytogenes mutants and the nonpathogenic species, Listeria innocua, translocated similarly to wild-type L. monocytogenes strains. The levels of uptake of listeriae by Peyer’s patches and villous intestine were similar and low, 50 to 250 CFU per cm2 of tissue. No listeria cells crossing the epithelial sheet of Peyer’s patches and villous intestine were observed by transmission electron microscopy. The lack of significant interaction of listeriae and the follicle-associated epithelium of Peyer’s patches was confirmed by scanning electron microscopy. The follicular tissue of Peyer’s patches was a preferential site of Listeria replication. With all doses tested, the rate of bacterial growth was 10 to 20 times higher in Peyer’s patches than in villous intestine. At early stages of Peyer’s patch infection, listeriae were observed inside mononuclear cells of the dome area. Listeriae then disseminated throughout the follicular tissue except for the germinal center. The virulence determinants hly and, to a lesser extent, actA, but not inlAB, were required for the completion of this process. This study suggests that Peyer’s patches are preferential sites for replication rather than for entry of L. monocytogenes, due to the presence of highly permissive mononuclear cells whose nature remains to be defined. PMID:9453636

A rivastigmine patch for the treatment of Alzheimer's disease and Parkinson's disease dementia.

PubMed

Cummings, Jeffrey; Winblad, Bengt

2007-11-01

Rivastigmine patch is the first transdermal treatment to be approved for Alzheimer's disease (AD) and Parkinson's disease dementia in the USA and for AD in Europe. It provides smooth, continuous drug delivery, and has the potential to maintain rivastigmine concentrations within an optimal therapeutic window while avoiding the peaks and troughs associated with oral drug delivery. The target dose, rivastigmine 9.5 mg/24 h patch (a 10 cm(2) patch), is given once daily and requires a simple one-step dose titration to the therapeutic dose. In a 24-week study in 1195 AD patients, the rivastigmine 9.5 mg/24 h patch provided similar efficacy to the highest dose range of capsules, with approximately three-times fewer reports of nausea and vomiting. Patients in the 9.5 mg/24 h patch and 12 mg/day capsule groups evidenced significant improvements versus placebo on both primary outcome measures: the Alzheimer's Disease Assessment Scale-Cognitive subscale; and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change; in addition to the following secondary outcome measures: Alzheimer's Disease Cooperative Study-Activities of Daily Living scale; Mini-Mental State Examination; and Trail Making Test Part A for assessment of attention, visual tracking and motor processing speed. Treatment differences on the Neuropsychiatric Inventory and Ten Point Clock-drawing Test did not reach statistical significance in this study. The patch may be the optimal way to treat dementia patients with rivastigmine.

In vitro and in vivo evaluation of a sublingual fentanyl wafer formulation

PubMed Central

Lim, Stephen CB; Paech, Michael J; Sunderland, Bruce; Liu, Yandi

2013-01-01

Background The objective of this study was to prepare a novel fentanyl wafer formulation by a freeze-drying method, and to evaluate its in vitro and in vivo release characteristics, including its bioavailability via the sublingual route. Methods The wafer formulation was prepared by freeze-drying an aqueous dispersion of fentanyl containing sodium carboxymethylcellulose and amylogum as matrix formers. Uniformity of weight, friability, and dissolution testing of the fentanyl wafer was achieved using standard methods, and the residual moisture content was measured. The fentanyl wafer was also examined using scanning electron microscopy and x-ray diffraction. The absolute bioavailability of the fentanyl wafer was evaluated in 11 opioid-naïve adult female patients using a randomized crossover design. Results In vitro release showed that almost 90% of the fentanyl dissolved in one minute. In vivo, the first detectable plasma fentanyl concentration was observed after 3.5 minutes and the peak plasma concentration between 61.5 and 67 minutes. The median absolute bioavailability was 53.0%. Conclusion These results indicate that this wafer has potential as an alternative sublingual fentanyl formulation. PMID:23596347

Dreaming and recall during sedation for colonoscopy.

PubMed

Stait, M L; Leslie, K; Bailey, R

2008-09-01

Dreaming is reported by one in five patients who are interviewed on emergence from general anaesthesia, but the incidence, predictors and consequences of dreaming during procedural sedation are not known. In this prospective observational study, 200 patients presenting for elective colonoscopy under intravenous sedation were interviewed on emergence to determine the incidences of dreaming and recall. Sedation technique was left to the discretion of the anaesthetist. The incidence of dreaming was 25.5%. Patients reporting dreaming were younger than those who did not report dreaming. Doses of midazolam and fentanyl were similar between dreamers and non-dreamers, however propofol doses were higher in patients who reported dreams than those who did not. Patients reported short, simple dreams about everyday life--no dream suggested near-miss recall of the procedure. Frank recall of the procedure was reported by 4% of the patients, which was consistent with propofol doses commensurate with light general anaesthesia. The only significant predictor of recall was lower propofol dose. Satisfaction with care was generally high, however dreamers were more satisfied with their care than non-dreamers.

New contraceptive patch wearability assessed by investigators and participants in a randomized phase 3 study.

PubMed

Kaunitz, Andrew M; Portman, David; Westhoff, Carolyn L; Mishell, Daniel R; Archer, David F; Foegh, Marie

2015-03-01

To evaluate skin irritation and patch adhesiveness of a new weekly low-dose levonorgestrel (LNG) and ethinyl estradiol (EE) contraceptive patch (LNG/EE patch). This analysis was part of an open-label, parallel-group, multicenter, phase 3 study that randomized healthy women to the LNG/EE patch (one patch weekly for three consecutive weeks, followed by a patch-free week for 13 cycles) or to an oral contraceptive for six cycles followed by seven LNG/EE patch cycles. Participants selected patch application sites of abdomen, buttock or upper torso. Investigators rated patch adhesiveness and skin irritation using standardized scales. Participants rated skin irritation and itching daily using standardized scales and recorded patch fall-off on daily diary cards. A total of 32,508 patches were applied (n=1273). At the five clinic visits in which investigators rated the patches, they rated adhesiveness=0 (no lift) for ≥84% of participants and skin irritation=absent/mild for 97% of patches. Participants reported that 2-3.7% of patches fell off and rated skin irritation as absent or mild for 92- 95% of patches, according to site. Investigator- and participant-rated assessments of LNG/EE patch adhesiveness and irritation demonstrated a low incidence of patch detachment, skin irritation and pruritus. This secondary analysis of a phase 3 clinical trial of a new weekly low-dose LNG and EE contraceptive patch, which used assessment by both investigators and participants, observed a low incidence of skin irritation, pruritus and patch detachment. Copyright © 2015 Elsevier Inc. All rights reserved.

Taking the alternative route: Women's experience of intranasal fentanyl, subcutaneous fentanyl or intramuscular pethidine for labour analgesia.

PubMed

Fleet, Julie-Anne; Jones, Meril; Belan, Ingrid

2017-10-01

To compare women's experience of receiving either intranasal fentanyl, subcutaneous fentanyl or intramuscular pethidine for labour analgesia. A content analysis was undertaken as part of the third phase of a larger randomised controlled trial, using the per-protocol dataset to examine women's experiences of treatment received. Healthy women birthing at term, who received intranasal fentanyl (n=41), subcutaneous fentanyl (n=37) and/or intramuscular pethidine (n=38) for labour analgesia, were contacted at 6 weeks postpartum to complete a phone questionnaire. A tertiary and regional maternity unit in South Australia. Over 80% of women who received intranasal or subcutaneous fentanyl reported that they would use the treatment again compared to 44.8% of women who had received pethidine (self-administered intranasal fentanyl provided more expressive responses emphasising the route provided a strong sense of control and enablement. Route of administration influenced the women's experience, more women who self-administered intranasal fentanyl reported positive emotional responses, with women reporting increased autonomy and satisfaction. Whereas, women who relied on the midwife to administer subcutaneous fentanyl or intramuscular pethidine, were more often focused on the physical effect of the drug. Pethidine was the least preferred option due to adverse effects. For women requesting parenteral analgesia, fentanyl administered by less invasive routes offers women additional options that may better meet their emotional, cognitive and physical needs than the current practice of administering intramuscular pethidine. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect of N-Methyl-D-Aspartate Receptor Antagonist Dextromethorphan on Opioid Analgesia in Pediatric Intensive Care Unit

PubMed Central

Al Alem, Hala; Al Shehri, Ali; Al-Jeraisy, Majed

2016-01-01

Objective. Pain control is an essential goal in the management of critical children. Narcotics are the mainstay for pain control. Patients frequently need escalating doses of narcotics. In such cases an adjunctive therapy may be beneficial. Dextromethorphan (DM) is NMDA receptor antagonist and may prevent tolerance to narcotics; however, its definitive role is still unclear. We sought whether dextromethorphan addition could decrease the requirements of fentanyl to control pain in critical children. Design. Double-blind, randomized control trial (RCT). Setting. Pediatric multidisciplinary ICU in tertiary care center. Patients. Thirty-six pediatric patients 2–14 years of age in a multidisciplinary PICU requiring analgesia were randomized into dextromethorphan and placebo. The subjects in both groups showed similarity in most of the characteristics. Interventions. Subjects while receiving fentanyl for pain control received dextromethorphan or placebo through nasogastric/orogastric tubes for 96 hours. Pain was assessed using FLACC and faces scales. Measurements and Main Results. This study found no statistical significant difference in fentanyl requirements between subjects receiving dextromethorphan and those receiving placebo (p = 0.127). Conclusions. Dextromethorphan has no effect on opioid requirement for control of acute pain in children admitted with acute critical care illness in PICU. The registration number for this trial is NCT01553435. PMID:27867308

Effect of N-Methyl-D-Aspartate Receptor Antagonist Dextromethorphan on Opioid Analgesia in Pediatric Intensive Care Unit.

PubMed

Naeem, Mohammed; Al Alem, Hala; Al Shehri, Ali; Al-Jeraisy, Majed

2016-01-01

Objective . Pain control is an essential goal in the management of critical children. Narcotics are the mainstay for pain control. Patients frequently need escalating doses of narcotics. In such cases an adjunctive therapy may be beneficial. Dextromethorphan (DM) is NMDA receptor antagonist and may prevent tolerance to narcotics; however, its definitive role is still unclear. We sought whether dextromethorphan addition could decrease the requirements of fentanyl to control pain in critical children. Design . Double-blind, randomized control trial (RCT). Setting . Pediatric multidisciplinary ICU in tertiary care center. Patients . Thirty-six pediatric patients 2-14 years of age in a multidisciplinary PICU requiring analgesia were randomized into dextromethorphan and placebo. The subjects in both groups showed similarity in most of the characteristics. Interventions . Subjects while receiving fentanyl for pain control received dextromethorphan or placebo through nasogastric/orogastric tubes for 96 hours. Pain was assessed using FLACC and faces scales. Measurements and Main Results . This study found no statistical significant difference in fentanyl requirements between subjects receiving dextromethorphan and those receiving placebo ( p = 0.127). Conclusions . Dextromethorphan has no effect on opioid requirement for control of acute pain in children admitted with acute critical care illness in PICU. The registration number for this trial is NCT01553435.

Association between UGT2B7 gene polymorphisms and fentanyl sensitivity in patients undergoing painful orthognathic surgery

PubMed Central

Muraoka, Wataru; Nishizawa, Daisuke; Fukuda, Kenichi; Kasai, Shinya; Hasegawa, Junko; Wajima, Koichi; Nakagawa, Taneaki

2016-01-01

Background Fentanyl is often used instead of morphine for the treatment of pain because it has fewer side effects. The metabolism of morphine by glucuronidation is known to be influenced by polymorphisms of the UGT2B7 gene. Some metabolic products of fentanyl are reportedly metabolized by glucuronate conjugation. The genes that are involved in the metabolic pathway of fentanyl may also influence fentanyl sensitivity. We analyzed associations between fentanyl sensitivity and polymorphisms of the UGT2B7 gene to clarify the hereditary determinants of individual differences in fentanyl sensitivity. Results This study examined whether single-nucleotide polymorphisms (SNPs) of the UGT2B7 gene affect cold pain sensitivity and the analgesic effects of fentanyl, evaluated by a standardized pain test and fentanyl requirements in healthy Japanese subjects who underwent uniform surgical procedures. The rs7439366 SNP of UGT2B7 is reportedly associated with the metabolism and analgesic effects of morphine. We found that this SNP is also associated with the analgesic effects of fentanyl in the cold pressor-induced pain test. It suggested that the C allele of the rs7439366 SNP may enhance analgesic efficacy. Two SNPs of UGT2B7, rs4587017 and rs1002849, were also found to be novel SNPs that may influence the analgesic effects of fentanyl in the cold pressor-induced pain test. Conclusions Fentanyl sensitivity for cold pressor-induced pain was associated with the rs7439366, rs4587017, and rs1002849 SNPs of the UGT2B7 gene. Our findings may provide valuable information for achieving satisfactory pain control and open to new avenues for personalized pain treatment. PMID:28256933

Use of intranasal fentanyl in children undergoing myringotomy and tube placement during halothane and sevoflurane anesthesia.

PubMed

Galinkin, J L; Fazi, L M; Cuy, R M; Chiavacci, R M; Kurth, C D; Shah, U K; Jacobs, I N; Watcha, M F

2000-12-01

Many children are restless, disoriented, and inconsolable immediately after bilateral myringotomy and tympanosotomy tube placement (BMT). Rapid emergence from sevoflurane anesthesia and postoperative pain may increase emergence agitation. The authors first determined serum fentanyl concentrations in a two-phase study of intranasal fentanyl. The second phase was a prospective, placebo-controlled, double-blind study to determine the efficacy of intranasal fentanyl in reducing emergence agitation after sevoflurane or halothane anesthesia. In phase 1, 26 children with American Society of Anesthesiologists (ASA) physical status I or II who were scheduled for BMT received intranasal fentanyl, 2 microg/kg, during a standardized anesthetic. Serum fentanyl concentrations in blood samples drawn at emergence and at postanesthesia care unit (PACU) discharge were determined by radioimmunoassay. In phase 2, 265 children with ASA physical status I or II were randomized to receive sevoflurane or halothane anesthesia along with either intranasal fentanyl (2 microg/kg) or saline. Postoperative agitation, Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) scores, and satisfaction of PACU nurses and parents with the anesthetic technique were evaluated. In phase 1, the mean fentanyl concentrations at 10 +/- 4 min (mean +/- SD) and 34 +/- 9 min after administering intranasal fentanyl were 0.80 +/- 0.28 and 0.64 +/- 0.25 ng/ml, respectively. In phase 2, the incidence of severe agitation, highest CHEOPS scores, and heart rate in the PACU were decreased with intranasal fentanyl. There were no differences between sevoflurane and halothane in these measures and in times to hospital discharge. The incidence of postoperative vomiting, hypoxemia, and slow respiratory rates were not increased with fentanyl. Serum fentanyl concentrations after intranasal administration exceed the minimum effective steady state concentration for analgesia in adults. The use of intranasal fentanyl during halothane or sevoflurane anesthesia for BMT is associated with diminished postoperative agitation without an increase in vomiting, hypoxemia, or discharge times.

Use of nicotine patches in breast-feeding mothers: transfer of nicotine and cotinine into human milk.

PubMed

Ilett, Kenneth F; Hale, Thomas W; Page-Sharp, Madhu; Kristensen, Judith H; Kohan, Rolland; Hackett, L Peter

2003-12-01

Our objective was to assess the extent of exposure to nicotine and cotinine in breast-fed infants during maternal smoking and later during maternal use of the nicotine transdermal patch to achieve smoking cessation. Fifteen lactating women (mean age, 32 years; mean weight, 72 kg) who were smokers (mean of 17 cigarettes per day) participated in a trial of the nicotine patch to assist in smoking cessation. Serial milk samples were collected from the women over sequential 24-hour periods when they were smoking and when they were stabilized on the 21-mg/d, 14-mg/d, and 7-mg/d nicotine patches. Nicotine and cotinine in milk were quantified by HPLC, and infant dose was calculated. Plasma concentrations of nicotine in the breast-fed infants were assessed, and the infants were also clinically assessed. Nicotine and cotinine concentrations in milk were not significantly different between smoking (mean of 17 cigarettes per day) and the 21-mg/d patch, but concentrations were significantly lower (P <.05) when patients were using the 14-mg/d and 7-mg/d patches than when smoking. There was also a downward trend in absolute infant dose (nicotine equivalents) from smoking or the 21-mg patch through to the 14-mg and 7-mg patches (P <.05 at both 14-mg and 7-mg doses, compared with smoking). Milk intake (shown as median and 25th to 75th percentile) by the breast-fed infants was similar while their mothers were smoking (585 mL/d [507-755 mL/d]) and subsequently when their mothers were using the 21-mg (717 mL/d [504-776 mL/d]), 14-mg (731 mL/d [535-864 mL/d]), and 7-mg (619 mL/d [520-706 mL/d]) patches (chi(2) = 3.19, P =.364). We conclude that the absolute infant dose of nicotine and its metabolite cotinine decreases by about 70% from when subjects were smoking or using the 21-mg patch to when they were using the 7-mg patch. In addition, use of the nicotine patch had no significant influence on the milk intake by the breast-fed infant. Undertaking maternal smoking cessation with the nicotine patch is, therefore, a safer option than continued smoking.

Opioid Rotation in Cancer Pain Treatment.

PubMed

Schuster, Michael; Bayer, Oliver; Heid, Florian; Laufenberg-Feldmann, Rita

2018-03-02

Rotating several different WHO level III opioid drugs is a therapeutic option for patients with chronic cancer-related pain who suffer from inadequate analgesia and/or intolerable side effects. The evidence favoring opioid rotation is controversial, and the current guidelines in Germany and other countries contain only weak recommendations for it. This review is based on pertinent publications retrieved by a systematic review of the literature on opioid rotation for adult patients with chronic cancerrelated pain who are regularly taking WHO level III opioids by the oral or trans - dermal route. 9 individual studies involving a total of 725 patients were included in the analysis, and 3 previous systematic reviews of studies involving a total of 2296 patients were also analyzed. Morphine, oxycodone, fentanyl, hydromorphone, and buprenorphine were used as first-line opioid drugs, and hydromorphone, bupre - norphine, tapentadol, fentanyl, morphine, oxymorphone, and methadone were used as second-line opioid drugs. In all of the studies, pain control was achieved for 14 days after each rotation. In most of them, the dose of the new drug introduced in each rotation needed to be increased above the dose initially calculated from a rotation ratio, with the exception of rotations to methadone. The frequency of side effects was only rarely lessened, but patients largely considered the result of opioid rotation to be positive. No particular opioid drug was found to be best. Opioid rotation can improve analgesia and patient satisfaction. The success of opioid rotation appears to depend on the magnitude of the initial dose, among other factors. Tables of equianalgesic doses should be considered no more than a rough guide for determining the dose of the new drug. Rotations to methadone should be carried out under clinical supervision in experienced hands.

Physico-chemical stability of butorphanol-tramadol and butorphanol-fentanyl patient-controlled analgesia infusion solutions over 168 hours.

PubMed

Chen, Fuchao; Fang, Baoxia; Li, Peng; Zhu, Xuesong; Zhou, Benhong

2014-08-01

This study was to investigate the physical and chemical compatibility of butorphanol with tramadol or fentanyl in 0.9% sodium chloride injections for patient controlled analgesia administration. The solutions were prepared in polyvinyl chloride (PVC) infusion bags and stored without protected from light exposure at room temperature (25 degrees C) or refrigerated (4 degrees C). Over a period of 168 hours, stabilities were determined by visual inspection, pH measurement, and high-pressure liquid chromatography (HPLC) assay of drug concentrations. At both temperatures, admixtures of butorphanol-tramadol and butorphanol-fentanyl were clear in appearance, and no color change or precipitation was observed during the study period. The maximum losses obtained were lower than 5% for the three drugs after 168 hours of storage. The results indicate that, at ambient or refrigerated storage conditions, the drug mixtures of butorphanol-tramadol and butorphanol-fentanyl in 0.9% sodium chloride injections were physically and chemically stable for at least 168 hours when stored in PVC syringes.

Supply-side response to declining heroin purity: fentanyl overdose episode in New Jersey.

PubMed

Hempstead, Katherine; Yildirim, Emel O

2014-06-01

The inelastic price demand observations characteristic of illegal drug markets have led to the conclusion that the burden of a negative supply shock would be completely reflected to consumers. This paper argues that the increasing availability of prescription opioids may threaten heroin sellers' profit margin and force them to find alternative methods to compensate buyers in the event of a supply shock. We investigate the 2006 fentanyl overdose episode in New Jersey and argue that the introduction of non-pharmaceutical fentanyl, its spatial distribution, and the timing of overdose deaths may have been related to trends in heroin purity. Using medical examiner data, as well as data from the Drug Enforcement Administration, Office of Diversion Control on retail sales of prescription opioids in a negative binomial specification, we show that month-to-month fluctuations in heroin purity have a significant effect on fentanyl-related overdoses, particularly in those areas where prescription opioids are highly available. Copyright © 2013 John Wiley & Sons, Ltd.

mu-Opioid receptor-independent fashion of the suppression of sodium currents by mu-opioid analgesics in thalamic neurons.

PubMed

Hashimoto, Keisuke; Amano, Taku; Kasakura, Akiko; Uhl, George R; Sora, Ichiro; Sakai, Norio; Kuzumaki, Naoko; Suzuki, Tsutomu; Narita, Minoru

2009-03-27

Most reports in the literature have shown that the effects of opioid analgesics are primarily mediated by mu-opioid receptor (MOR), whereas other potential targets of opioid analgesics have not been thoroughly characterized. In this study, we found that extracellular application of morphine, fentanyl or oxycodone, which are all considered to be MOR agonists, at relatively high concentrations, but not endogenous mu-opioid peptides, produced a concentration-dependent suppression of sodium currents in cultured thalamic neurons. These effects of opioids were not affected by either a MOR antagonist naloxone or a deletion of MOR gene. Among these opioids, fentanyl strongly suppressed sodium currents to the same degree as lidocaine, and both morphine and oxycodone slightly but significantly reduced sodium currents when they were present extracellularly. In contrast, the intracellular application of morphine, but not oxycodone, fentanyl or lidocaine, reduced sodium currents. These results suggest that morphine, fentanyl and oxycodone each produce the MOR-independent suppression of sodium currents by distinct mechanisms in thalamic neurons.

Atopy patch tests in young adult patients with atopic dermatitis and controls: dose-response relationship, objective reading, reproducibility and clinical interpretation.

PubMed

Bygum, Anette; Mortz, Charlotte Gotthard; Andersen, Klaus Ejner

2003-01-01

The clinical interpretation and reproducibility of atopy patch tests was studied in 23 selected young adult patients with atopic dermatitis and 25 healthy controls using standard inhalant allergens. Non-invasive measurements were used for objective assessment of test reactions and the participants were retested after 6 weeks. Ten of 19 (53%) evaluable patients with atopic dermatitis had at least one positive atopy patch test. However, there was no clear clinical relevance of the atopy patch test results when related to patient history and distribution of dermatitis. Reproducible and dose-dependent results were obtained with Dermatophagoides pteronyssinus, grass and cat with a reproducibility rate of 0.69 to 0.81 in patients and 0.60-0.96 in controls. A unique finding was a significant positive correlation between a positive atopy patch test, allergen dose and increase in transepidermal water loss and erythema, while measurement of capacitance did not distinguish between positive and negative reactions. The results of the present study do not support the routine use of atopy patch tests in the evaluation of adult patients with atopic dermatitis.

Pharmacokinetics of a novel transdermal rivastigmine patch for the treatment of Alzheimer’s disease: a review

PubMed Central

Kurz, A; Farlow, M; Lefèvre, G

2009-01-01

Background: Cholinesterase inhibitors have all been available in oral formulations, but a rivastigmine transdermal patch has now been developed and is approved in many countries worldwide for the treatment of mild-to-moderate Alzheimer’s disease (AD) (including the USA, Latin America, Europe and Asia). Objectives: To review the available pharmacokinetic data that supported the rationale behind the development of the rivastigmine transdermal patch and its clinical effects in dementia therapy. This article will also discuss how the patch may alter the treatment paradigm for patients with AD. Results: The 9.5 mg/24 h rivastigmine patch was shown to provide comparable exposure to the highest recommended doses of capsules (12 mg/day) with significantly lower maximum plasma concentration (Cmax 8.7 vs. 21.6 ng/ml) and slower absorption rate (tmax 8.1 vs. 1.4 h). In a clinical trial of 1195 AD patients, this translated into similar efficacy with three times fewer reports of nausea and vomiting (7.2% vs. 23.1%, and 6.2% vs. 17.0% respectively). Consequently, more patients in the 9.5 mg/24 h patch group achieved their target therapeutic dose at the end of the study, compared with those in the 12 mg/day capsule group (95.9% vs. 64.4%). Conclusion: The rivastigmine patch provides continuous drug delivery over 24 h and similar efficacy to the highest recommended dose of oral rivastigmine with improved tolerability. This may allow patients to achieve optimal therapeutic doses and to benefit from a longer duration of treatment. PMID:19392927

Potential drug sequestration during extracorporeal membrane oxygenation: results from an ex vivo experiment.

PubMed

Mehta, Nilesh M; Halwick, David R; Dodson, Brenda L; Thompson, John E; Arnold, John H

2007-06-01

Using an ex vivo simulation model we set out to estimate the amount of drug lost due to sequestration within the extracorporeal circuit over time. Simulated closed-loop extracorporeal membrane oxygenation (ECMO) circuits were prepared using a 1.5-m2 silicone membrane oxygenator. Group A consisted of heparin, dopamine, ampicillin, vancomycin, phenobarbital and fentanyl. Group B consisted of epinephrine, cefazolin, hydrocortisone, fosphenytoin and morphine. Drugs were tested in crystalloid and blood-primed circuits. After administration of a one-time dose of drugs in the priming fluid, baseline drug concentrations were obtained (P0). A simultaneous specimen was stored for stability testing at 24 h (P4). Serial post-membrane drug concentrations were then obtained at 30 min (P1), 3 h (P2) and 24 h (P3) from circuit fluid. One hundred and one samples were analyzed. At the end of 24 h in crystalloid-primed circuits, 71.8% of ampicillin, 96.7% of epinephrine, 17.6% of fosphenytoin, 33.3% of heparin, 17.5% of morphine and 87% of fentanyl was lost. At the end of 24 h in blood-primed extracorporeal circuits, 15.4% of ampicillin, 21% of cefazolin, 71% of voriconazole, 31.4% of fosphenytoin, 53.3% of heparin and 100% of fentanyl was lost. There was a significant decrease in overall drug concentrations from 30 min to 24 h for both crystalloid-primed circuits (p = 0.023) and blood-primed circuits (p = 0.04). Our ex vivo study demonstrates serial losses of several drugs commonly used during ECMO therapy. Therapeutic concentrations of fentanyl, voriconazole, antimicrobials and heparin cannot be guaranteed in patients on ECMO.

Opioid analgesia on the battlefield: a retrospective review of data from Operation HERRICK.

PubMed

Lewis, Pip; Wright, C; Hooper, C

2018-04-06

Acute pain secondary to trauma is commonly encountered on the battlefield. The use of morphine to manage pain during combat has been well established since the 19th century. Despite this, there is relatively little research on analgesia use in this environment. This study aims to review the use and complications of morphine and other opioids during Operation HERRICK. A database search of the Joint Theatre Trauma Registry was completed looking for all incidences of morphine, fentanyl or naloxone use from February 2007 to September 2014. Microsoft Excel was used to analyse the results. Opioid analgesia was administered to 5801 casualties. Morphine was administered 6742 times to 3808 patients. Fentanyl was administered 9672 times to 4318 patients. Naloxone was used 18 times on 14 patients, giving a complication rate of 0.24%. Opioid doses prior to naloxone administration range from 0 to 72 mg of morphine and from 0 to 100 mcg of fentanyl. Four casualties (two local civilians and two coalition forces) received naloxone despite no recorded opioids being administered. Opium abuse was prevalent among the local population in Afghanistan, and this could explain the rationale behind two local national casualties receiving naloxone without any documented opioids being given. The use of opioids in a battlefield environment is extremely safe. Complication rates are similar to previously published data which is reassuring. The efficacy of different opioids was not covered by this study, and further analysis is required, particularly following the introduction of oral transmucosal fentanyl citrate and the availability of novel non-opioid analgesics. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

The use of a battery of pain models to detect analgesic properties of compounds: a two‐part four‐way crossover study

PubMed Central

Okkerse, Pieter; van Amerongen, Guido; de Kam, Marieke L.; Stevens, Jasper; Butt, Richard P.; Gurrell, Rachel; Dahan, Albert; van Gerven, Joop M.; Hay, Justin L.

2017-01-01

Aim The aim was to investigate the ability of a battery of pain models to detect analgesic properties of commonly used analgesics in healthy subjects. Methods The battery consisted of tests eliciting electrical, mechanical and thermal (contact heat and cold pressor)‐pain and included a UVB model, the thermal grill illusion and a paradigm of conditioned pain modulation. Subjects were administered fentanyl 3 μg kg–1, phenytoin 300 mg, (S)‐ketamine 10 mg and placebo (part I), or imipramine 100 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo (part II). Pain measurements were performed at baseline and up to 10 h post‐dose. Endpoints were analysed using a mixed model analysis of variance. Results Sixteen subjects (8 female) completed each part. The pain tolerance threshold (PTT) for electrical stimulation was increased (all P < 0.05) compared to placebo for (S)‐ketamine (+10.1%), phenytoin (+8.5%) and pregabalin (+10.8%). The PTT for mechanical pain was increased by pregabalin (+14.1%). The cold pressor PTT was increased by fentanyl (+17.1%) and pregabalin (+46.4%). Normal skin heat pain detection threshold was increased by (S)‐ketamine (+3.3%), fentanyl (+2.8%) and pregabalin (+4.1%). UVB treated skin pain detection threshold was increased by fentanyl (+2.6%) and ibuprofen (+4.0%). No differences in conditioned pain modulation were observed. Conclusion This study shows that these pain models are able to detect changes in pain thresholds after administration of different classes of analgesics in healthy subjects. The analgesic compounds all showed a unique profile in their effects on the pain tasks administered. PMID:27862179

The use of a battery of pain models to detect analgesic properties of compounds: a two-part four-way crossover study.

PubMed

Okkerse, Pieter; van Amerongen, Guido; de Kam, Marieke L; Stevens, Jasper; Butt, Richard P; Gurrell, Rachel; Dahan, Albert; van Gerven, Joop M; Hay, Justin L; Groeneveld, Geert Jan

2017-05-01

The aim was to investigate the ability of a battery of pain models to detect analgesic properties of commonly used analgesics in healthy subjects. The battery consisted of tests eliciting electrical, mechanical and thermal (contact heat and cold pressor)-pain and included a UVB model, the thermal grill illusion and a paradigm of conditioned pain modulation. Subjects were administered fentanyl 3 μg kg -1 , phenytoin 300 mg, (S)-ketamine 10 mg and placebo (part I), or imipramine 100 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo (part II). Pain measurements were performed at baseline and up to 10 h post-dose. Endpoints were analysed using a mixed model analysis of variance. Sixteen subjects (8 female) completed each part. The pain tolerance threshold (PTT) for electrical stimulation was increased (all P < 0.05) compared to placebo for (S)-ketamine (+10.1%), phenytoin (+8.5%) and pregabalin (+10.8%). The PTT for mechanical pain was increased by pregabalin (+14.1%). The cold pressor PTT was increased by fentanyl (+17.1%) and pregabalin (+46.4%). Normal skin heat pain detection threshold was increased by (S)-ketamine (+3.3%), fentanyl (+2.8%) and pregabalin (+4.1%). UVB treated skin pain detection threshold was increased by fentanyl (+2.6%) and ibuprofen (+4.0%). No differences in conditioned pain modulation were observed. This study shows that these pain models are able to detect changes in pain thresholds after administration of different classes of analgesics in healthy subjects. The analgesic compounds all showed a unique profile in their effects on the pain tasks administered. © 2016 The British Pharmacological Society.

An update on pharmacological, pharmacokinetic properties and drug-drug interactions of rotigotine transdermal system in Parkinson's disease and restless legs syndrome.

PubMed

Elshoff, Jan-Peer; Cawello, Willi; Andreas, Jens-Otto; Mathy, Francois-Xavier; Braun, Marina

2015-04-01

This narrative review reports on the pharmacological and pharmacokinetic properties of rotigotine, a non-ergolinic D₃/D₂/D₁ dopamine receptor agonist approved for the treatment of early- and advanced-stage Parkinson's disease (PD) and moderate to severe restless legs syndrome (RLS). Rotigotine is formulated as a transdermal patch providing continuous drug delivery over 24 h, with a plasma concentration profile similar to that of administration via continuous intravenous infusion. Absolute bioavailability after 24 h transdermal delivery is 37 % of the applied rotigotine dose. Following a single administration of rotigotine transdermal system (24-h patch-on period), most of the absorbed drug is eliminated in urine and feces as sulphated and glucuronidated conjugates within 24 h of patch removal. The drug shows a high apparent volume of distribution (>2500 L) and a total body clearance of 300-600 L/h. Rotigotine transdermal system provides dose-proportional pharmacokinetics up to supratherapeutic dose rates of 24 mg/24 h, with steady-state plasma drug concentrations attained within 1-2 days of daily dosing. The pharmacokinetics of rotigotine transdermal patch are similar in healthy subjects, patients with early- or advanced-stage PD, and patients with RLS when comparing dose-normalized area under the plasma concentration-time curve (AUC) and maximum plasma drug concentration (Cmax), as well as half-life and other pharmacokinetic parameters. Also, it is not influenced in a relevant manner by age, sex, ethnicity, advanced renal insufficiency, or moderate hepatic impairment. No clinically relevant drug-drug interactions were observed following co-administration of rotigotine with levodopa/carbidopa, domperidone, or the CYP450 inhibitors cimetidine or omeprazole. Also, pharmacodynamics and pharmacokinetics of an oral hormonal contraceptive were not influenced by rotigotine co-administration. Rotigotine was generally well tolerated, with an adverse event profile consistent with dopaminergic stimulation and use of a transdermal patch. These observations, combined with the long-term efficacy demonstrated in clinical studies, support the use of rotigotine as a continuous non-ergot D₃/D₂/D₁ dopamine receptor agonist in the treatment of PD and RLS.

21 CFR 524.916 - Fentanyl.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Fentanyl. 524.916 Section 524.916 Food and Drugs..., AND RELATED PRODUCTS OPHTHALMIC AND TOPICAL DOSAGE FORM NEW ANIMAL DRUGS § 524.916 Fentanyl. (a) Specifications. Each milliliter of solution contains 50 milligrams (mg) fentanyl. (b) Sponsor. See No. 000986 in...

76 FR 19997 - Determination That FENTORA (Fentanyl Citrate) Buccal Tablet, 300 Micrograms, Was Not Withdrawn...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-11

...] Determination That FENTORA (Fentanyl Citrate) Buccal Tablet, 300 Micrograms, Was Not Withdrawn From Sale for... Food and Drug Administration (FDA) has determined that FENTORA (fentanyl citrate) buccal tablet, 300... allow FDA to approve abbreviated new drug applications (ANDAs) for fentanyl citrate buccal tablet, 300...

21 CFR 524.916 - Fentanyl.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Fentanyl. 524.916 Section 524.916 Food and Drugs..., AND RELATED PRODUCTS OPHTHALMIC AND TOPICAL DOSAGE FORM NEW ANIMAL DRUGS § 524.916 Fentanyl. (a) Specifications. Each milliliter of solution contains 50 milligrams (mg) fentanyl. (b) Sponsor. See No. 050929 in...

Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine.

PubMed

Kress, Hans G

2009-03-01

Buprenorphine was not used widely in clinical practice over many years, mainly due to analgesic potency and clinical safety concerns based on misinterpreted animal data. Contrary to previous concerns, however, no analgesic ceiling effect and no antagonism of combined pure mu-opioid receptor agonists is seen within the therapeutic dose range. In recent studies, buprenorphine could be effectively and safely combined with full mu-agonists, and switching between buprenorphine and another opioid provided comparable pain relief based on equianalgesic doses. Moreover, buprenorphine exerts an antihyperalgesic effect, which is due -- at least in part -- to antagonistic activity at kappa-opioid receptors. Buprenorphine pharmacokinetics are not altered by advanced age or renal dysfunction. In addition, the risk of respiratory depression is lower than with other opioids including morphine, hydromorphone, methadone and fentanyl. Unlike morphine and fentanyl, there is no immunosuppressive activity with buprenorphine at therapeutic analgesic doses. Transdermal buprenorphine has significantly improved the clinical use of the drug, providing continuous buprenorphine release for up to 96 h. In clinical trials, patients receiving transdermal buprenorphine experienced significantly greater pain relief, better sleep, and a reduced need for rescue therapy, compared to placebo. Large-scale post-marketing studies have confirmed the effectiveness of transdermal buprenorphine in treating moderate-to-severe cancer and non-cancer pain including neuropathic syndromes. Finally, the comparably low incidence of CNS adverse events and constipation, and the possibility of use in severe renal dysfunction without a need for dose adjustment make buprenorphine well suited for chronic pain management in at-risk patients, such as diabetics, elderly or renally impaired individuals including those requiring haemodialysis.

Pharmacokinetics, safety and tolerability of rotigotine transdermal patch in healthy Japanese and Caucasian subjects.

PubMed

Cawello, Willi; Kim, Seong R; Braun, Marina; Elshoff, Jan-Peer; Ikeda, Junji; Funaki, Tomoo

2014-02-01

Rotigotine is a dopamine receptor agonist with activity across the D1 through to D5 receptors as well as select serotonergic and adrenergic sites; continuous transdermal delivery of rotigotine with replacement of the patch once daily maintains stable plasma concentrations over 24 h. Rotigotine is indicated for the treatment of early and advanced-stage Parkinson's disease and moderate-to-severe idiopathic restless legs syndrome. The pharmacokinetics and pharmacodynamics of a drug may vary between subjects of different ethnic origin. This study evaluated the pharmacokinetics, safety, and tolerability of single-dose treatment with rotigotine transdermal patch in Japanese and Caucasian subjects. In this open-label, parallel-group study, healthy male and female subjects of Japanese or Caucasian ethnic origin were matched by sex, body mass index, and age. A single transdermal patch delivering 2 mg/24 h rotigotine (patch content 4.5 mg) was applied to the ventral/lateral abdomen for 24 h. The main outcome measures were the plasma concentrations of unconjugated and total rotigotine and its desalkyl metabolites and derived pharmacokinetic parameters (area under the concentration-time curve from time zero to last quantifiable concentration [AUClast], maximum plasma concentration [Cmax], and body weight- and dose-normalized values). The pharmacokinetic analysis included 48 subjects (24 Japanese, 24 Caucasian). The mean apparent dose of rotigotine was 2.0±0.5 mg for Japanese subjects and 2.08±0.58 mg for Caucasians. Plasma concentration-time profiles of unconjugated rotigotine and of the main metabolites were similar for both ethnic groups. Parameters of model-independent pharmacokinetics, Cmax, time to Cmax (tmax), and AUClast, for unconjugated rotigotine showed no statistically significant differences between Japanese and Caucasian subjects. Values of concentration-dependent pharmacokinetic parameters were higher in female subjects; this difference was minimized after correction for body weight. A statistically significant difference between ethnic groups was observed for total rotigotine concentrations (total rotigotine=unconjugated rotigotine+conjugated rotigotine), with slightly lower values in Caucasians after correction for body weight and apparent dose. No relevant differences were observed between males and females. Inter-individual variability was high. The terminal half-life for unconjugated rotigotine was 5.3 h in Japanese subjects and 5.7 h in Caucasians; corresponding values for total rotigotine were 8.6 h and 9.6 h. Less than 0.1% of the apparent dose was renally excreted as the parent compound. Renal elimination of total rotigotine covers 11.7% of absorbed dose in Japanese subjects and 10.8% of the absorbed dose in Caucasians, whereas the renal elimination via total despropyl rotigotine was 8.2 and 7.1%, respectively. The corresponding values for total desthienylethyl rotigotine were 3.5% in Japanese subjects and 4.2% Caucasians. Most adverse events were mild in intensity and typical for dopamine agonists or for transdermal therapeutics. Administration of a single patch delivering 2 mg/24 h rotigotine resulted in comparable pharmacokinetic profiles in Japanese and Caucasian subjects. The rotigotine transdermal patch was generally well-tolerated. Our findings suggest similar dose requirements for Japanese and Caucasian populations.

Suicide by fentanyl.

PubMed

Sutlović, Davorka; Definis-Gojanović, Marija

2007-09-01

Fentanyl is a potent, short-acting narcotic analgesic widely used as surgical anaesthetic. This article presents a case in which fentanyl was self-injected by a 41-year old nurse, an employee at the hospital emergency department, who was found dead at home. She had no known history of drug and alcohol abuse. Two syringes, one empty and one filled with a clear liquid, were found near the body, while a needle was stuck into her hand. Toxicological analysis showed fentanyl poisoning. Fentanyl overdose was declared the cause of death and the manner of death was classified as suicide. To our knowledge, death due to the intravenous injection of fentanyl has not previously been reported in Croatia.

The anesthetic effects on vasopressor modulation of cerebral blood flow in an immature swine model.

PubMed

Bruins, Benjamin; Kilbaugh, Todd J; Margulies, Susan S; Friess, Stuart H

2013-04-01

The effect of various sedatives and anesthetics on vasopressor modulation of cerebral blood flow (CBF) in children is unclear. In adults, isoflurane has been described to decrease CBF to a lesser extent than fentanyl and midazolam. Most large-animal models of neurocritical care use inhaled anesthetics for anesthesia. Investigations involving modulations of CBF would have improved translatability within a model that more closely approximates the current practice in the pediatric intensive care unit. Fifteen 4-week-old piglets were given 1 of 2 anesthetic protocols: total IV anesthesia (TIVA) (midazolam 1 mg/kg/h and fentanyl 100 μg/kg/h, n = 8) or ISO (isoflurane 1.5%-2% and fentanyl 100 μg/kg/h, n = 7). Mean arterial blood pressure, intracranial pressure (ICP), CBF, and brain tissue oxygen tension were measured continuously as piglets were exposed to escalating doses of arginine vasopressin, norepinephrine (NE), and phenylephrine (PE). Baseline CBF was similar in the 2 groups (ISO 38 ± 10 vs TIVA 35 ± 26 mL/100 g/min) despite lower baseline cerebral perfusion pressure in the ISO group (45 ± 11 vs 71 ± 11 mm Hg; P < 0.0005). Piglets in the ISO group displayed increases in ICP with PE and NE (11 ± 4 vs 16 ± 4 mm Hg and 11 ± 8 vs 18 ± 5 mm Hg; P < 0.05), but in the TIVA group, only exposure to PE resulted in increases in ICP when comparing maximal dose values with baseline data (11 ± 4 vs 15 ± 5 mm Hg; P < 0.05). Normalized CBF displayed statistically significant increases regarding anesthetic group and vasopressor dose when piglets were exposed to NE and PE (P < 0.05), suggesting an impairment of autoregulation within ISO, but not TIVA. The vasopressor effect on CBF was limited when using a narcotic-benzodiazepine-based anesthetic protocol compared with volatile anesthetics, consistent with a preservation of autoregulation. Selection of anesthetic drugs is critical to investigate mechanisms of cerebrovascular hemodynamics, and in translating critical care investigations between the laboratory and bedside.

21 CFR 522.800 - Droperidol and fentanyl.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Droperidol and fentanyl. 522.800 Section 522.800... Droperidol and fentanyl. (a) Specifications. Each milliliter of solution contains 20 milligrams (mg) of droperidol and 0.4 mg of fentanyl citrate. (b) Sponsor. See No. 000061 in § 510.600(c) of this chapter. (c...

Solution-state structure and affinities of cyclodextrin: Fentanyl complexes by nuclear magnetic resonance spectroscopy and molecular dynamics simulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mayer, Brian P.; Kennedy, Daniel J.; Lau, Edmond Y.

Cyclodextrins (CDs) are investigated for their ability to form inclusion complexes with the analgesic fentanyl and three similar molecules: acetylfentanyl, thiofentanyl, and acetylthiofentanyl. Stoichiometry, binding strength, and complex structure are revealed through nuclear magnetic resonance (NMR) techniques and discussed in terms of molecular dynamics (MD) simulations. It was found that β-cyclodextrin is generally capable of forming the strongest complexes with the fentanyl panel. Two-dimensional NMR data and computational chemical calculations are used to derive solution-state structures of the complexes. Binding of the fentanyls to the CDs occurs at the amide phenyl ring, leaving the majority of the molecule solvated bymore » water, an observation common to all four fentanyls. This finding suggests a universal binding behavior, as the vast majority of previously synthesized fentanyl analogues contain this structural moiety. Furthermore, this baseline study serves as the most complete work on CD:fentanyl complexes to date and provides the insights into strategies for producing future generations of designer cyclodextrins capable of stronger and more selective complexation of fentanyl and its analogues.« less

Solution-state structure and affinities of cyclodextrin: Fentanyl complexes by nuclear magnetic resonance spectroscopy and molecular dynamics simulation

DOE PAGES

Mayer, Brian P.; Kennedy, Daniel J.; Lau, Edmond Y.; ...

2016-02-04

Cyclodextrins (CDs) are investigated for their ability to form inclusion complexes with the analgesic fentanyl and three similar molecules: acetylfentanyl, thiofentanyl, and acetylthiofentanyl. Stoichiometry, binding strength, and complex structure are revealed through nuclear magnetic resonance (NMR) techniques and discussed in terms of molecular dynamics (MD) simulations. It was found that β-cyclodextrin is generally capable of forming the strongest complexes with the fentanyl panel. Two-dimensional NMR data and computational chemical calculations are used to derive solution-state structures of the complexes. Binding of the fentanyls to the CDs occurs at the amide phenyl ring, leaving the majority of the molecule solvated bymore » water, an observation common to all four fentanyls. This finding suggests a universal binding behavior, as the vast majority of previously synthesized fentanyl analogues contain this structural moiety. Furthermore, this baseline study serves as the most complete work on CD:fentanyl complexes to date and provides the insights into strategies for producing future generations of designer cyclodextrins capable of stronger and more selective complexation of fentanyl and its analogues.« less

[Solutions for the clinical problems of analgesics for cancer pain treatment in Japan].

PubMed

Kokubun, Hideya; Matoba, Motohiro; Yamada, Yasuhiko; Yago, Kazuo

2011-01-01

The pain experienced by cancer patients can be managed in 70-90% of cases by the World Health Organisation protocol for cancer pain. However, cancer pain treatment in Japan is not sufficiently effective. To use medicine safely and effectively, various problems must be solved. Therefore, in this study, appropriate usage of cancer pain treatment was examined. We were able to use acetaminophen suppositories (800 mg each) in cancer pain patients. It was suggested that high serum concentrations of oxycodone and hydrocotarnine might be observed in geriatric patients or in the state of decreased hepatic blood flow, making dose adjustment is necessary for such patients. We also clarified that the conversion ratio from oral oxycodone to intravenous ocycodone/hydrocotarnine was 0.71±0.12. In addition, we clarified the pharmacokinetics of controlled-release oxycodone in patients with cancer pain. Moreover, the findings of our study indicate that in the steady state, the serum concentrations of fentanyl are not maintained at a constant level for 3 days following the use of transdermal fentanyl. We established a method of appropriately passing a nasal duct for sustained release of fine granules of morphine sulfate. Resolution of the clinical problems associated with cancer pain treatments is anticipated to allow the proper use of cancer pain treatments in Japan.

Effectiveness of morphine, fentanyl, and methoxyflurane in the prehospital setting.

PubMed

Middleton, Paul M; Simpson, Paul M; Sinclair, Gary; Dobbins, Timothy A; Math, B; Bendall, Jason C

2010-01-01

To compare the effectiveness of intravenous (IV) morphine, intranasal (IN) fentanyl, and inhaled methoxyflurane when administered by paramedics to patients with moderate to severe pain. We conducted a retrospective comparative study of adult patients with moderate to severe pain treated by paramedics from the Ambulance Service of New South Wales who received IV morphine, IN fentanyl, or inhaled methoxyflurane either alone or in combination between January 1, 2004, and November 30, 2006. We used multivariate logistic regression to analyze data extracted from a clinical database containing routinely entered information from patient health care records. The primary outcome measure was effective analgesia, defined as a reduction in pain severity of > or = 30% of initial pain score using an 11-point verbal numeric rating scale (VNRS-11). The study population comprised 52,046 patients aged between 16 and 100 years with VNRS-11 scores of > or = 5. All analgesic agents were effective in the majority of patients (81.8%, 80.0%, and 59.1% for morphine, fentanyl, and methoxyflurane, respectively). There was very strong evidence that methoxyflurane was inferior to both morphine and fentanyl (p < 0.0001). There was strong evidence that morphine was more effective than fentanyl (p = 0.002). There was no evidence that combination analgesia was better than either fentanyl or morphine alone. Inhaled methoxyflurane, IN fentanyl, and IV morphine are all effective analgesic agents in the out-of-hospital setting. Morphine and fentanyl are significantly more effective analgesic agents than methoxyflurane. Morphine appears to be more effective than IN fentanyl; however, the benefit of IV morphine may be offset to some degree by the ability to administer IN fentanyl without the need for IV access.

Detection of illicit online sales of fentanyls via Twitter.

PubMed

Mackey, Tim K; Kalyanam, Janani

2017-01-01

A counterfeit fentanyl crisis is currently underway in the United States.  Counterfeit versions of commonly abused prescription drugs laced with fentanyl are being manufactured, distributed, and sold globally, leading to an increase in overdose and death in countries like the United States and Canada.  Despite concerns from the U.S. Drug Enforcement Agency regarding covert and overt sale of fentanyls online, no study has examined the role of the Internet and social media on fentanyl illegal marketing and direct-to-consumer access.  In response, this study collected and analyzed five months of Twitter data (from June-November 2015) filtered for the keyword "fentanyl" using Amazon Web Services.  We then analyzed 28,711 fentanyl-related tweets using text filtering and a machine learning approach called a Biterm Topic Model (BTM) to detect underlying latent patterns or "topics" present in the corpus of tweets.  Using this approach we detected a subset of 771 tweets marketing the sale of fentanyls online and then filtered this down to nine unique tweets containing hyperlinks to external websites.  Six hyperlinks were associated with online fentanyl classified ads, 2 with illicit online pharmacies, and 1 could not be classified due to traffic redirection.  Importantly, the one illicit online pharmacy detected was still accessible and offered the sale of fentanyls and other controlled substances direct-to-consumers with no prescription required at the time of publication of this study.   Overall, we detected a relatively small sample of Tweets promoting illegal online sale of fentanyls.  However, the detection of even a few online sellers represents a public health danger and a direct violation of law that demands further study.

Drug Delivery and Transport into the Central Circulation: An Example of Zero-Order In vivo Absorption of Rotigotine from a Transdermal Patch Formulation.

PubMed

Cawello, Willi; Braun, Marina; Andreas, Jens-Otto

2018-01-13

Pharmacokinetic studies using deconvolution methods and non-compartmental analysis to model clinical absorption of drugs are not well represented in the literature. The purpose of this research was (1) to define the system of equations for description of rotigotine (a dopamine receptor agonist delivered via a transdermal patch) absorption based on a pharmacokinetic model and (2) to describe the kinetics of rotigotine disposition after single and multiple dosing. The kinetics of drug disposition was evaluated based on rotigotine plasma concentration data from three phase 1 trials. In two trials, rotigotine was administered via a single patch over 24 h in healthy subjects. In a third trial, rotigotine was administered once daily over 1 month in subjects with early-stage Parkinson's disease (PD). A pharmacokinetic model utilizing deconvolution methods was developed to describe the relationship between drug release from the patch and plasma concentrations. Plasma-concentration over time profiles were modeled based on a one-compartment model with a time lag, a zero-order input (describing a constant absorption via skin into central circulation) and first-order elimination. Corresponding mathematical models for single- and multiple-dose administration were developed. After single-dose administration of rotigotine patches (using 2, 4 or 8 mg/day) in healthy subjects, a constant in vivo absorption was present after a minor time lag (2-3 h). On days 27 and 30 of the multiple-dose study in patients with PD, absorption was constant during patch-on periods and resembled zero-order kinetics. Deconvolution based on rotigotine pharmacokinetic profiles after single- or multiple-dose administration of the once-daily patch demonstrated that in vivo absorption of rotigotine showed constant input through the skin into the central circulation (resembling zero-order kinetics). Continuous absorption through the skin is a basis for stable drug exposure.

Pain Relievers - Multiple Languages

MedlinePlus

... español (Spanish) Bilingual PDF Health Information Translations Fentanyl - Opioid addiction, part 6 - English PDF Fentanyl - Opioid addiction, part 6 - español (Spanish) PDF Fentanyl - Opioid addiction, ...

Drug profile: transdermal rivastigmine patch in the treatment of Alzheimer disease.

PubMed

Emre, Murat; Bernabei, Roberto; Blesa, Rafael; Bullock, Roger; Cunha, Luis; Daniëls, Hugo; Dziadulewicz, Edward; Förstl, Hans; Frölich, Lutz; Gabryelewicz, Tomasz; Levin, Oleg; Lindesay, James; Martínez-Lage, Pablo; Monsch, Andreas; Tsolaki, Magda; van Laar, Teus

2010-08-01

Cholinesterase inhibitors constitute one of the mainstays of treatment of Alzheimer disease (AD). Gastrointestinal side effects, difficulty accessing therapeutic doses and poor patient compliance have been identified as barriers to effective treatment with these substances. The rivastigmine transdermal patch provides continuous delivery of drug through the skin into the bloodstream, avoiding the fluctuations in plasma concentration associated with oral administration. This pharmacokinetic profile is associated with reduced side effects, resulting in easier access to expected target doses. These benefits, along with other practical advantages of the transdermal patch, may contribute to enhanced patient compliance. Here, we present a review of the current literature on rivastigmine patch, and offer advice based on our own collective clinical experience. Rivastigmine patch provides an efficient option for managing patients with AD, to be considered among the first line therapies for the disease.

Does intravenous induction dosing among patients undergoing gastrointestinal surgical procedures follow current recommendations: a study of contemporary practice.

PubMed

Akhtar, Shamsuddin; Liu, Jia; Heng, Joseph; Dai, Feng; Schonberger, Robert B; Burg, Matthew M

2016-09-01

It is recommended to correct intravenous induction doses by up to 50% for patients older than 65 years. The objectives were to determine (a) the degree to which anesthesia providers correct induction doses for age and (b) additionally adjust for American Society of Anesthesiologists physical status (ASA-PS) class (severity of illness) and (c) whether postinduction hypotension is more common among patients aged >65. Retrospective chart review. Academic medical center. A total of 1869 adult patients receiving general anesthesia for GI surgical procedures from February 2013 to January 2014. Patients were divided into 3 age groups (age <65, 65-79, ≥80 years) and then further stratified into ASA-PS class (I/II vs III/IV). Multiple pairwise comparisons were conducted using Welch t tests for continuous variables to determine whether dosing was different for the older groups vs the younger group; separate analyses were performed within and across ASA-PS class. This approach was also used to determine differences in mean arterial pressure change in the older groups vs the younger group, whereas the rates of hypotension among different age groups were compared by Cochran-Armitage trend test. No significant decrease in dosing between age groups was observed for fentanyl and midazolam. For propofol, there was a significantly lower dosing for older patients: 17% for patients aged 65-79 and 29% for those aged >80, which was still in less than the recommendations. An inverse relationship was observed between propofol dosing and ASA-PS class, but no consistent relationship was noted for fentanyl and midazolam. There were a significantly larger drop in mean arterial pressure and a greater likelihood of hypotension following induction in patients aged 65-79 years and >80 years as compared with those aged <65 years. This study shows that the administered dose of anesthetic induction agents is significantly higher than that recommended for patients older than 65 years. This failure to age-adjust dose may contribute to hypotensive episodes. Copyright © 2016 Elsevier Inc. All rights reserved.

75 FR 37295 - Control of Immediate Precursor Used in the Illicit Manufacture of Fentanyl as a Schedule II...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-29

... are the most potent opioids available for human and veterinary use. Fentanyl produces opioid effects that are indistinguishable from morphine or heroin, but fentanyl has a greater potency and a shorter duration of action. Fentanyl is approximately 50 to 100 times more potent than morphine and 30 to 50 times...

Fentanyl self-testing outside supervised injection settings to prevent opioid overdose: Do we know enough to promote it?

PubMed

McGowan, Catherine R; Harris, Magdalena; Platt, Lucy; Hope, Vivian; Rhodes, Tim

2018-05-11

Since 2013, North America has experienced a sharp increase in unintentional fatal overdoses: fentanyl, and its analogues, are believed to be primarily responsible. Currently, the most practical means for people who use drugs (PWUD) to avoid or mitigate risk of fentanyl-related overdose is to use drugs in the presence of someone who is in possession of, and experienced using, naloxone. Self-test strips which detect fentanyl, and some of its analogues, have been developed for off-label use allowing PWUD to test their drugs prior to consumption. We review the evidence on the off-label sensitivity and specificity of fentanyl test strips, and query whether the accuracy of fentanyl test strips might be mediated according to situated practices of use. We draw attention to the weak research evidence informing the use of fentanyl self-testing strips. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Fentanyl-associated fatalities among illicit drug users in Wayne County, Michigan (July 2005-May 2006).

PubMed

Algren, D Adam; Monteilh, Carolyn P; Punja, Mohan; Schier, Joshua G; Belson, Martin; Hepler, Bradford R; Schmidt, Carl J; Miller, Corinne E; Patel, Manish; Paulozzi, Leonard J; Straetemans, Masja; Rubin, Carol

2013-03-01

During the summer of 2005, multiple cities in the United States began to report outbreaks of fentanyl-associated fatalities among illicit drug users. The objectives of this study were to (1) determine if an outbreak of fentanyl-associated fatalities occurred in mid-2005 to mid-2006 and (2) to examine trends and compare features of fentanyl-contaminated heroin-associated fatalities (FHFs) with non-fentanyl, heroin-associated fatalities (NFHFs) among illicit drug users. Baseline prevalence of fentanyl- and heroin-associated deaths was estimated from January to May 2005 based on recorded cause of death (determined by the medical examiner (ME)) using the Wayne County, MI, USA toxicology database. The database was then queried for both FHFs and NFHFs between July 1, 2005 and May 12, 2006. A FHF was defined as having fentanyl or norfentanyl (metabolite) detected in any postmortem biological sample and either (1) detection of heroin or its metabolite (6-acetylmorphine) and/or cocaine or its metabolite (benzoylecgonine) in a postmortem biological specimen or (2) confirmation of fentanyl abuse as the cause of death by the ME or a medical history available sufficient enough to exclude prescription fentanyl or other therapeutic opioid use. A NFHF was defined as detection of heroin, 6-acetylmorphine (heroin metabolite) or morphine in any postmortem biological specimen, heroin overdose listed as the cause of death by the ME, and absence of fentanyl detection on postmortem laboratory testing. Information was systematically collected, trended for each group and then compared between the two groups with regard to demographic, exposure, autopsy, and toxicology data. Logistic regression was performed using SAS v 9.1 examining the effects of age, gender, and marital status with fentanyl group status. Monthly prevalence of fentanyl-associated fatalities among illicit drug users increased from an average of two in early 2005 to a peak of 24 in May, 2006. In total, 101 FHFs and 90 NFHFs were analyzed. The median age of decedents was 46 and 45 years for the fentanyl and non-fentanyl groups, respectively. Fentanyl-contaminated heroin-associated fatalities (FHFs) were more likely to be female (p = 0.003). Women aged over 44 years (OR = 4.67;95 % CI = 1.29-16.96) and divorced/widowed women (OR = 14.18;95 % CI = 1.59-127.01) were more likely to be FHFs when compared to women aged less than 44 years and single, respectively. A significant interaction occurred between gender and age, and gender and marital status. Most FHFs had central (heart) blood samples available for fentanyl testing (n = 96; 95 %): fentanyl was detected in most (n = 91; 95 %). Of these, close to half had no detectable heroin (or 6-acetylmorphine) concentrations (n = 37; 40.7 %). About half of these samples had detectable cocaine concentrations (n = 20; 54 %). Median fentanyl concentration in central blood samples was 0.02 μg/ml (n = 91, range <0.002-0.051 μg/ml) and 0.02 μg/ml (n = 32, range <0.004-0.069 μg/ml) in peripheral blood samples. The geometric mean of the ratio of central to peripheral values was 2.10 (median C/P = 1.75). At autopsy, pulmonary edema was the most frequently encountered finding for both groups (77 %). Illicit drugs may contain undeclared ingredients that may increase the likelihood of fatality in users. Gender differences in fentanyl-related mortality may be modified by age and/or marital status. These findings may help inform public health and prevention activities if fatalities associated with fentanyl-contaminated illicit drugs reoccur.

From high doses of oral rivastigmine to transdermal rivastigmine patches: user experience and satisfaction among caregivers of patients with mild to moderate Alzheimer disease.

PubMed

Reñé, R; Ricart, J; Hernández, B

2014-03-01

Rivastigmine, a treatment for mild to moderate Alzheimer disease (AD), is the first cholinesterase inhibitor to be available in the transdermal format. We aim to describe user experience and satisfaction with the rivastigmine patch, as well as any clinical changes perceived in patients. Observational, cross-sectional, multicentre study with 239 investigators and 1851 informal caregivers of patients with mild to moderate AD. Patients were treated with transdermal rivastigmine patches for ≥ 6 months and had previously received high doses of oral rivastigmine. Mean caregiver age was 59.8±14.4 years and 70.9% were women. They spent 10.0±7.1hours per day providing care and 79.8% lived with the patient. Patch instructions were described as easy to follow by 97.1% of the caregivers and 92.1% of them rated patch application as easy or very easy. The most commonly cited disadvantage was adhesion problems (26.8%). Discontinuation of treatment was due to cutaneous reactions in most cases. Overall, 76.5% of the caregivers were satisfied or very satisfied with transdermal treatment and 77.4% considered that its interference with daily activities was minimal or null. The patch was preferred to oral treatment by 94.3% of caregivers. Clinical Global Impression of Change ratings improved according to 61.3% of the caregivers and 53% of the investigators. Few caregivers reported medication forgetfulness. Most caregivers of patients with mild to moderate AD preferred the transdermal format of rivastigmine to the oral format. Caregivers also reported overall satisfaction, ease of use, and reduced impact on daily activities for transdermal rivastigmine format, in addition to patient improvement compared to their condition under the previous treatment. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Notes from the field: increase in fentanyl-related overdose deaths - Rhode Island, November 2013-March 2014.

PubMed

Mercado-Crespo, Melissa C; Sumner, Steven A; Spelke, M Bridget; Sugerman, David E; Stanley, Christina

2014-06-20

During November 2013-March 2014, twice as many all-intent drug overdose deaths were reported in Rhode Island as were reported during the same period in previous years. Most deaths were among injection-drug users, and a large percentage involved fentanyl, a synthetic opioid that is 50-100 times more potent than morphine. Clusters of fentanyl-related deaths have been reported recently in several states. From April 2005 to March 2007, time-limited active surveillance from CDC and the Drug Enforcement Administration identified 1,013 deaths caused by illicit fentanyl use in New Jersey; Maryland; Chicago, Illinois; Detroit, Michigan; and Philadelphia, Pennsylvania. Acetyl fentanyl, an illegally produced fentanyl analog, caused a cluster of overdose deaths in northern Rhode Island in 2013.

Rivastigmine From Capsules to Patch: Therapeutic Advances in the Management of Alzheimer’s Disease and Parkinson’s Disease Dementia

PubMed Central

Micca, Joseph L.; Grossberg, George T.; Velting, Drew M.

2014-01-01

Objective: To discuss the pharmacology, mechanism of action, and chemical properties of the cholinesterase inhibitor (ChEI) rivastigmine; to provide a rationale for transdermal delivery and supportive clinical data, along with practical guidance on rivastigmine patch use in Alzheimer’s disease and Parkinson’s disease dementia. Data Sources: Pivotal studies of rivastigmine capsules and patch were identified using PubMed and the rivastigmine US prescribing information. PubMed searches were performed in 2013 using rivastigmine as a keyword. Study Selection: English-language articles related to rivastigmine considered of relevance to primary care physicians were included. Data Synthesis: Pharmacologic differences exist between rivastigmine and ChEIs. Clinical studies demonstrate symptomatic efficacy of oral rivastigmine across all stages of Alzheimer’s disease and mild-to-moderate Parkinson’s disease dementia. However, gastrointestinal adverse events limit access to optimal therapeutic doses. Strategies that lower maximum plasma concentrations (Cmax) and prolong time to Cmax, ie, transdermal delivery, may improve tolerability. Clinical registration studies have demonstrated improved tolerability of rivastigmine 9.5-mg/24-h patch versus 6-mg twice-daily capsules in mild-to-moderate Alzheimer’s disease, and a positive benefit-risk profile of 13.3-mg/24-h versus 9.5-mg/24-h patch in patients needing enhanced efficacy. Clinical data comparing 13.3-mg/24-h versus 4.6-mg/24-h patch in severe Alzheimer’s disease demonstrated efficacy on cognition and activities of daily living. These data led to approval of rivastigmine patch in severe Alzheimer’s disease. Transdermal delivery also has practical advantages, including simple, once-daily administration and a visual indicator of compliance. Potential application site reactions can be minimized and need not be a barrier to treatment. Conclusions: In addition to practical advantages, rivastigmine patch may improve clinical outcomes throughout the course of Alzheimer’s disease by providing access to high-dose efficacy without compromising tolerability. PMID:25667813

Intranasal Fentanyl Intoxication Leading to Diffuse Alveolar Hemorrhage.

PubMed

Ruzycki, Shannon; Yarema, Mark; Dunham, Michael; Sadrzadeh, Hossein; Tremblay, Alain

2016-06-01

Increasing rates of opioid abuse, particularly fentanyl, may lead to more presentations of unusual effects of opioid toxicity. Diffuse alveolar hemorrhage is a rare complication of fentanyl overdose. A 45-year-old male presented in hypoxic respiratory failure secondary to diffuse alveolar hemorrhage requiring intubation. Comprehensive drug screening detected fentanyl without exposure to cocaine. Further history upon the patient's recovery revealed exposure to snorted fentanyl powder immediately prior to presentation. Diffuse alveolar hemorrhage is a potential, though rare, presentation of opioid intoxication. Recognition of less common complications of opioid abuse such as diffuse alveolar hemorrhage is important in proper management of overdoses.

Fentanyl Sublingual Spray

MedlinePlus

Fentanyl sublingual spray is used to treat breakthrough pain (sudden episodes of pain that occur despite round ... effects of the medication) to narcotic pain medications. Fentanyl is in a class of medications called narcotic ( ...

Fentanyl Nasal Spray

MedlinePlus

Fentanyl nasal spray is used to treat breakthrough pain (sudden episodes of pain that occur despite round ... effects of the medication) to narcotic pain medications. Fentanyl is in a class of medications called narcotic ( ...

Behavioral response and kinetics of terrestrial atrazine exposure in American toads (bufo americanus)

USGS Publications Warehouse

Storrs, Mendez S.I.; Tillitt, D.E.; Rittenhouse, T.A.G.; Semlitsch, R.D.

2009-01-01

Amphibians in terrestrial environments obtain water through a highly vascularized pelvic patch of skin. Chemicals can also be exchanged across this patch. Atrazine (ATZ), a widespread herbicide, continues to be a concern among amphibian ecologists based on potential exposure and toxicity. Few studies have examined its impact on the terrestrial juvenile or adult stages of toads. In the current study, we asked the following questions: (1) Will juvenile American toads (Bufo americanus) avoid soils contaminated with ATZ? (2) Can they absorb ATZ across the pelvic patch? (3) If so, how is it distributed among the organs and eventually eliminated? We conducted a behavioral choice test between control soil and soil dosed with ecologically relevant concentrations of ATZ. In addition, we examined the uptake, distribution, and elimination of water dosed with 14C-labeled ATZ. Our data demonstrate that toads do not avoid ATZ-laden soils. ATZ crossed the pelvic patch rapidly and reached an apparent equilibrium within 5 h. The majority of the radiolabeled ATZ ended up in the intestines, whereas the greatest concentrations were observed in the gall bladder. Thus, exposure of adult life stages of amphibians through direct uptake of ATZ from soils and runoff water should be considered in risk evaluations. ?? 2009 Springer Science+Business Media, LLC.

Labour analgesia with intrathecal fentanyl decreases maternal stress.

PubMed

Cascio, M; Pygon, B; Bernett, C; Ramanathan, S

1997-06-01

Lumbar epidural analgesia (LEA) decreases maternal stress as measured by maternal circulating plasma catecholamine concentrations. Intrathecal fentanyl (ITF) provides effective labour analgesia but its effect on maternal epinephrine (Epi) and norepinephrine (NE) concentrations is not known. This study assesses whether ITF reduces maternal stress in the same manner as conventional LEA. Twenty-four healthy women in active labour received either 25 micrograms ITF (n = 12) or epidural lidocaine 1.5% (n = 12) for analgesia. Venous blood samples were collected before anaesthesia and at five minute intervals for 30 min following anaesthesia for the measurement of plasma Epi and NE by high performance liquid chromatography. Maternal blood pressure (BP), heart rate (HR), visual analog scores (VAS) to pain and pruritus were recorded at the same time. Both ITF and LEA decreased pain VAS scores, maternal BP, and plasma Epi concentrations with only minimal effects on plasma NE concentrations. Intrathecal fentanyl (ITF) and LEA reduced plasma epi to a similar extent, with ITF reducing the levels slightly faster than LEA. Intrathecal fentanyl(ITF) and LEA reduced plasma Epi concentrations by 52% and 51%, respectively (P value < 0.01). We conclude that ITF is as effective as LEA in producing pain relief in the labouring patient. Intrathecal Fentanyl (ITF) is also capable of reducing maternal plasma epinephrine concentration, thus avoiding the possibly deleterious side effects of excess amounts of this catecholamine during labour.

A Comparison of the Effects of Fentanyl and Remifentanil on Nausea, Vomiting, and Pain after Cesarean Section

PubMed Central

Jabalameli, Mitra; Rouholamin, Safoura; Gourtanian, Fatemeh

2011-01-01

Background: The effects of different opioids on postoperative nausea and vomiting (PONV) and pain have not been conclusively determined. The aim of this study was to compare the effects of fentanyl, remifentanil or fentanyl plus morphine on the incidence of PONV and pain in women subjected to cesarean section under general anesthesia. Methods: The study was a randomized clinical trial recruiting 96 parturients with American Society of Anesthesiologists (ASA) physical status I and II. They scheduled for cesarean section under general anesthesia using sodium thiopental, succynylcholine, and isoflurane O2/N2O 50/50 mixture. After clamping the umbilical cord, the patients were given fentanyl (2 µg/kg/h), remifentanil (0.05 µg/kg/h), or fentanyl (2 µg/kg) pulse morphine (0.1 mg/kg) intravenously. Visual analog scale for pain and nausea, frequency of PONV, meperidine and metoclopramide consumption were evaluated at recovery, and 4, 8, 12 and 24 hours after the surgery. Results: There was no significant difference between the three groups in terms of frequency of nausea, vomiting, and mean nausea and pain scores at any time points. None of the patients required the administration of metoclopramide. However, the mean VAS for pain in remifentanil-treated group was insignificantly more than that in fentanyl- or fentanyl plus morphine-treated group at recovery or 4 hours after the surgery. The mean mepridine consumption in remifentanil-treated group was significantly (P=0.001) more than that in fentanyl- or fentanyl plus morphine-treated group in 24 hours after the surgery respectively. There was no significant difference in hemodynamic parameters of the three groups in all measurements after the surgery. Conclusion: The findings of this study showed that early postoperative analgesia was better with fentanyl, and postoperative meperidine consumption was significantly less with fentanyl than with remifentanil or combined fentayl and morphine. PMID:23357939

Prevalence and correlates of fentanyl-contaminated heroin exposure among young adults who use prescription opioids non-medically.

PubMed

Macmadu, Alexandria; Carroll, Jennifer J; Hadland, Scott E; Green, Traci C; Marshall, Brandon D L

2017-05-01

The rate of overdose deaths caused by fentanyl-contaminated heroin (FCH) use is increasing rapidly in the United States. We examined risk factors for exposure to FCH and experiences with FCH use among young adult non-medical prescription opioids (NMPO) users. We analyzed data from the Rhode Island Young Adult Prescription Drug Study (RAPiDS), which enrolled young adults aged 18 to 29 reporting prior 30day NMPO use between January 2015 and February 2016. Participants completed questionnaires ascertaining drug use patterns and risk behaviors, including FCH exposure. Logistic regression was used to assess factors associated with known or suspected FCH exposure. Of 199 participants, the median age was 25 (IQR: 22, 27), 130 (65.3%) were male, and 122 (61.3%) were of White, non-Hispanic race/ethnicity. In total, 22 (11%) reported known or suspected FCH exposure in the prior six months. Several drug use patterns and risk behaviors were associated with FCH exposure, including: regular heroin and cocaine use; diverted pharmaceutical fentanyl use in the prior six months; NMPO use to avoid withdrawal symptoms; longer duration of NMPO use; regular injection drug use; and prior overdose (all p<0.001). Among participants who reported FCH exposure, 59% were unaware that their heroin was contaminated with fentanyl prior to last use, 59% reported that FCH provides a better high, and all recognized that fentanyl increases overdose risk. Exposure to fentanyl-contaminated heroin is an emerging trend among young adult NMPO users in Rhode Island. Overdose prevention programs addressing FCH use are urgently needed. Copyright © 2017 Elsevier Ltd. All rights reserved.

A 3D-printed local drug delivery patch for pancreatic cancer growth suppression.

PubMed

Yi, Hee-Gyeong; Choi, Yeong-Jin; Kang, Kyung Shin; Hong, Jung Min; Pati, Ruby Gupta; Park, Moon Nyeo; Shim, In Kyong; Lee, Chan Mi; Kim, Song Cheol; Cho, Dong-Woo

2016-09-28

Since recurrence and metastasis of pancreatic cancer has a worse prognosis, chemotherapy has been typically performed to attack the remained malignant cells after resection. However, it is difficult to achieve the therapeutic concentration at the tumor site with systemic chemotherapy. Numerous local drug delivery systems have been studied to overcome the shortcomings of systemic delivery. However, because most systems involve dissolution of the drug within the carrier, the concentration of the drug is limited to the saturation solubility, and consequently cannot reach the sufficient drug dose. Therefore, we hypothesized that 3D printing of a biodegradable patch incorporated with a high drug concentration would provide a versatile shape to be administered at the exact tumor site as well as an appropriate therapeutic drug concentration with a controlled release. Here, we introduce the 3D-printed patches composed of a blend of poly(lactide-co-glycolide), polycaprolactone, and 5-fluorouracil for delivering the anti-cancer drug in a prolonged controlled manner and therapeutic dose. 3D printing technology can manipulate the geometry of the patch and the drug release kinetics. The patches were flexible, and released the drug over four weeks, and thereby suppressed growth of the subcutaneous pancreatic cancer xenografts in mice with minimized side effects. Our approach reveals that 3D printing of bioabsorbable implants containing anti-cancer drugs could be a powerful method for an effective local delivery of chemotherapeutic agents to treatment of cancers. Copyright © 2016 Elsevier B.V. All rights reserved.

Detection of illicit online sales of fentanyls via Twitter

PubMed Central

Mackey, Tim K.; Kalyanam, Janani

2017-01-01

A counterfeit fentanyl crisis is currently underway in the United States.  Counterfeit versions of commonly abused prescription drugs laced with fentanyl are being manufactured, distributed, and sold globally, leading to an increase in overdose and death in countries like the United States and Canada.  Despite concerns from the U.S. Drug Enforcement Agency regarding covert and overt sale of fentanyls online, no study has examined the role of the Internet and social media on fentanyl illegal marketing and direct-to-consumer access.  In response, this study collected and analyzed five months of Twitter data (from June-November 2015) filtered for the keyword “fentanyl” using Amazon Web Services.  We then analyzed 28,711 fentanyl-related tweets using text filtering and a machine learning approach called a Biterm Topic Model (BTM) to detect underlying latent patterns or “topics” present in the corpus of tweets.  Using this approach we detected a subset of 771 tweets marketing the sale of fentanyls online and then filtered this down to nine unique tweets containing hyperlinks to external websites.  Six hyperlinks were associated with online fentanyl classified ads, 2 with illicit online pharmacies, and 1 could not be classified due to traffic redirection.  Importantly, the one illicit online pharmacy detected was still accessible and offered the sale of fentanyls and other controlled substances direct-to-consumers with no prescription required at the time of publication of this study.   Overall, we detected a relatively small sample of Tweets promoting illegal online sale of fentanyls.  However, the detection of even a few online sellers represents a public health danger and a direct violation of law that demands further study. PMID:29259769

Fentanyl inhibits proliferation and invasion of colorectal cancer via β-catenin

PubMed Central

Zhang, Xiu-Lai; Chen, Min-Li; Zhou, Sheng-Li

2015-01-01

Background and aim: Fentanyl is widely used for relieving pain and narcotizing in cancer patients. However, there are few published reports regarding the effects of fentanyl on tumor control and treatment. Here we investigated the effects of fentanyl on tumor growth and cell invasion in the human colorectal carcinoma (HCT116) cells. Methods: Nude mice xenografts of HCT116 cells were established to assess the inhibition effect on tumor growth by fentanyl. MTT and Transwell were employed to determine the cell survival rate and cell invasion, respectively. MicroRNAs and mRNAs expression were quantified by real-time PCR. β-catenin and matrix metalloproteinases (MMP-2 and MMP-9) expression were assayed by western blotting. β-Catenin-specific small interfering RNA (Si-β-catenin) and miR-182 mimics were transfected in cells to investigate the mechanism underlying the effects of fentanyl on the colorectal tumor and HCT116 cells. Results: Treatment with fentanyl inhibited the tumor growth and HCT116 cells invasion. Fentanyl also downregulated the expression of β-catenin and miR-182 in both xenograft tumors and HCT116 cells, and decreased the protein level of MMP-9 in HCT116 cells. Downregulation of β-Catenin resulted in the decrease of miR-182 expression in colorectal cells. In addition, the overexpression of miR-182 reversed the effect of fentanyl on MMP-9 expression and cell invasion of HCT116 cells. Conclusions: The current study demonstrated that the inhibition of tumor growth and cell invasion in colorectal cancer by fentanyl is probably due to downregulation of miR-182 and MMP-9 expression by β-catenin. PMID:25755709

Evaluation of plasma fentanyl concentrations in infants during cardiopulmonary bypass with low-volume circuits.

PubMed

Kussman, Barry D; Zurakowski, David; Sullivan, Lorna; McGowan, Francis X; Davis, Peter J; Laussen, Peter C

2005-06-01

The purpose of the study was to measure changes in plasma fentanyl concentrations during infant cardiac surgery using a bypass circuit with low priming volume and to examine the relation of plasma fentanyl concentration and temperature to Bispectral Index (BIS) as an index of conscious level during infant cardiac surgery. Prospective cohort study. Tertiary care, academic children's hospital. Fifteen neonates and infants undergoing cardiac surgery with hypothermic cardiopulmonary bypass (CPB). Patients were anesthetized with fentanyl, receiving a 30 microg/kg bolus for induction immediately followed by continuous infusion of 0.3 microg/kg/min until skin closure. Intraoperative data and total plasma fentanyl concentration were measured at preinduction; 30 minutes postinduction; sternotomy; aortic cannulation; at 4, 30, and 60 minutes on CPB; and at 1 and 30 minutes off CPB. At the onset of CPB, fentanyl declined from 15 +/- 6 to 11 +/- 5 ng/mL (p < 0.01), increasing to 16 +/- 5 ng/mL (p < 0.01) at 30 minutes on CPB and maintaining a similar level until 30 minutes off CPB. BIS decreased from 88 +/- 20 to 42 +/- 11 (p = 0.02) with induction, declined further during cooling to 9 +/- 11 at the nadir temperature ( p < 0.001), and increased during rewarming to 29 +/- 9 at 1 minute (p < 0.001) and 35 +/- 10 at 30 minutes off CPB ( p < 0.01). Because of wide individual variation in BIS, there was no significant correlation between fentanyl and BIS and temperature. There was minimal variability in the plasma fentanyl concentration using a low-volume bypass circuit and constant infusion of fentanyl during surgery. There appears to be minimal utility for using BIS during infant cardiac surgery with no relationship between fentanyl concentration, temperature, and BIS established.

A cluster of fentanyl-related deaths among drug addicts in Sweden.

PubMed

Kronstrand, R; Druid, H; Holmgren, P; Rajs, J

1997-08-22

During a 16-month period, nine fatalities occurred among white male drug-addicts, where fentanyl was detected at postmortem toxicological analysis. The street samples associated with these cases confirmed the presence of fentanyl as an additive in low-concentration amphetamine powders with caffeine, phenazone and sugar as cutting agents. In seven of the cases, an acute intoxication by fentanyl was considered to be the immediate cause of death, and in one case, it was likely, but no analysis of fentanyl was performed in blood, and in another case the death was suicide by hanging. This appears to be the first report of a cluster of fentanyl-related deaths outside the United States, and the occurrence of fentanyl in combination with amphetamine has not previously been reported. In addition, in all cases, femoral blood was collected, and samples were handled and analysed according to standardized, quality-controlled procedures. The previous history, circumstances surrounding the death, autopsy findings, histology and toxicology examination of each case are presented. The gas chromatographic-mass spectrometric method for fentanyl is also described. Fentanyl concentrations ranged from 0.5 to 17 ng g-1 blood, and from 5 to 160 ng ml-1 urine. Other drugs found were amphetamine (8 cases), ethanol (5 cases) and benzodiazepines (5 cases). Morphine was found in only one case. The average age of men was 33.9 years (range 22-44); six were found in their own of friend's apartment, two inside buildings (stairways) and one was found outdoors. We conclude that fentanyl is a dangerous substance that should be considered in drug-addict deaths even outside the United States, particularly when the remaining toxicology is unremarkable, and the cause of death cannot be ascertained

Comparison of rocuronium and succinylcholine on postintubation sedative and analgesic dosing in the emergency department.

PubMed

Korinek, Justin D; Thomas, Rachel M; Goddard, Luke A; St John, Alexander E; Sakles, John C; Patanwala, Asad E

2014-06-01

Rocuronium and succinylcholine are both commonly used neuromuscular blockers for rapid sequence intubation in the emergency department (ED). The objective of this study was to determine if patients who receive rocuronium are more likely to receive lower doses of postintubation sedatives and analgesics compared with patients who receive succinylcholine. This was a retrospective cohort study carried out in a tertiary, academic ED. Consecutive adult patients, who were intubated using etomidate for induction of sedation, were included. Patients were categorized on the basis of whether they received (a) rocuronium or (b) succinylcholine for paralysis. The dosing of postintubation sedative and analgesic infusions were compared 30 min after initiation between the two groups. A total of 254 patients were included in the final analysis (rocuronium=127 and succinylcholine=127). In the overall cohort, 90.2% (n=229) of patients were administered a sedative postintubation in the ED. Most of these patients were initiated on propofol infusions. The mean propofol infusion rate at 30 min was 30±23 mcg/kg/min in the rocuronium group and 42±24 mcg/kg/min in the succinylcholine group (P=0.002). A total of 42.5% of patients (n=108) received an analgesic infusion (all patients received fentanyl). The mean fentanyl infusion rate at 30 min was 0.65±0.55 and 0.86±0.49 mcg/kg/h in the rocuronium and succinylcholine groups, respectively (P=0.041). Patients who receive rocuronium are more likely to receive lower doses of sedative and analgesic infusions after intubation. This may place them at risk of being awake under paralysis.

Music during interventional radiological procedures, effect on sedation, pain and anxiety: a randomised controlled trial

PubMed Central

Kulkarni, S; Johnson, P C D; Kettles, S; Kasthuri, R S

2012-01-01

Objective : To assess the effects of playing patient-selected music during interventional procedures on (1) the doses of sedation and analgesia and (2) anxiety levels. Methods : Patients undergoing interventional radiological procedures were randomised to either the intervention (music) or the control (no music) group. Patients in the intervention group had music of their choice played via headphones during the procedure. The primary outcomes were reductions in the doses of drugs for sedation (midazolam) and analgesia (fentanyl). Anxiety levels were assessed both before and after the procedure using the validated State Anxiety Inventory. Mean pulse rate and average of mean blood pressures were also recorded before and during the procedures as surrogate indicators of anxiety levels. Results : 100 patients were randomised in a 1:1 ratio. There were 58 males and 42 females, with a mean age of 58 years. Sedation was required in 21 (42%) patients in the music group compared with 30 (60%) patients in the control group (p=0.046). The mean [standard deviation (SD)] midazolam dose was 2.1 mg (2.3 mg) in the control group and 1.3 mg (2.2 mg) in the music group (p=0.027). The mean (SD) fentanyl dose was 29 mg (40 mg) in the control group and 18 mg (34 mg) in the music group (p=0.055). There was no significant effect of music on the change from baseline in anxiety levels (p=0.74), pulse rate (p=0.56) or blood pressure (p=0.34). Conclusion : Sedation requirements are significantly reduced by playing self-selected music to the patient during interventional radiology procedures. By lowering sedation during interventional radiology, music makes the procedure safer. It also contributes favourably to the overall patient experience. PMID:22422386

The influence of intrapartum opioid use on breastfeeding experience at 6 weeks post partum: A secondary analysis.

PubMed

Fleet, Julie-Anne; Jones, Meril; Belan, Ingrid

2017-07-01

To examine breastfeeding experiences up to 6 weeks postpartum for mothers administered intranasal fentanyl, subcutaneous fentanyl or intramuscular pethidine for intrapartum analgesia. A secondary analysis was undertaken using the per-protocol dataset to examine the third phase of a larger randomised controlled trial. This phase of the study examined breastfeeding intention and experience from the first hour of birth to 6 weeks postpartum. Medical records were audited and women were contacted at 6 weeks postpartum to complete a telephone questionnaire. Two maternity hospitals in South Australia. Healthy women birthing at term received intranasal fentanyl (n=37), subcutaneous fentanyl (n=37), or intramuscular pethidine (n=35). While maternal characteristics and birth outcomes were comparable between groups, women who received either intranasal fentanyl or subcutaneous fentanyl experienced fewer difficulties in establishing breastfeeding by 6 weeks postpartum when compared to intramuscular pethidine (p<0.01). Women who received fentanyl reported that their neonates had less difficulties establishing breastfeeding, compared to those who received pethidine. Therefore, for woman who intend to breastfeed, fentanyl should be the preferred opiate, for the relief of pain in labour. When providing education to women in relation to intrapartum pain relief it is important to consider the potential influence on breastfeeding experience. This research provides evidence that fentanyl is a suitable alternative to pethidine for women requesting parenteral analgesia in labour. Copyright © 2017 Elsevier Ltd. All rights reserved.

Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone).

PubMed

Pergolizzi, Joseph; Böger, Rainer H; Budd, Keith; Dahan, Albert; Erdine, Serdar; Hans, Guy; Kress, Hans-Georg; Langford, Richard; Likar, Rudolf; Raffa, Robert B; Sacerdote, Paola

2008-01-01

SUMMARY OF CONSENSUS: 1. The use of opioids in cancer pain: The criteria for selecting analgesics for pain treatment in the elderly include, but are not limited to, overall efficacy, overall side-effect profile, onset of action, drug interactions, abuse potential, and practical issues, such as cost and availability of the drug, as well as the severity and type of pain (nociceptive, acute/chronic, etc.). At any given time, the order of choice in the decision-making process can change. This consensus is based on evidence-based literature (extended data are not included and chronic, extended-release opioids are not covered). There are various driving factors relating to prescribing medication, including availability of the compound and cost, which may, at times, be the main driving factor. The transdermal formulation of buprenorphine is available in most European countries, particularly those with high opioid usage, with the exception of France; however, the availability of the sublingual formulation of buprenorphine in Europe is limited, as it is marketed in only a few countries, including Germany and Belgium. The opioid patch is experimental at present in U.S.A. and the sublingual formulation has dispensing restrictions, therefore, its use is limited. It is evident that the population pyramid is upturned. Globally, there is going to be an older population that needs to be cared for in the future. This older population has expectations in life, in that a retiree is no longer an individual who decreases their lifestyle activities. The "baby-boomers" in their 60s and 70s are "baby zoomers"; they want to have a functional active lifestyle. They are willing to make trade-offs regarding treatment choices and understand that they may experience pain, providing that can have increased quality of life and functionality. Therefore, comorbidities--including cancer and noncancer pain, osteoarthritis, rheumatoid arthritis, and postherpetic neuralgia--and patient functional status need to be taken carefully into account when addressing pain in the elderly. World Health Organization step III opioids are the mainstay of pain treatment for cancer patients and morphine has been the most commonly used for decades. In general, high level evidence data (Ib or IIb) exist, although many studies have included only few patients. Based on these studies, all opioids are considered effective in cancer pain management (although parts of cancer pain are not or only partially opioid sensitive), but no well-designed specific studies in the elderly cancer patient are available. Of the 2 opioids that are available in transdermal formulation--fentanyl and buprenorphine--fentanyl is the most investigated, but based on the published data both seem to be effective, with low toxicity and good tolerability profiles, especially at low doses. 2. The use of opioids in noncancer-related pain: Evidence is growing that opioids are efficacious in noncancer pain (treatment data mostly level Ib or IIb), but need individual dose titration and consideration of the respective tolerability profiles. Again no specific studies in the elderly have been performed, but it can be concluded that opioids have shown efficacy in noncancer pain, which is often due to diseases typical for an elderly population. When it is not clear which drugs and which regimes are superior in terms of maintaining analgesic efficacy, the appropriate drug should be chosen based on safety and tolerability considerations. Evidence-based medicine, which has been incorporated into best clinical practice guidelines, should serve as a foundation for the decision-making processes in patient care; however, in practice, the art of medicine is realized when we individualize care to the patient. This strikes a balance between the evidence-based medicine and anecdotal experience. Factual recommendations and expert opinion both have a value when applying guidelines in clinical practice. 3. The use of opioids in neuropathic pain: The role of opioids in neuropathic pain has been under debate in the past but is nowadays more and more accepted; however, higher opioid doses are often needed for neuropathic pain than for nociceptive pain. Most of the treatment data are level II or III, and suggest that incorporation of opioids earlier on might be beneficial. Buprenorphine shows a distinct benefit in improving neuropathic pain symptoms, which is considered a result of its specific pharmacological profile. 4. The use of opioids in elderly patients with impaired hepatic and renal function: Functional impairment of excretory organs is common in the elderly, especially with respect to renal function. For all opioids except buprenorphine, half-life of the active drug and metabolites is increased in the elderly and in patients with renal dysfunction. It is, therefore, recommended that--except for buprenorphine--doses be reduced, a longer time interval be used between doses, and creatinine clearance be monitored. Thus, buprenorphine appears to be the top-line choice for opioid treatment in the elderly. 5. Opioids and respiratory depression: Respiratory depression is a significant threat for opioid-treated patients with underlying pulmonary condition or receiving concomitant central nervous system (CNS) drugs associated with hypoventilation. Not all opioids show equal effects on respiratory depression: buprenorphine is the only opioid demonstrating a ceiling for respiratory depression when used without other CNS depressants. The different features of opioids regarding respiratory effects should be considered when treating patients at risk for respiratory problems, therefore careful dosing must be maintained. 6. Opioids and immunosuppression: Age is related to a gradual decline in the immune system: immunosenescence, which is associated with increased morbidity and mortality from infectious diseases, autoimmune diseases, and cancer, and decreased efficacy of immunotherapy, such as vaccination. The clinical relevance of the immunosuppressant effects of opioids in the elderly is not fully understood, and pain itself may also cause immunosuppression. Providing adequate analgesia can be achieved without significant adverse events, opioids with minimal immunosuppressive characteristics should be used in the elderly. The immunosuppressive effects of most opioids are poorly described and this is one of the problems in assessing true effect of the opioid spectrum, but there is some indication that higher doses of opioids correlate with increased immunosuppressant effects. Taking into consideration all the very limited available evidence from preclinical and clinical work, buprenorphine can be recommended, while morphine and fentanyl cannot. 7. Safety and tolerability profile of opioids: The adverse event profile varies greatly between opioids. As the consequences of adverse events in the elderly can be serious, agents should be used that have a good tolerability profile (especially regarding CNS and gastrointestinal effects) and that are as safe as possible in overdose especially regarding effects on respiration. Slow dose titration helps to reduce the incidence of typical initial adverse events such as nausea and vomiting. Sustained release preparations, including transdermal formulations, increase patient compliance.

pKa of fentanyl varies with temperature: implications for acid-base management during extremes of body temperature.

PubMed

Thurlkill, Richard L; Cross, David A; Scholtz, J Martin; Pace, C Nick

2005-12-01

The pKa of fentanyl has not been measured previously at varying extremes of body temperature. The goal of this laboratory investigation was to test the hypothesis that the pKa of fentanyl changes with temperature. The investigation involved measuring the pKa values of aqueous fentanyl at varying temperatures. The investigation was conducted in a controlled laboratory environment. No human or animal subjects were involved. Because no live subjects were involved in the investigation, no interventions were necessary. This paper reports the effect of temperature on the pKa of fentanyl. The pKa of aqueous fentanyl was measured at 15 degrees C, 25 degrees C, 37 degrees C, 42 degrees C, and 47.5 degrees C by potentiometric titration in 0.01 mmol/L of potassium chloride after extensive degassing. Data were analyzed using the least squares method with an appropriately fitting equation. The pKa of fentanyl was found to change in a similar manner to the neutral point of water at varying temperatures. This finding has implications for the bioavailability of fentanyl at extremes of body temperature in association with the clinical acid-base management of the patient. Clinical implications for differing methods of intraoperative acid-base management at varying temperatures are discussed.

[A case of gastric cancer accompanied by disseminated carcinomatosis of bone marrow wherein long-term chemotherapy was enabled by early supportive palliative care].

PubMed

Yamagiwa, Tetsuya; Amakawa, Ryuichi; Takeda, Yasuhiro; Fukuda, Akiko; Ito, Satoko; Nakayama, Shinya; Shiotani, Tomohiro; Watanabe, Go; Kita, Kenkichi; Yamaoka, Yoshio

2014-02-01

Here we report gastric cancer accompanied by bone marrow carcinomatosis in a patient for whom long-term chemotherapy was enabled by early pain-relief therapy. A 45-year-old man was admitted to our hospital because of back pain associated with multiple spinal tumors in June 2011. Blood tests showed a trend toward disseminated intravascular coagulation(DIC) and gastric cancer was suspected as the primary lesion. Because pain was severe, emergency pain relief was provided by flurbiprofen axetil and a continuous subcutaneous infusion of fentanyl citrate. After bone marrow examination gave a diagnosis of poorly differentiated adenocarcinoma, we performed sequential methotrexate(MTX)and 5-fluorouracil(5-FU)therapy. The therapy successfully decreased tumor marker levels, and alkaline phosphatase and lactate dehydrogenase levels normalized. Finally, gastric cancer accompanied by bone marrow carcinomatosis was diagnosed. Because the patient had anxiety and spiritual pain from the time of admission, psychiatric care was also required. In November 2011, the tumor recurred, and we switched therapy to a combination of S-1 and cisplatin. The patient's pain was controlled by combined treatment with a fentanyl patch and etodolac, and he was discharged in December 2011. However, severe pain recurred and pain therapy was continued. DIC developed in February 2012 and transiently resolved after resuming combination therapy with MTX and 5-FU; however, it subsequently recurred, leading to the patient's death in May 2012.

Comparison of Butorphanol and Fentanyl for the Relief of Postoperative Shivering Associated with Spinal Anesthesia

PubMed Central

Manne, Venkata Sesha Sai Krishna; Gondi, Srinivasa Rao

2017-01-01

Aim: The aim of this study was to compare fentanyl and butorphanol for the relief of postoperative shivering in spinal anesthesia. Materials and Methods: A total of 100 American Society of Anesthesiologists physical status Class I and II patients aged 19–60 years belonging to both sexes who were posted for elective surgical procedures under spinal anesthesia were divided into two groups (fentanyl and butorphanol) and monitored intraoperatively for the occurrence of shivering and time taken to control shivering after administration of fentanyl and butorphanol drugs. Results: Relief of shivering is rapid and more effective with fentanyl than butorphanol. There is a significant increase in pulse rate, mean arterial pressure, respiratory rate (RR), and decreased in oxygen saturation at the onset of shivering and also a decrease in core body temperature. Sedation, nausea, vomiting, and recurrence of shivering are more with butorphanol with fentanyl. Conclusion: On the basis of the study, it is concluded that fentanyl is more effective and takes less time to control perioperative shivering as compared to butorphanol. PMID:28298762

A nonadjuvanted transcutaneous tetanus patch is effective in boosting anti-tetanus toxoid immune responses.

PubMed

Seid, Robert C; Reinisch, Christoph; Schlegl, Robert; Moehlen, Michael; Meinke, Andreas; Lundberg, Urban

2014-02-01

Dry tetanus toxoid (TTx) patches were formulated without any adjuvant, with excipients to impart antigen stabilization and to enhance skin delivery. The booster effects of the TTx patches were assessed using a guinea pig model. The study revealed significant rises in TTx IgG titers induced by the TTx patches after a low-dose subcutaneous (s.c.) prime with TTx adsorbed to aluminum hydroxide. The TTx patch can therefore be considered an effective alternative to a subcutaneous booster.

High-order noise analysis for low dose iterative image reconstruction methods: ASIR, IRIS, and MBAI

NASA Astrophysics Data System (ADS)

Do, Synho; Singh, Sarabjeet; Kalra, Mannudeep K.; Karl, W. Clem; Brady, Thomas J.; Pien, Homer

2011-03-01

Iterative reconstruction techniques (IRTs) has been shown to suppress noise significantly in low dose CT imaging. However, medical doctors hesitate to accept this new technology because visual impression of IRT images are different from full-dose filtered back-projection (FBP) images. Most common noise measurements such as the mean and standard deviation of homogeneous region in the image that do not provide sufficient characterization of noise statistics when probability density function becomes non-Gaussian. In this study, we measure L-moments of intensity values of images acquired at 10% of normal dose and reconstructed by IRT methods of two state-of-art clinical scanners (i.e., GE HDCT and Siemens DSCT flash) by keeping dosage level identical to each other. The high- and low-dose scans (i.e., 10% of high dose) were acquired from each scanner and L-moments of noise patches were calculated for the comparison.

Self-identification of nonpharmaceutical fentanyl exposure following heroin overdose

PubMed Central

Griswold, Matthew K.; Chai, Peter R.; Krotulski, Alex J.; Friscia, Melissa; Chapman, Brittany; Boyer, Edward W.; Logan, Barry K.; Babu, Kavita M.

2018-01-01

Objective To compare user self-identification of nonpharmaceutical fentanyl exposure with confirmatory urine drug testing in emergency department (ED) patients presenting after heroin overdose. Methods This was a cross-sectional study of adult ED patients who presented after a heroin overdose requiring naloxone administration. Participants provided verbal consent after which they were asked a series of questions regarding their knowledge, attitudes and beliefs toward heroin and non-pharmaceutical fentanyl. Participants also provided urine samples, which were analyzed using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry to identify the presence of fentanyl, heroin metabolites, other clandestine opioids, common pharmaceuticals and drugs of abuse. Results Thirty participants were enrolled in the study period. Ten participants (33%) had never required naloxone for an overdose in the past, 20 participants (67%) reported recent abstinence, and 12 participants (40%) reported concomitant cocaine use. Naloxone was detected in all urine drug screens. Heroin or its metabolites were detected in almost all samples (93.3%), as were fentanyl (96.7%) and its metabolite, norfentanyl (93.3%). Acetylfentanyl was identified in nine samples (30%) while U-47700 was present in two samples (6.7%). Sixteen participants self-identified fentanyl in their heroin (sensitivity 55%); participants were inconsistent in their qualitative ability to identify fentanyl in heroin. Conclusions Heroin users presenting to the ED after heroin overdose requiring naloxone are unable to accurately identify the presence of nonpharmaceutical fentanyl in heroin. Additionally, cutting edge drug testing methodologies identified fentanyl exposures in 96.7% of our patients, as well as unexpected clandestine opioids (like acetylfentanyl and U-47700). PMID:28681615

Self-identification of nonpharmaceutical fentanyl exposure following heroin overdose.

PubMed

Griswold, Matthew K; Chai, Peter R; Krotulski, Alex J; Friscia, Melissa; Chapman, Brittany; Boyer, Edward W; Logan, Barry K; Babu, Kavita M

2018-01-01

To compare user self-identification of nonpharmaceutical fentanyl exposure with confirmatory urine drug testing in emergency department (ED) patients presenting after heroin overdose. This was a cross-sectional study of adult ED patients who presented after a heroin overdose requiring naloxone administration. Participants provided verbal consent after which they were asked a series of questions regarding their knowledge, attitudes and beliefs toward heroin and nonpharmaceutical fentanyl. Participants also provided urine samples, which were analyzed using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry to identify the presence of fentanyl, heroin metabolites, other clandestine opioids, common pharmaceuticals and drugs of abuse. Thirty participants were enrolled in the study period. Ten participants (33%) had never required naloxone for an overdose in the past, 20 participants (67%) reported recent abstinence, and 12 participants (40%) reported concomitant cocaine use. Naloxone was detected in all urine drug screens. Heroin or its metabolites were detected in almost all samples (93.3%), as were fentanyl (96.7%) and its metabolite, norfentanyl (93.3%). Acetylfentanyl was identified in nine samples (30%) while U-47700 was present in two samples (6.7%). Sixteen participants self-identified fentanyl in their heroin (sensitivity 55%); participants were inconsistent in their qualitative ability to identify fentanyl in heroin. Heroin users presenting to the ED after heroin overdose requiring naloxone are unable to accurately identify the presence of nonpharmaceutical fentanyl in heroin. Additionally, cutting edge drug testing methodologies identified fentanyl exposures in 96.7% of our patients, as well as unexpected clandestine opioids (like acetylfentanyl and U-47700).

The distribution and redistribution of fentanyl & norfentanyl in post mortem samples.

PubMed

Chatterton, C N; Scott-Ham, M

2018-03-01

This article compares 249 post mortem case reports that were positive for fentanyl/norfentanyl. All the cases were submitted to, and analyzed by, the toxicology department of the Office of the Chief Medical Examiner, Edmonton, Alberta, Canada. This study highlights the varied distribution of fentanyl in the body after death as a result of misadventure, i.e., these are accidental drug overdose cases as opposed to a study of analytical data resulting from fentanyl use/administration in a clinical environment and/or death as a result of suicide. Post mortem samples were collected from more than one anatomical site and analyzed for fentanyl and norfentanyl using liquid chromatography-tandem mass spectrometry. Ante-mortem samples were available in 4 of these cases and were also analyzed. Post mortem mean blood fentanyl concentrations were found to be 13.2ng/mL (femoral), 19.1ng/mL (iliac) and 42.0ng/mL (subclavian). For norfentanyl the mean concentrations were 4.6ng/mL (femoral), 4.6ng/mL (iliac) and 7.4ng/mL (subclavian). Mean vitreous fentanyl and norfentanyl concentrations were 10.8ng/mL and 3.5ng/mL respectively. Mean liver fentanyl and norfentanyl concentrations were found to be 185.5ng/g and 18.8ng/g respectively. This study demonstrates the importance of multi-site sample collection and subsequent analysis for a thorough post mortem toxicological investigation. The study also highlights the risks and limitations associated with the interpretation of post mortem analytical results concerning fentanyl. Copyright © 2018 Elsevier B.V. All rights reserved.

Neither xenon nor fentanyl induces neuroapoptosis in the newborn pig brain.

PubMed

Sabir, Hemmen; Bishop, Sarah; Cohen, Nicki; Maes, Elke; Liu, Xun; Dingley, John; Thoresen, Marianne

2013-08-01

Some inhalation anesthetics increase apoptotic cell death in the developing brain. Xenon, an inhalation anesthetic, increases neuroprotection when combined with therapeutic hypothermia after hypoxic-ischemic brain injury in newborn animals. The authors, therefore, examined whether there was any neuroapoptotic effect of breathing 50% xenon with continuous fentanyl sedation for 24 h at normothermia or hypothermia on newborn pigs. Twenty-six healthy pigs (<24-h old) were randomized into four groups: (1) 24  h of 50% inhaled xenon with fentanyl at hypothermia (Trec = 33.5 °C), (2) 24 h of 50% inhaled xenon with fentanyl at normothermia (Trec = 38.5 °C), (3) 24 h of fentanyl at normothermia, or (4) nonventilated juvenile controls at normothermia. Five additional nonrandomized pigs inhaled 2% isoflurane at normothermia for 24 h to verify any proapoptotic effect of inhalation anesthetics in our model. Pathological cells were morphologically assessed in cortex, putamen, hippocampus, thalamus, and white matter. To quantify the findings, immunostained cells (caspase-3 and terminal deoxynucleotidyl transferase-mediated deoxyuridine-triphosphate nick-end labeling) were counted in the same brain regions. For groups (1) to (4), the total number of apoptotic cells was less than 5 per brain region, representing normal developmental neuroapoptosis. After immunostaining and cell counting, regression analysis showed that neither 50% xenon with fentanyl nor fentanyl alone increased neuroapoptosis. Isoflurane caused on average a 5- to 10-fold increase of immunostained cells. At normothermia or hypothermia, neither 24 h of inhaled 50% xenon with fentanyl sedation nor fentanyl alone induces neuroapoptosis in the neonatal pig brain. Breathing 2% isoflurane increases neuroapoptosis in neonatal pigs.

A series of forensic toxicology and drug seizure cases involving illicit fentanyl alone and in combination with heroin, cocaine or heroin and cocaine.

PubMed

Marinetti, Laureen J; Ehlers, Brooke J

2014-10-01

The Montgomery County Coroner's Office Toxicology Section and the Miami Valley Regional Crime Lab (MVRCL) Drug Chemistry Section have been receiving case work in drug seizures, death cases and human performance cases involving products marketed as heroin or as illicit fentanyl. Upon analysis by the Drug Chemistry Section, these products were found to contain various drug(s) including illicit fentanyl only, illicit fentanyl and heroin, illicit fentanyl and cocaine and illicit fentanyl, heroin and cocaine. Both the Chemistry and Toxicology Sections began seeing these combinations starting in late October 2013. The percentage of the combinations encountered by the MVRCL as well as the physical appearance of the product, and the results of presumptive screening tests will be discussed. The demographics of the users and the results of toxicology and autopsy findings on the decedents will also be discussed. According to regional drug task force undercover agents, there is evidence that some of the products are being sold as illicit fentanyl and not just as a heroin product. Also, there is no evidence to support that the fentanyl source is being diverted from pharmaceutical grade fentanyl. The chemistry section currently has over 109 confirmed cases, and the toxicology section currently has 81 confirmed drug deaths, 8 driving under the influence of drugs and 1 suicidal hanging. Both sections are continuing to see these cases at the present time. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Prehospital and En Route Analgesic Use in the Combat Setting: A Prospectively Designed, Multicenter, Observational Study

DTIC Science & Technology

2015-03-01

combat medic has access to both opioid and nonopioid analgesics.3 Morphine and fentanyl are effective opioid analgesics and are commonly used...transmucosal (TM) fentanyl8,9 or parenteral ketamine. YM fentanyl has been shown to be a safe, effective, and easy method of administer- ing analgesics in a...a subsequent different drug, or the same drug via an alternative route). Ketamine was most frequently administered, followed by fentanyl , mor- phine

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

PubMed

Barter, Linda S; Hawkins, Michelle G; Pypendop, Bruno H

2015-02-01

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.

A Cluster of Fentanyl-Laced Heroin Deaths in 2015 in Melbourne, Australia.

PubMed

Rodda, Luke N; Pilgrim, Jennifer L; Di Rago, Matthew; Crump, Kerryn; Gerostamoulos, Dimitri; Drummer, Olaf H

2017-05-01

The prevalence of opioid use in therapeutic and recreational settings has steadily increased throughout the western world. The addition of fentanyl into heroin products can produce potentially dangerous consequences, even to opioid tolerant individuals who may be unaware of such additions. Following an observed spike of heroin-fentanyl related deaths in Melbourne, Australia, a study was undertaken to determine the prevalence of these cases. All reportable deaths occurring in Victoria during 2015 and submitted to the toxicology laboratory were analysed using LC-MS-MS to confirm the combination of the heroin marker 6-acetylmorphine and/or morphine, and fentanyl. Over 4,000 coronial cases in 2015 underwent toxicological analysis for these drugs, there were nine cases identified that involved fentanyl-laced heroin. There was no specific mention of fentanyl use in any of these cases. All occurred within 2 months and in two distinct locations. The first four deaths occurred within 3 days of each other, in neighboring suburbs. The ages ranged from 25 to 57 years with an average of 40 and median of 37 years, and consisted of eight males and one female. The average and median femoral blood concentration of fentanyl was 18 and 20 ng/mL (range: <1-45 ng/mL), and morphine 140 and 80 ng/mL (range: 20-400 ng/mL), respectively. All nine cases had 6-acetylmorphine detectable in blood. Urine analysis was also performed where available. A syringe, powder and spoon found at the scene of one case were also analysed and found to be positive for both heroin and fentanyl, which supported the likelihood of fentanyl-laced heroin. This is the first reported case series of fatalities involving heroin and fentanyl outside of North America in published literature. These findings may help inform public health and prevention strategies serving to decrease the potential for such fatalities in the future. © Crown copyright 2017.

Measles vaccination using a microneedle patch☆

PubMed Central

Edens, Chris; Collins, Marcus L.; Ayers, Jessica; Rota, Paul A.; Prausnitz, Mark R.

2013-01-01

Measles vaccination programs would benefit from delivery methods that decrease cost, simplify logistics, and increase safety. Conventional subcutaneous injection is limited by the need for skilled healthcare professionals to reconstitute and administer injections, and by the need for safe needle handling and disposal to reduce the risk of disease transmission through needle re-use and needlestick injury. Microneedles are micron-scale, solid needles coated with a dry formulation of vaccine that dissolves in the skin within minutes after patch application. By avoiding the use of hypodermic needles, vaccination using a microneedle patch could be carried out by minimally trained personnel with reduced risk of blood-borne disease transmission. The goal of this study was to evaluate measles vaccination using a microneedle patch to address some of the limitations of subcutaneous injection. Viability of vaccine virus dried onto a microneedle patch was stabilized by incorporation of the sugar, trehalose, and loss of viral titer was less than 1 log10(TCID50) after storage for at least 30 days at room temperature. Microneedle patches were then used to immunize cotton rats with the Edmonston-Zagreb measles vaccine strain. Vaccination using microneedles at doses equaling the standard human dose or one-fifth the human dose generated neutralizing antibody levels equivalent to those of a subcutaneous immunization at the same dose. These results show that measles vaccine can be stabilized on microneedles and that vaccine efficiently reconstitutes in vivo to generate a neutralizing antibody response equivalent to that generated by subcutaneous injection. PMID:23044406

Drug withdrawal symptoms in children after continuous infusions of fentanyl.

PubMed

French, J P; Nocera, M

1994-04-01

The purpose of this research was to determine the extent to which critically ill infants exhibited signs and symptoms of narcotic withdrawal after receiving continuous infusions of fentanyl. The convenience sample consisted of 12 pediatric intensive care unit (PICU) patients under 25 months of age who received fentanyl infusions for at least 24 hours. Drug withdrawal symptoms were monitored using the Neonatal Abstinence Score Tool (NAST), which assigns a score to each behavior indicative of withdrawal. A score of 8 or greater indicates Neonatal Abstinence Syndrome (NAS). Scoring began 4 hours after discontinuation of fentanyl and was conducted once per hour for 8 hours. Six subjects had a NAST score exceeding 8; these infants frequently exhibited tremors with or without stimulation, increased muscle tone, insomnia, and increased respiratory rate and effort. There were significant correlations between fentanyl dosage and NAST score (r = .76, p < 0.01), between length of infusion of fentanyl and NAST score (r = .70, p < 0.05), and between chloral hydrate dosage and NAST score (r = .62, p < 0.05). These findings suggest the need for an observation protocol and a possible weaning regimen after fentanyl is discontinued.

Plasma concentrations of fentanyl with subcutaneous infusion in palliative care patients.

PubMed

Miller, R S; Peterson, G M; Abbott, F; Maddocks, I; Parker, D; McLean, S

1995-12-01

1. Plasma concentrations of fentanyl were measured by g.c. in 20 patients (median age: 75 years and range: 54-86 years; eight females) in palliative care receiving the drug by continuous s.c. infusion (median rate: 1200 micrograms day-1 and range: 100-5000 micrograms day-1). 2. The infusion rate was significantly related to the duration of therapy (Spearman rho = 0.56, P < 0.05). The total steady-state plasma concentrations of fentanyl ranged between 0.1 and 9 ng ml-1, with a median of 1 ng ml-1. The unbound fraction of fentanyl in the plasma ranged from 17.8 to 44.4%, with a median value of 33.6%. Infusion rates and both total and unbound plasma concentrations of fentanyl were correlated (Spearman rho = 0.92, P < 0.05 in each case). Even with standardization for dosage, there was an eightfold variation in total plasma concentrations and 3.5-fold variation in unbound plasma concentrations of fentanyl. 3. There is considerable inter-patient variability in the pharmacokinetics of fentanyl with s.c. infusion in the palliative care setting, which necessitates careful titration of dosage according to individual clinical response.

Determinants of Fentanyl and other Potent μ Opioid Agonist Misuse in Opioid-Dependent Individuals

PubMed Central

Cicero, Theodore J.; Ellis, Matthew S.; Paradis, Alethea; Ortbal, Zachary

2010-01-01

Purpose Based on preclinical and clinical abuse liability assessments, fentanyl and other potent μ opioid agonists (e.g. hydromorphone and morphine) should be the most misused opioids if accessibility in the real world were not an issue. Since the latter is seldom true, we postulated that there would be a significant mismatch between actual and predicted rates of misuse. Methods We recruited 1,818 prescription-opioid dependent patients entering drug treatment programs to complete an anonymous survey, covering drug use and health related issues. Results Hydrocodone and oxycodone products were the drugs of choice in 75% of patients, whereas potent μ opioid agonists (fentanyl, hydromorphone and morphine), with the greatest predicted abuse potential, were very rarely chosen (<5% each). Most unexpectedly, the rank order of the actual drug of choice and the preferred drug in an ideal world were highly correlated. The reason most commonly given for the failure to endorse fentanyl, for example, as an actual or preferred drug, was fear of toxicity and overdose. We found few differences in drug use patterns between a subset of high-risk, impaired health care professionals (N=196) and all other patients other than source of drug, (forged prescriptions and doctors more common and dealers much less common in the HC sample). Conclusions These results indicate that it should not be assumed- particularly for new drug formulations- that a high potential for abuse will result in actual abuse; and, most importantly, that the hesitancy to use potent opioids because of fears of abuse may be misguided. PMID:20597128

Variation in diurnal sedation in mechanically ventilated patients who are managed with a sedation protocol alone or a sedation protocol and daily interruption.

PubMed

Mehta, Sangeeta; Meade, Maureen; Burry, Lisa; Mallick, Ranjeeta; Katsios, Christina; Fergusson, Dean; Dodek, Peter; Burns, Karen; Herridge, Margaret; Devlin, John W; Tanios, Maged; Fowler, Robert; Jacka, Michael; Skrobik, Yoanna; Olafson, Kendiss; Cook, Deborah

2016-08-01

Mechanically ventilated patients may receive more sedation during the night than during the day, potentially delaying extubation. We compared nighttime and daytime benzodiazepine and opioid administration in adult patients enrolled in a multicenter sedation trial comparing protocolized sedation alone or protocolized sedation combined with daily sedation interruption; and we evaluated whether nighttime and daytime doses were associated with liberation from mechanical ventilation. This is a secondary analysis of a randomized trial which was conducted in 16 North American medical-surgical ICUs. In all 423 patients, nurses applied a validated sedation scale hourly to titrate benzodiazepine and opioid infusions to achieve a light level of sedation. Using fentanyl equivalents and midazolam equivalents, we compared dosages administered during night (19:00 to 07:00) and day (07:00 to 19:00) shifts. Using multivariable logistic regression we evaluated the association between nighttime and daytime opioid and sedative doses, and spontaneous breathing trial (SBT) conduct, SBT success, and extubation. Nighttime benzodiazepine and opioid doses were significantly higher than daytime doses (mean difference midazolam equivalents 23.3 mg, 95 % CI 12.9, 33.8, p < 0.0001; mean difference fentanyl equivalents 356 mcg, 95 % CI 130, 582, p = 0.0021). Mean Sedation Agitation Scale score was similar between night and day, and was at target (3.2 vs 3.3, 95 % CI -0.05, 0.02, p = 0.35). Self-reported nurse workload was similar during the night and day. Patients were more often restrained during day shifts (76.3 % vs 73.7 %, p < 0.0001), and there were more unintentional device removals during the day compared with night (15.9 % vs 9.1 %, p < 0.0001). Increases in nighttime drug doses were independently associated with failure to meet SBT screening criteria, SBT failure, and the decision not to extubate the patient despite successful SBT. Patients received higher doses of opioids and benzodiazepines at night. Higher nighttime doses were associated with SBT failure and delayed extubation. ClinicalTrials.gov NCT00675363 . Registered 7 May 2008.

[High dose L-dopa infusion during general anesthesia for gastrectomy in a patient with parkinsonism].

PubMed

Horai, Tetsuya; Nishiyama, Tomoki; Yamamoto, Hirotoshi; Hanaoka, Kazuo

2002-01-01

A 68-year-old man with parkinsonism was scheduled for gastrectomy. Levodopa 1400 mg, droxidopa 300 mg and bromocriptine-mesylate 7.5 mg had been administered orally per day to control the symptom before surgery. On the day before surgery, oral medication was stopped and intravenous infusion of levodopa 100 mg.h-1 was started. Without any premedication but with levodopa infusion, anesthesia was induced with thiopental 175 mg and fentanyl 0.05 mg. Tracheal intubation was facilitated with vecuronium 6 mg and an epidural catheter was inserted. Anesthesia was maintained with O2, N2O and sevoflurane, combined with epidural block using mepivacaine. When blood pressure decreased, phenylephrine but not ephedrine was effective to increase blood pressure. Intravenous infusion of levodopa was continued for 19 days with decreasing doses from 8th postoperative day when injection of levodopa into the intestinal tube was started. On the 53rd day, he left the hospital without any complications. Serum concentrations of levodopa during and after surgery were 50 to 100 times higher than the therapeutic levels. However, he developed no complications, which suggests a wide safety range of levodopa. In conclusion, high dose levodopa infusion was effective in controlling the symptoms of Parkinsonism during general anesthesia.

A randomized controlled study comparing intrathecal hyperbaric bupivacaine-fentanyl mixture and isobaric bupivacaine-fentanyl mixture in common urological procedures

PubMed Central

Upadya, Madhusudan; Neeta, S; Manissery, Jesni Joseph; Kuriakose, Nigel; Singh, Rakesh Raushan

2016-01-01

Background and Aims: Bupivacaine is available in isobaric and hyperbaric forms for intrathecal use and opioids are used as additives to modify their effects. The aim of this study was to compare the efficacy and haemodynamic effect of intrathecal isobaric bupivacaine-fentanyl mixture and hyperbaric bupivacaine-fentanyl mixture in common urological procedures. Methods: One hundred American Society of Anesthesiologists physical status 1 and 2 patients undergoing urological procedures were randomized into two groups. Group 1 received 3 ml of 0.5% isobaric bupivacaine with 25 μg fentanyl while Group 2 received 3 ml of 0.5% hyperbaric bupivacaine with 25 μg fentanyl. The parameters measured include heart rate, blood pressure, respiratory rate, onset and duration of motor and sensory blockade. Student's unpaired t-test and the χ2 test were used to analyse the results, using the SPSS version 11.5 software. Results: The haemodynamic stability was better with isobaric bupivacaine fentanyl mixture (Group 1) than with hyperbaric bupivacaine fentanyl mixture (Group 2). The mean onset time in Group 1 for both sensory block (4 min) and motor block (5 min) was longer compared with Group 2. The duration of sensory block (127.8 ± 38.64 min) and motor block (170.4 ± 27.8 min) was less with isobaric bupivacaine group compared with hyperbaric bupivacaine group (sensory blockade 185.4 ± 16.08 min and motor blockade 201.6 ± 14.28 min). Seventy percent of patients in Group 2 had maximum sensory block level of T6 whereas it was 53% in Group 1. More patients in Group 1 required sedation compared to Group 2. Conclusion: Isobaric bupivacaine fentanyl mixture was found to provide adequate anaesthesia with minimal incidence of haemodynamic instability. PMID:26962255

Two Fatal Intoxications Involving Butyryl Fentanyl

PubMed Central

Poklis, Justin; Poklis, Alphonse; Wolf, Carl; Hathaway, Cindie; Arbefeville, Elise; Chrostowski, Leszek; Devers, Kelly; Hair, Laura; Mainland, Mary; Merves, Michele; Pearson, Julia

2016-01-01

We present the case histories, autopsy findings and toxicology findings of two fatal intoxications involving the designer drug, butyryl fentanyl. The quantitative analysis of butyryl fentanyl in postmortem fluids and tissues was performed by an ultrahigh-performance liquid chromatography tandem mass spectrometry method. In the first case, butyryl fentanyl was the only drug detected with concentrations of 99 ng/mL in peripheral blood, 220 ng/mL in heart blood, 32 ng/mL in vitreous humor, 590 ng/mL in gastric contents, 93 ng/g in brain, 41 ng/g in liver, 260 ng/mL in bile and 64 ng/mL in urine. The cause of death was ruled fatal intoxication by butyryl fentanyl. In the second case, butyryl fentanyl was detected along with acetyl fentanyl, alprazolam and ethanol. The butyryl fentanyl concentrations were 3.7 ng/mL in peripheral blood, 9.2 ng/mL in heart blood, 9.8 ng/mL in vitreous humor, 4,000 ng/mL in gastric contents, 63 ng/g in brain, 39 ng/g in liver, 49 ng/mL in bile and 2 ng/mL in urine. The acetyl fentanyl concentrations were 21 ng/mL in peripheral blood, 95 ng/mL in heart blood, 68 ng/mL in vitreous humor, 28,000 ng/mL in gastric contents, 200 ng/g in brain, 160 ng/g in liver, 330 ng/mL in bile and 8 ng/mL in urine. In addition, the alprazolam concentration was 40 ng/mL and the ethanol concentration was 0.11 g/dL, both measured in peripheral blood. The cause of death in the second case was ruled a mixed drug intoxication. In both cases, the manner of death was accident. PMID:27339481

Effectiveness of prehospital morphine, fentanyl, and methoxyflurane in pediatric patients.

PubMed

Bendall, Jason C; Simpson, Paul M; Middleton, Paul M

2011-01-01

To compare the effectiveness of intravenous morphine, intranasal (IN) fentanyl, and inhaled methoxyflurane for managing moderate to severe pain in pediatric patients in the out-of-hospital setting. We conducted a retrospective comparative study of 3,312 pediatric patients aged between 5 and 15 years who had moderate to severe pain (pain score ≥ 5) and who received intravenous morphine, IN fentanyl, or inhaled methoxyflurane, either alone or in combination, between January 1, 2004, and November 30, 2006. Multivariate logistic regression was used to analyze data extracted from a clinical database containing routinely entered information from patient health care records. The primary outcome measure was effective analgesia, defined as a reduction in pain severity of ≥ 30% of initial pain score using an 11-point verbal numeric rating scale. Effective analgesia was achieved in 82.5% of cases overall. All analgesic agents were effective in the majority of patients (87.5%, 89.5%, and 78.3% for morphine, fentanyl, and methoxyflurane, respectively). There was evidence that methoxyflurane was less effective than both morphine (odds ratio [OR] 0.52; 95% confidence interval [CI] 0.36-0.74) and fentanyl (OR 0.43; 95% CI 0.29-0.62; p < 0.0001). There was no clinical or statistical evidence of difference in the effectiveness of fentanyl and morphine in this population (OR 1.22; 95% CI 0.74-2.01). There was no evidence that combination analgesia was better than either fentanyl or morphine alone. Intranasal fentanyl and intravenous morphine are equally effective analgesic agents in pediatric patients with moderate to severe acute pain in the out-of-hospital setting. Methoxyflurane is less effective in comparison with both morphine and fentanyl, but is an effective analgesic in the majority of children.

Epidural Analgesia With Bupivacaine and Fentanyl Versus Ropivacaine and Fentanyl for Pain Relief in Labor

PubMed Central

Guo, Shanbin; Li, Bo; Gao, Chengjie; Tian, Yue

2015-01-01

Abstract The aim of this study was to compare the efficacy and safety of the combinational use of bupivacaine and fentanyl versus ropivacaine and fentanyl in epidural analgesia for labor. Multiple electronic databases were searched by using appropriate MeSH terms, and keywords for original research papers published before October 2014. Meta-analyses were based on mean differences between the groups as well as odds ratios. Statistical heterogeneity was tested by I2 index. Fifteen randomized controlled trials, recruiting 2097 parturient mothers overall, were selected for the meta-analyses. Concentrations of the preparations used (weight/volume; mean and standard deviations) were bupivacaine 0.1023% ± 0.0375%, ropivacaine 0.1095% ± 0.042%, and fentanyl 0.00021% ± 0.000089%. There were no statistically significant differences between both the combinations in the mean change in Visual Analog Score for pain during labor, incidence of instrumental or cesarean delivery, neonate Apgar score of <7, maternal satisfaction, duration of either first or second stage of labor, oxytocin use for induction, onset of analgesia, and duration of analgesia. Women who received ropivacaine and fentanyl had significantly lower incidence of motor blocks (odds ratio [95% CI] = 0.38 [0.30, 0.48] P < 0.00001, fixed effect and 0.38 [0.27, 0.54] P < 0.0001, random effects I2 30%) when compared with women who received bupivacaine and fentanyl. Incidence of side effects was similar for both the combinations. Analgesia with ropivacaine in combination with fentanyl at 0.1%:0.0002% ratio for labor pain relief is associated with lower incidence of motor blocks in comparison with analgesia with bupivacaine and fentanyl at similar ratio (0.1%: 0.0002%). PMID:26061307

Fentanyl and heroin contained in seized illicit drugs and overdose-related deaths in British Columbia, Canada: An observational analysis.

PubMed

Baldwin, Nicholas; Gray, Roger; Goel, Anirudh; Wood, Evan; Buxton, Jane A; Rieb, Launette Marie

2018-04-01

Due to the alarming rise in opioid-related overdose deaths, a public health emergency was declared in British Columbia (BC). In this study, we examined the relationship between illicit fentanyl and heroin found in seized drugs and illicit overdose deaths in BC. An observational cross-sectional survey was conducted using BC data from Health Canada's Drug Analysis Service, which analyzes drug samples seized by law enforcement agencies, and non-intentional illicit overdoses from the BC Coroner's Service, from 2000 to 2016. Initial scatter plots and subsequent multivariate regression analysis were performed to describe the potential relationship between seized illicit fentanyl samples and overdose deaths and to determine if this differed from seized heroin and overdose deaths. Fentanyl samples were analyzed for other drug content. Fentanyl is increasingly being found combined with other opioid and non-opioid illicit drugs. Strong positive relationships were found between the number of seized fentanyl samples and total overdose deaths (R2 = 0.97) as well as between seized fentanyl and fentanyl-detected overdose deaths (R2 = 0.99). A positive association was found between the number of seized heroin samples and total overdose deaths (R2 = 0.78). This research contributes to the expanding body of evidence implicating illicit fentanyl use (often combined with heroin or other substances) in overdose deaths in BC. Policy makers and healthcare providers are urged to implement drug treatment and harm reduction strategies for people at risk of overdose associated with current trends in illicit opioid use. Copyright © 2018 Elsevier B.V. All rights reserved.

An observational prospective cohort study of incidence and characteristics of failed spinal anaesthesia for caesarean section.

PubMed

Sng, B L; Lim, Y; Sia, A T H

2009-07-01

A prospective cohort study was performed in 800 parturients undergoing elective caesarean section under spinal anaesthesia from May 2005 to April 2006 in a large maternity hospital in Singapore, in order to determine the incidence of and risk factors for total and partial failure of spinal anaesthesia. A routine single-shot spinal technique using intrathecal 0.5% heavy bupivacaine 2.0 mL (10 mg) and morphine 100 microg was administered with a 27-gauge Whitacre spinal needle via a 20-gauge introducer. Demographic, surgical and anaesthetic data were collected to determine risk factors for failure of spinal anaesthesia. Incidence of total failure requiring conversion to general anaesthesia was 0.5% (4 cases) in which three cases had inadequate block (loss of sensation to cold less than T6) and one case had no sensory block. Thirty-three parturients (4.1%) required intravenous fentanyl and seven (0.9%) required Entonox for intraoperative analgesic supplementation. Postpartum sterilization (P<0.001) was an independent risk factor for partial failure requiring intravenous fentanyl and Entonox. Spinal anaesthesia using bupivacaine 10 mg with morphine 100 microg produces reliable anaesthesia for elective caesarean section. Postpartum sterilization involves exteriorisation of the uterus with additional surgical manipulation and hence may necessitate analgesic supplementation. The initial use of a combined spinal-epidural technique or the addition of intrathecal fentanyl or clonidine or an increased dose of local anaesthetic may be considered to decrease the incidence of intraoperative pain.

Soft, stretchable, epidermal sensor with integrated electronics and photochemistry for measuring personal UV exposures.

PubMed

Shi, Yunzhou; Manco, Megan; Moyal, Dominique; Huppert, Gil; Araki, Hitoshi; Banks, Anthony; Joshi, Hemant; McKenzie, Richard; Seewald, Alex; Griffin, Guy; Sen-Gupta, Ellora; Wright, Donald; Bastien, Philippe; Valceschini, Florent; Seité, Sophie; Wright, John A; Ghaffari, Roozbeh; Rogers, John; Balooch, Guive; Pielak, Rafal M

2018-01-01

Excessive ultraviolet (UV) radiation induces acute and chronic effects on the skin, eye and immune system. Personalized monitoring of UV radiation is thus paramount to measure the extent of personal sun exposure, which could vary with environment, lifestyle, and sunscreen use. Here, we demonstrate an ultralow modulus, stretchable, skin-mounted UV patch that measures personal UV doses. The patch contains functional layers of ultrathin stretchable electronics and a photosensitive patterned dye that reacts to UV radiation. Color changes in the photosensitive dyes correspond to UV radiation intensity and are analyzed with a smartphone camera. A software application has feature recognition, lighting condition correction, and quantification algorithms that detect and quantify changes in color. These color changes are then correlated with corresponding shifts in UV dose, and compared to existing UV dose risk levels. The soft mechanics of the UV patch allow for multi-day wear in the presence of sunscreen and water. Two evaluation studies serve to demonstrate the utility of the UV patch during daily activities with and without sunscreen application.

Soft, stretchable, epidermal sensor with integrated electronics and photochemistry for measuring personal UV exposures

PubMed Central

Shi, Yunzhou; Manco, Megan; Moyal, Dominique; Huppert, Gil; Araki, Hitoshi; Banks, Anthony; Joshi, Hemant; McKenzie, Richard; Seewald, Alex; Griffin, Guy; Sen-Gupta, Ellora; Wright, Donald; Bastien, Philippe; Valceschini, Florent; Seité, Sophie; Wright, John A.; Ghaffari, Roozbeh; Rogers, John; Balooch, Guive

2018-01-01

Excessive ultraviolet (UV) radiation induces acute and chronic effects on the skin, eye and immune system. Personalized monitoring of UV radiation is thus paramount to measure the extent of personal sun exposure, which could vary with environment, lifestyle, and sunscreen use. Here, we demonstrate an ultralow modulus, stretchable, skin-mounted UV patch that measures personal UV doses. The patch contains functional layers of ultrathin stretchable electronics and a photosensitive patterned dye that reacts to UV radiation. Color changes in the photosensitive dyes correspond to UV radiation intensity and are analyzed with a smartphone camera. A software application has feature recognition, lighting condition correction, and quantification algorithms that detect and quantify changes in color. These color changes are then correlated with corresponding shifts in UV dose, and compared to existing UV dose risk levels. The soft mechanics of the UV patch allow for multi-day wear in the presence of sunscreen and water. Two evaluation studies serve to demonstrate the utility of the UV patch during daily activities with and without sunscreen application. PMID:29293664

Fentanyl-induced respiratory depression is attenuated in pregnant patients

PubMed Central

Sun, Jie; Yu, Min; Fang, Yin; Ding, Zhengnian

2017-01-01

Background Respiratory depression is a complication of intravenous fentanyl administration. The effect of pregnancy on respiratory depression following opioid administration is unclear. This study investigated the effect of pregnancy on fentanyl-induced respiratory depression. Patients and methods Female patients were divided into three groups (n=20 per group): control group (non-pregnant and scheduled for laparoscopic surgery), early pregnancy group (pregnant for 45–60 days and scheduled for abortion), and postpartum group (5–7 days postpartum scheduled for complete curettage of uterine cavity). All patients received an intravenous infusion of fentanyl 2 μg/kg. Respiratory rate (RR), end-tidal pressure of carbon dioxide (PETCO2), and pulse oxygen saturation (SpO2) were recorded continuously from just before fentanyl infusion to 15 min after commencing infusion. Plasma levels of progesterone were measured. Results SpO2 levels in the early pregnancy and postpartum groups were significantly higher and the levels of RR and PETCO2 were significantly lower than the control group. RR and SpO2 levels were significantly decreased in all groups, whereas PETCO2 was significantly increased after fentanyl infusion. The rates of RR increase and SpO2 decrease were significantly faster in the control group than in the other groups. The lowest SpO2 after intravenous fentanyl administration was significantly positively correlated with plasma progesterone levels. Conclusion Pregnancy improves fentanyl-induced respiratory depression, which may be associated with the increased levels of plasma progesterone. PMID:29200828

Enhancement of Skin Permeation and Skin Immunization of Ovalbumin Antigen via Microneedles.

PubMed

Pamornpathomkul, Boonnada; Rojanarata, Theerasak; Opanasopit, Praneet; Ngawhirunpat, Tanasait

2017-10-01

The purpose of this study was to evaluate the use of different types of microneedles and doses of ovalbumin antigen for in vitro skin permeation and in vivo immunization. In vitro skin permeation experiments and confocal laser scanning microscopy revealed that hollow microneedles had a superior enhancing effect on skin permeation compared with a solid microneedle patch and untreated skin by efficiently delivering ovalbumin-fluorescein conjugate into the deep skin layers. The flux and cumulative amount of ovalbumin-fluorescein conjugate at 8 h after administering with various conditions could be ranked as follows: hollow MN; high dose > medium dose > low dose > MN patch; high dose > medium dose > low dose > untreated skin; high dose > medium dose > low dose > without ovalbumin-fluorescein conjugate. As the dose of ovalbumin-fluorescein conjugate was increased to 500 μg, the antigen accumulated in the skin to a greater extent, as evidenced by the increasing green fluorescence intensity. When the hollow microneedle was used for the delivery of ovalbumin into the skin of mice, it was capable of inducing a stronger immunoglobulin G immune response than conventional subcutaneous injection at the same antigen dose. Immunoglobulin G levels in the hollow MN group were 5.7, 11.6, and 13.3 times higher than those of the subcutaneous injection group for low, medium, and high doses, respectively. Furthermore, the mice immunized using the hollow microneedle showed no signs of skin infection or pinpoint bleeding. The results suggest that the hollow MN is an efficient device for delivering the optimal dose of antigen via the skin for successful immunization.

76 FR 64945 - Teva Pharmaceutical Industries Ltd. and Cephalon, Inc.; Analysis of Agreement Containing Consent...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-19

... Pharmaceutical, Inc. (``Par'') all of Teva's rights and assets relating to its generic transmucosal fentanyl citrate lozenges (``fentanyl citrate'') and generic extended release cyclobenzaprine hydrochloride..., by lessening competition in the U.S. markets for fentanyl citrate, cyclobenzaprine hydrochloride, and...

Treatment dose-response in amblyopia therapy: the Monitored Occlusion Treatment of Amblyopia Study (MOTAS).

PubMed

Stewart, Catherine E; Moseley, Merrick J; Stephens, David A; Fielder, Alistair R

2004-09-01

Amblyopia is the commonest visual disorder of childhood. Yet the contributions of the two principal treatments (spectacle wear and occlusion) to outcome are unknown. This study was undertaken to investigate the dose-response relationship of amblyopia therapy. The study comprised three distinct phases: baseline, in which repeat measures of visual function were undertaken to confirm the initial visual deficit; refractive adaptation: an 18-week period of spectacle wear with six weekly measurements of logarithm of the minimum angle of resolution (logMAR) visual acuity; occlusion: in which participants were prescribed 6 hours of "patching" per day. In the latter phase, occlusion was objectively monitored and logMAR visual acuity recorded at 2-week intervals until any observed gains had ceased. Data were obtained from 94 participants (mean age, 5.1 +/- 1.4 years) with amblyopia associated with strabismus (n = 34), anisometropia (n = 23), and both anisometropia and strabismus (n = 37). Eighty-six underwent refractive adaptation. Average concordance with patching was 48%. The relationship between logMAR visual acuity gain and total occlusion dose was monotonic and linear. Increasing dose rate beyond 2 h/d hastened the response but did not improve outcome. More than 80% of the improvement during occlusion occurred within 6 weeks. Treatment outcome was significantly better for children younger than 4 years (n = 17) than in those older than 6 years (n = 24; P = 0.0014). Continuous objective monitoring of the amount of patching therapy received has provided insight into the dose-response relationship of occlusion therapy for amblyopia. Patching is most effective within the first few weeks of treatment, even for those in receipt of a relatively small dose. Further studies are needed to elucidate the neural basis for the dose-response functions. Copyright Association for Research in Vision and Ophthalmology

Inhibitory effect of fentanyl citrate on the release of endothlin-1 induced by bradykinin in melanoma cells.

PubMed

Andoh, Tsugunobu; Shinohara, Akira; Kuraishi, Yasushi

2017-02-01

Our previous study showed that the μ-opioid receptor agonist fentanyl citrate inhibits endothelin-1-and bradykinin-mediated pain responses in mice orthotopically inoculated with melanoma cells. We also demonstrated that bradykinin induces endothelin-1 secretion in melanoma cells. However, the analgesic mechanisms of fentanyl citrate remain unclear. Thus, the present study was conducted to determine whether fentanyl citrate affects bradykinin-induced endothelin-1 secretion in B16-BL6 melanoma cells. The amount of endothelin-1 in the culture medium was measured using an enzyme immunoassay. The expression of endothelin-1, kinin B 2 receptors, and μ-opioid receptors in B16-BL/6 melanoma cells was determined using immunocytochemistry. Fentanyl citrate inhibited bradykinin-induced endothelin-1 secretion. The inhibitory effect of fentanyl citrate on the secretion of endothelin-1 was attenuated by the μ-opioid receptor antagonist naloxone methiodide. The immunoreactivities of endothelin-1, kinin B 2 receptors, and μ-opioid receptors in B16-BL6 melanoma cells were observed. These results suggest that fentanyl citrate regulates bradykinin-induced endothelin-1 secretion through μ-opioid receptors in melanoma cells. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Postoperative pain medication requirements in patients undergoing computer-assisted (“Robotic”) and standard laparoscopic procedures for newly diagnosed endometrial cancer.

PubMed

Leitao, Mario M; Malhotra, Vivek; Briscoe, Gabriel; Suidan, Rudy; Dholakiya, Priyal; Santos, Kevin; Jewell, Elizabeth L; Brown, Carol L; Sonoda, Yukio; Abu-Rustum, Nadeem R; Barakat, Richard R; Gardner, Ginger J

2013-10-01

Laparoscopy (LSC) offers superior patient outcomes compared to laparotomy. Small retrospective/prospective series have suggested robotics offers further reduction in postoperative pain and pain medication use compared to standard LSC. Our objective was to compare postoperative pain in patients undergoing robotically assisted (RBT) versus standard LSC for newly diagnosed endometrial cancer. All preoperative endometrial cancer cases scheduled for RBT and LSC from May 1, 2007 to June 9, 2010 were identified. For this analysis, we only included cases not requiring conversion to laparotomy. All patients were offered intravenous (IV) patient-controlled analgesia (PCA) postoperatively. Intraoperative equivalent fentanyl doses (IEFDs) and pain scores in the postanesthesia care unit (PACU) were assessed. IV PCA was used in 206 RBTs (86 %) and 208 LSCs (88 %). Median IEFD was 425 μg for LSCs and 500 μg for RBTs (P = 0.03). Median pain scores on PACU arrival were similar in both groups. Median highest pain score was 5 for LSCs and 4 for RBTs (P = 0.007). Linear regression demonstrated that the IEFD was not correlated with the highest pain score (R = 0.09; P = 0.07). Fentanyl was used postoperatively in 196 of 206 RBTs (95 %) and 187 of 208 LSCs (90 %). The total fentanyl doses were 242.5 (range 0-2705) μg and 380 (range 0-2625) μg, respectively (P < 0.001). The median hourly fentanyl doses were 16.7 (range 0-122.5) μg and 23.5 (range 0-132.4) μg, respectively (P = 0.005). Simultaneous multiple regression analysis further demonstrated RBT was independently associated with a lower total fentanyl dose compared to LSC (P = 0.02). RBT is independently associated with significantly lower postoperative pain and pain medication requirements compared to LSC. The amount of intraoperative fentanyl analgesia does not appear to correlate with postoperative pain.Endometrial cancer is the most common gynecologic malignancy in the United States, with an estimated 47,130 new cases in 2012.1 An estimated 287,100 women were diagnosed with endometrial cancer worldwide in 2008.2 Surgery is the primary treatment of choice for the majority of these women.3 The standard surgical approach has been total abdominal hysterectomy, bilateral salpingo-oophorectomy, and staging via laparotomy. Multiple retrospective series have shown that a less invasive surgical approach via laparoscopy (LSC) is feasible and safe, and also associated with improved perioperative outcomes compared to laparotomy in these patients.4 The Gynecologic Oncology Group (GOG) published results of the largest randomized trial (LAP2) comparing LSC to laparotomy in patients with newly diagnosed endometrial carcinoma in 2009.5,6 This landmark study essentially changed the accepted standard surgical approach in this group. Postoperative complications, median blood loss, and median length of stay (LOS), despite increased operative time, were significantly lower in LSC patients despite 25 % requiring conversion to laparotomy.5 The first 802 eligible patients randomized in LAP2 also participated in a quality-of-life (QOL) study. Within 6 weeks of surgery, patients assigned to LSC reported significantly better QOL on all scales other than fear of recurrence.6 Overall, during this 6-week postoperative period, patients assigned to LSC had superior QOL, fewer physical symptoms, less pain and pain-related interference with functioning, better physical functioning and emotional state, earlier resumption of normal activities, earlier return to work, and better body image compared to those assigned to laparotomy.6 Recurrence-free and overall survivals were the same in both groups.7 Multiple published retrospective series have shown possible benefits, such as reduced postoperative pain, using the robotic (RBT) platform compared to LSC or laparotomy in patients with endometrial cancer.8-11 In a randomized trial, LSC was found to be associated with less postoperative pain compared to vaginal approaches in patients undergoing hysterectomy for benign gynecologic disease.12 A small retrospective series reported further reductions in postoperative pain in patients who had undergone an RBT hysterectomy compared to a standard total LSC hysterectomy for benign indications.13 A recent cost analysis suggested that patients experienced less pain and required less pain medication use after RBT procedures compared to LSC for endometrial cancer.14 Based on these reports, we sought to analyze postoperative pain and the use of pain medication in patients undergoing RBT compared to standard transperitoneal LSC procedures for newly diagnosed endometrial cancer during a concurrent time period. Of note, current RBT surgery is not truly robotic in that it is not autonomous. A more appropriate term is “computer-assisted surgery,” but to satisfy current convention, we refer to it as “robotic surgery” in this manuscript.

Low-dose levonorgestrel and ethinyl estradiol patch and pill: a randomized controlled trial.

PubMed

Kaunitz, Andrew M; Portman, David; Westhoff, Carolyn L; Archer, David F; Mishell, Daniel R; Rubin, Arkady; Foegh, Marie

2014-02-01

To compare a new low-dose levonorgestrel and ethinyl estradiol contraceptive patch (Patch) with a combination oral contraceptive (Pill; 100 micrograms levonorgestrel, 20 micrograms ethinyl estradiol) regarding efficacy, safety, compliance, and unscheduled uterine bleeding. Women (17-40 years; body mass index 16-60) were randomized in a 3:1 ratio to one of two groups: Patch only (13 cycles) or Pill (six cycles) followed by Patch (seven cycles). Investigators evaluated adverse events during cycles 2, 4, 6, 9, and 13. Participants recorded drug administration and uterine bleeding on daily diary cards. Compliance was assessed by measuring levonorgestrel and ethinyl estradiol plasma levels. Pearl Index (pregnancies per 100 woman-years) was calculated to evaluate efficacy. Participants (N=1,504) were randomized to Patch (n=1,129) or Pill (n=375). Approximately 30% were obese, more than 40% were racial or ethnic minorities, and more than 55% were new users of hormonal contraceptives. Laboratory-verified noncompliance (undetectable plasma drug levels) was 11% of Patch and 12.6% of Pill users at cycle 6. Pearl Indices (95% confidence intervals) for the intention-to-treat population (cycles 1-6) were 4.45 (2.34-6.57) for Patch and 4.02 (0.50-7.53) for Pill; excluding laboratory-verified noncompliant participants, Pearl Indices were 2.82 (0.98-4.67) for Patch and 3.80 (0.08-7.52) for Pill (differences not statistically significant). Incidence of unscheduled bleeding and incidence and severity of adverse events were similar for both contraceptives (no statistically significant difference). Efficacy and safety of the new contraceptive Patch are comparable to those of a Pill. Laboratory-verified noncompliance and bleeding profile are similar between the two treatments. The Patch was well tolerated. ClinicalTrials.gov, www.clinicaltrials.gov, NCT01181479. I.

Chlorpyrifos exposures in Egyptian cotton field workers.

PubMed

Farahat, Fayssal M; Fenske, Richard A; Olson, James R; Galvin, Kit; Bonner, Matthew R; Rohlman, Diane S; Farahat, Taghreed M; Lein, Pamela J; Anger, W Kent

2010-06-01

Neurobehavioral deficits have been reported in Egyptian pesticide application teams using organophosphorus (OP) pesticides, but whether these effects are related to OP pesticide exposures has yet to be established. In preparation for a comprehensive study of the relationship between OP pesticide dose and neurobehavioral deficits, we assessed exposure within this population. We conducted occupational surveys and workplace observations, and collected air, dermal patch and biological samples from applicators, technicians and engineers involved in chlorpyrifos applications during cotton production to test the hypotheses that: (1) dermal exposure was an important contributor to internal dose and varied across body regions; and (2) substantial differences would be seen across the three job categories. Applicators were substantially younger and had shorter exposure histories than did technicians and engineers. Applicators and technicians were observed to have relatively high levels of skin or clothing contact with pesticide-treated foliage as they walked through the fields. Both dermal patch loadings of chlorpyrifos and measurements of a chlorpyrifos-specific metabolite (TCPy) in urine confirmed substantial exposure to and skin absorption of chlorpyrifos that varied according to job category; and dermal patch loading was significantly higher on the thighs than on the forearms. These findings support our hypotheses and support the need for research to examine neurobehavioral performance and exposures in this population. More importantly, the exposures reported here are sufficiently high to recommend urgent changes in work practices amongst these workers. Copyright 2010 Elsevier Inc. All rights reserved.

Chlorpyrifos Exposures in Egyptian Cotton Field Workers

PubMed Central

Farahat, Fayssal M.; Fenske, Richard A.; Olson, James R.; Galvin, Kit; Bonner, Matthew R.; Rohlman, Diane S.; Lein, Pamela J.; Anger, W. Kent

2013-01-01

Neurobehavioral deficits have been reported in Egyptian pesticide application teams using organophosphorus (OP) pesticides, but whether these effects are related to OP pesticide exposures has yet to be established. In preparation for a comprehensive study of the relationship between OP pesticide dose and neurobehavioral deficits, we assessed exposure within this population. We conducted occupational surveys and workplace observations, and collected air, dermal patch and biological samples from applicators, technicians and engineers involved in chlorpyrifos applications during cotton production to test the hypotheses that: 1) dermal exposure was an important contributor to internal dose and varied across body regions; and 2) substantial differences would be seen across the three job categories. Applicators were substantially younger and had shorter exposure histories than did technicians and engineers. Applicators and technicians were observed to have relatively high levels of skin or clothing contact with pesticide-treated foliage as they walked through the fields. Both dermal patch loadings of chlorpyrifos and measurements of a chlorpyrifos-specific metabolite (TCPy) in urine confirmed substantial exposure to and skin absorption of chlorpyrifos that varied according to job category; and dermal patch loading was significantly higher on the thighs than on the forearms. These findings support our hypotheses and support the need for research to examine neurobehavioral performance and exposures in this population. More importantly, the exposures reported here are sufficiently high to recommend urgent changes in work practices amongst these workers. PMID:20193710

Dose-dependent effects of Lactobacillus rhamnosus on serum interleukin-17 production and intestinal T-cell responses in pigs challenged with Escherichia coli.

PubMed

Zhu, Yao-Hong; Li, Xiao-Qiong; Zhang, Wei; Zhou, Dong; Liu, Hao-Yu; Wang, Jiu-Feng

2014-03-01

The mechanism underlying the dose effect of probiotics on ameliorating diarrhea has not been fully elucidated. Here, low (1 × 10(9) CFU/ml) or high (1 × 10(11) CFU/ml) doses of Lactobacillus rhamnosus ATCC 7469 were administered orally to piglets for 1 week before F4 (K88)-positive enterotoxigenic Escherichia coli (F4(+) ETEC) challenge. Administration of a low, but not a high, dose of L. rhamnosus decreased the percentage of CD3(+) CD4(+) CD8(-) T cells in the peripheral blood. Notably, transiently increased serum concentrations of interleukin-17A (IL-17A) were observed after F4(+) ETEC challenge in pigs pretreated with a high dose of L. rhamnosus. Administration of L. rhamnosus increased the percentage of the small intestinal lamina propria CD3(+) CD4(+) CD8(-) cells and Peyer's patch CD3(+) CD4(-) CD8(-) and CD3(-) CD4(-) CD8(+) cells. The percentage of ileal intraepithelial CD3(+) CD4(-) CD8(+) cells increased only in the high-dose piglets. Administration of L. rhamnosus downregulated expression of ileal IL-17A after F4(+) ETEC challenge but had no effect on expression of gamma interferon (IFN-γ), IL-12, IL-4, and FOXP3 mRNA in the small intestine. Expression of jejunal IL-2, ileal transforming growth factor β1 (TGF-β1), and ileal IL-10 was upregulated in the low-dose piglets after F4(+) ETEC challenge. Our findings suggest that amelioration of infectious diarrhea in piglets by L. rhamnosus is associated with the generation of lamina propria CD3(+) CD4(+) CD8(-) T cells, the expansion of Peyer's patch CD3(+) CD4(-) CD8(-) and CD3(-) CD4(-) CD8(+) cells, and the attenuation of F4(+) ETEC-induced increase in CD3(+) CD4(+) CD8(+) T cells in the small intestine. However, consumption of high doses of L. rhamnosus may increase levels of serum IL-17A after F4(+) ETEC challenge, thus eliciting a strong proinflammatory response.

Dose-Dependent Effects of Lactobacillus rhamnosus on Serum Interleukin-17 Production and Intestinal T-Cell Responses in Pigs Challenged with Escherichia coli

PubMed Central

Zhu, Yao-Hong; Li, Xiao-Qiong; Zhang, Wei; Zhou, Dong; Liu, Hao-Yu

2014-01-01

The mechanism underlying the dose effect of probiotics on ameliorating diarrhea has not been fully elucidated. Here, low (1 × 109 CFU/ml) or high (1 × 1011 CFU/ml) doses of Lactobacillus rhamnosus ATCC 7469 were administered orally to piglets for 1 week before F4 (K88)-positive enterotoxigenic Escherichia coli (F4+ ETEC) challenge. Administration of a low, but not a high, dose of L. rhamnosus decreased the percentage of CD3+ CD4+ CD8− T cells in the peripheral blood. Notably, transiently increased serum concentrations of interleukin-17A (IL-17A) were observed after F4+ ETEC challenge in pigs pretreated with a high dose of L. rhamnosus. Administration of L. rhamnosus increased the percentage of the small intestinal lamina propria CD3+ CD4+ CD8− cells and Peyer's patch CD3+ CD4− CD8− and CD3− CD4− CD8+ cells. The percentage of ileal intraepithelial CD3+ CD4− CD8+ cells increased only in the high-dose piglets. Administration of L. rhamnosus downregulated expression of ileal IL-17A after F4+ ETEC challenge but had no effect on expression of gamma interferon (IFN-γ), IL-12, IL-4, and FOXP3 mRNA in the small intestine. Expression of jejunal IL-2, ileal transforming growth factor β1 (TGF-β1), and ileal IL-10 was upregulated in the low-dose piglets after F4+ ETEC challenge. Our findings suggest that amelioration of infectious diarrhea in piglets by L. rhamnosus is associated with the generation of lamina propria CD3+ CD4+ CD8− T cells, the expansion of Peyer's patch CD3+ CD4− CD8− and CD3− CD4− CD8+ cells, and the attenuation of F4+ ETEC-induced increase in CD3+ CD4+ CD8+ T cells in the small intestine. However, consumption of high doses of L. rhamnosus may increase levels of serum IL-17A after F4+ ETEC challenge, thus eliciting a strong proinflammatory response. PMID:24389928

Knee strength retention and analgesia with continuous perineural fentanyl infusion after total knee replacement: randomized controlled trial.

PubMed

Mangar, Devanand; Karlnoski, Rachel A; Sprenker, Collin J; Downes, Katheryne L; Taffe, Narrene; Wainwright, Robert; Gustke, Kenneth; Bernasek, Thomas L; Camporesi, Enrico

2014-04-01

Despite providing adequate pain relief, a femoral nerve block can induce postoperative muscle weakness after total knee arthoplasty (TKA). Fentanyl has been shown to have peripheral effects but has not been used as a perineural infusate alone after TKA. Sixty patients scheduled for TKA were randomized to one of three blinded groups: a continuous 24 h infusion of either fentanyl 3 μg/ml, ropivacaine 0.1%, or 0.9% normal saline through a femoral nerve sheath catheter at 10 ml/h. The main outcome was maximum voluntary isometric contraction (MVIC) in the quadriceps femoris (knee extension), measured by a handheld dynamometer (Nm/kg). Other variables assessed were preoperative and postoperative visual analog scale (VAS) scores, hamstrings MVIC (knee flexion), active range of motion of the operative knee, distance ambulated, incidence of knee buckling, supplemental morphine usage, postoperative side effects, and serum fentanyl levels. Quadriceps MVIC values were significantly greater in the fentanyl group compared to the group that received ropivacaine (median values, 0.08 vs. 0.03 Nm/kg; p = 0.028). The incidence of postoperative knee buckling upon ambulation was higher in the ropivacaine group compared to the fentanyl group, although not statistically significant (40% vs. 15 %, respectively; p = 0.077). VAS scores while ambulating were not significantly different between the fentanyl group and the ropivacaine group (p = 0.270). Postoperative morphine consumption, nausea and vomiting, and resting VAS scores were similar among the three groups. A continuous perineural infusion of fentanyl produced greater strength retention than ropivacaine post-TKA.

Heroin and fentanyl overdoses in Kentucky: Epidemiology and surveillance.

PubMed

Slavova, Svetla; Costich, Julia F; Bunn, Terry L; Luu, Huong; Singleton, Michael; Hargrove, Sarah L; Triplett, Jeremy S; Quesinberry, Dana; Ralston, William; Ingram, Van

2017-08-01

The study aims to describe recent changes in Kentucky's drug overdose trends related to increased heroin and fentanyl involvement, and to discuss future directions for improved drug overdose surveillance. The study used multiple data sources (death certificates, postmortem toxicology results, emergency department [ED] records, law enforcement drug submissions, and prescription drug monitoring records) to describe temporal, geographic, and demographic changes in drug overdoses in Kentucky. Fentanyl- and heroin-related overdose death rates increased across all age groups from years 2011 to 2015 with the highest rates consistently among 25-34-year-olds. The majority of the heroin and fentanyl overdose decedents had histories of substantial exposures to legally acquired prescription opioids. Law enforcement drug submission data were strongly correlated with drug overdose ED and mortality data. The 2016 crude rate of heroin-related overdose ED visits was 104/100,000, a 68% increase from 2015 (62/100,000). More fentanyl-related overdose deaths were reported between October, 2015, and September, 2016, than ED visits, in striking contrast with the observed ratio of >10 to 1 heroin-related overdose ED visits to deaths. Many fatal fentanyl overdoses were associated with heroin adulterated with fentanyl; <40% of the heroin overdose ED discharge records listed procedure codes for drug screening. The lack of routine ED drug testing likely resulted in underreporting of non-fatal overdoses involving fentanyl and other synthetic drugs. In order to inform coordinated public health and safety responses, drug overdose surveillance must move from a reactive to a proactive mode, utilizing the infrastructure for electronic health records. Copyright © 2017 Elsevier B.V. All rights reserved.

An Acute Butyr-Fentanyl Fatality: A Case Report with Postmortem Concentrations.

PubMed

McIntyre, Iain M; Trochta, Amber; Gary, Ray D; Wright, Jennifer; Mena, Othon

2016-03-01

In this case report, we present an evaluation of the distribution of postmortem concentrations of butyr-fentanyl in a fatality attributed principally to the drug. A man who had a history of intravenous drug abuse was found unresponsive on the bathroom floor of his home. Drug paraphernalia was located on the bathroom counter. Toxicology testing, which initially screened positive for fentanyl by enzyme-linked immunosorbent assay, subsequently confirmed butyr-fentanyl, which was then quantitated by gas chromatography-mass spectrometry-specific ion monitoring (GC-MS SIM) analysis following liquid-liquid extraction. The butyr-fentanyl peripheral blood concentration was quantitated at 58 ng/mL compared with the central blood concentration of 97 ng/mL. The liver concentration was 320 ng/g, the vitreous was 40 ng/mL, the urine was 670 ng/mL and the gastric contained 170 mg. Acetyl-fentanyl was also detected in all biological specimens tested. Peripheral blood concentration was quantitated at 38 ng/mL compared with the central blood concentration of 32 ng/mL. The liver concentration was 110 ng/g, the vitreous was 38 ng/mL, the urine was 540 ng/mL and the gastric contained <70 mg. The only other drug detected was a relatively low concentration of benzoylecgonine. The cause of death was certified as acute butyr-fentanyl, acetyl-fentanyl and cocaine intoxication, and the manner of death was certified as accident. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Changes in blood glucose level during and after light sedations using propofol-fentanyl and midazolam-fentanyl in diabetic patients who underwent cataract surgery.

PubMed

Khalighinejad, Pooyan; Rahimi, Mojtaba; Naghibi, Khosro; Niknam, Negar

2015-01-01

Surgeries may trigger the stress response which leads to changes in blood glucose level, and studies suggest that different sedation and anesthesia methods have different effects on blood glucose level. The aim of this study was to investigate changes of blood glucose levels in diabetic patients and compare them in two sedation methods of propofol + fentanyl and midazolam + fentanyl. Totally, 80 diabetic candidates for cataract surgery who had all the inclusion criteria, underwent cataract surgery using two methods of propofol (1 mg/kg/h) + fentanyl (2 μg/kg) (Group P) and midazolam (0.03 mg/kg) + fentanyl (2 μg/kg) (Group M) for light sedation. In the end, 70 patients (Group P n = 35 and Group M n = 35) remained in the study. Patients' blood glucose levels, vital signs, and hemodynamic data were assessed 30 min prior to the surgery, each 15 min during surgery and at the end of surgery. Hemodynamic parameters did not have a statistically significant difference between the two groups mean blood glucose level in Group M was 149.15 mg/dl and in Group P was 149.2 mg/dl, and based on repeated measures analysis of variance test, significant differences were not observed between the two groups (P = 0.99). T-test showed no significant differences in the blood glucose level at any time of the study between the two groups. Light sedation methods of propofol + fentanyl and midazolam + fentanyl did not have any differences in alteration of blood glucose level.

Evaluation of rotigotine transdermal patch for the treatment of apathy and motor symptoms in Parkinson's disease.

PubMed

Hauser, Robert A; Slawek, Jaroslaw; Barone, Paolo; Dohin, Elisabeth; Surmann, Erwin; Asgharnejad, Mahnaz; Bauer, Lars

2016-06-07

This multicenter, double-blind, placebo-controlled study assessed the efficacy of rotigotine transdermal patch on apathy and motor symptoms in patients with Parkinson's disease (PD). Patients with PD-associated apathy (Unified Parkinson's Disease Rating Scale [UPDRS] I item 4 [motivation] ≥2 and patient-rated Apathy Scale [AS] ≥14) were randomized 1:1:1 to "low-dose" rotigotine (≤6 mg/24 h for early PD [those not receiving levodopa] or ≤8 mg/24 h for advanced PD [those receiving levodopa]), "high-dose" rotigotine (≤8 mg/24 h for early PD or ≤16 mg/24 h for advanced PD), or placebo, and maintained at optimal/maximal dose for 12 weeks. Coprimary efficacy variables were: change from baseline to End of Maintenance in patient-rated AS and UPDRS II + III total score. Recruitment was stopped after an interim futility analysis; therefore, all p values are exploratory. Of 122 patients randomized, 81.1 % completed the study (placebo, n = 32/40 [80.0 %]; low-dose rotigotine, n = 30/41 [73.2 %]; high-dose rotigotine, n = 37/41 [90.2 %]). No treatment difference was observed in the change in patient-rated AS (least squares mean [95 % confidence interval (CI)] difference: low-dose, 0.04 [-2.42, 2.50], p =0.977; high-dose, -0.22 [-2.61, 2.18], p = 0.859). Rotigotine improved UPDRS II + III total scores versus placebo (least squares mean [95 % CI] treatment difference: low-dose, -7.29 [-12.30, -2.28], p = 0.005; high-dose, -6.06 [-10.90, -1.21], p = 0.015), and the "mood/apathy" domain of the Non-Motor Symptom Scale as rated by the investigator (secondary outcome). The most frequent adverse events in rotigotine-treated patients were application site reactions, somnolence, and nausea. Rotigotine did not improve PD-associated apathy as rated by the patient but provided clinically relevant improvement in motor control and activities of daily living. ClinicalTrials.gov identifier NCT01782222 . Trial registration date: January 30, 2013.

78 FR 44432 - New Animal Drugs; Change of Sponsor; Fentanyl; Iron Injection

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-24

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Parts 510, 522, and 524 [Docket No. FDA-2013-N-0002] New Animal Drugs; Change of Sponsor; Fentanyl; Iron Injection AGENCY..., NADA 141-337 for RECUVYRA (fentanyl) Transdermal Solution to Elanco Animal Health, A Division of Eli...

Heroin uncertainties: Exploring users' perceptions of fentanyl-adulterated and -substituted 'heroin'.

PubMed

Ciccarone, Daniel; Ondocsin, Jeff; Mars, Sarah G

2017-08-01

The US is experiencing an unprecedented opioid overdose epidemic fostered in recent years by regional contamination of the heroin supply with the fentanyl family of synthetic opioids. Since 2011 opioid-related overdose deaths in the East Coast state of Massachusetts have more than tripled, with 75% of the 1374 deaths with an available toxicology positive for fentanyl. Fentanyl is 30-50X more potent than heroin and its presence makes heroin use more unpredictable. A rapid ethnographic assessment was undertaken to understand the perceptions and experiences of people who inject drugs sold as 'heroin' and to observe the drugs and their use. A team of ethnographers conducted research in northeast Massachusetts and Nashua, New Hampshire in June 2016, performing (n=38) qualitative interviews with persons who use heroin. (1) The composition and appearance of heroin changed in the last four years; (2) heroin is cheaper and more widely available than before; and (3) heroin 'types' have proliferated with several products being sold as 'heroin'. These consisted of two types of heroin (alone), fentanyl (alone), and heroin-fentanyl combinations. In the absence of available toxicological information on retail-level heroin, our research noted a hierarchy of fentanyl discernment methods, with embodied effects considered most reliable in determining fentanyl's presence, followed by taste, solution appearance and powder color. This paper presents a new 'heroin' typology based on users' reports. Massachusetts' heroin has new appearances and is widely adulterated by fentanyl. Persons who use heroin are trying to discern the substances sold as heroin and their preferences for each form vary. The heroin typology presented is inexact but can be validated by correlating users' discernment with drug toxicological testing. If validated, this typology would be a valuable harm reduction tool. Further research on adaptations to heroin adulteration could reduce risks of using heroin and synthetic opioid combinations. Copyright © 2017 Elsevier B.V. All rights reserved.

COMPARISON OF INTRAMUSCULAR FENTANYL-MIDAZOLAM, FENTANYL-MIDAZOLAM-KETAMINE, AND KETAMINE-MEDETOMIDINE FOR IMMOBILIZATION OF JAPANESE MACAQUES ( MACACA FUSCATA).

PubMed

Ølberg, Rolf-Arne; Sinclair, Melissa; Barker, Ian K; Crawshaw, Graham

2018-03-01

The combination of fentanyl and midazolam is commonly used as a sedative in humans. The objective of this study was to evaluate the sedative properties and physiological effects of fentanyl-midazolam and fentanyl-midazolam-ketamine compared with medetomidine-ketamine given intramuscularly in Japanese macaques ( Macaca fuscata). In a randomized crossover design, eight Japanese macaques were hand-injected with either 30 μg/kg fentanyl + 0.3 mg/kg midazolam (FM), 15 μg/kg fentanyl + 0.3 mg/kg midazolam + 5.0 mg/kg ketamine (FMK), or 0.05 mg/kg medetomidine + 5.0 mg/kg ketamine (MedK). Heart rate; indirect systolic, mean, and diastolic arterial pressure; respiratory rate; blood gas concentrations; rectal temperature; and duration of immobilization were recorded. Mixed linear models were used to evaluate the effects of drug treatment on all continuous variables, with a significance level of P < 0.05. Only three of seven animals receiving FM were successfully immobilized. All eight animals in both the FMK and MedK treatment groups had a rapid, smooth induction and were successfully immobilized. Both FMK and MedK treatments resulted in significant hypoxia and the animals required supplemental oxygen via face mask. The mean duration of FMK immobilization was 42 ± 10 min, significantly shorter than the 65 ± 14 min for the animals receiving MedK. Immobilization with MedK resulted in significantly lower heart rates, and significantly higher arterial pressure compared with FMK. Hypoventilation was significantly more pronounced in FMK-treated animals compared with MedK treatments. Immobilization with FMK resulted in a gradual, slow recovery whereas MedK-treated animals woke up more rapidly. Fentanyl-midazolam alone is not a useful sedative in Japanese macaques. A combination of fentanyl and midazolam with ketamine can be used as an alternative to medetomidine-ketamine in this species.

The fentanyl concentration required for immobility under propofol anesthesia is reduced by pre-treatment with flurbiprofen axetil.

PubMed

Kodaka, Mitsuharu; Tsukakoshi, Mikiko; Miyao, Hideki; Tsuzaki, Koichi; Ichikawa, Junko; Komori, Makiko

2013-12-01

We hypothesized that nonsteroidal anti-inflammatory drugs decrease the plasma fentanyl concentration required to produce immobility in 50% of patients in response to skin incision (Cp50incision) compared with placebo under target-controlled infusion (TCI) propofol anesthesia. Sixty-two unpremedicated patients scheduled to undergo gynecologic laparoscopy were randomly assigned to receive placebo (control group) or flurbiprofen axetil 1 mg·kg(-1) (flurbiprofen group) preoperatively. General anesthesia was induced with fentanyl and propofol, and intubation was performed after succinylcholine 1 mg·kg(-1). Propofol was administered via a target-controlled infusion (TCI) system (Diprifusor™) set at an effect-site concentration of 5 μg·mL(-1). Fentanyl was given by a TCI system using the STANPUMP software (Schafer model). The concentration for the first patient was set at 3 ng·mL(-1) and modified in each group according to the up-down method. Skin incision was performed after more than ten minutes equilibration time. Serum fentanyl concentration, bispectral index (BIS), and hemodynamic parameters were measured two minutes before and after skin incision. The Cp50incision of fentanyl was derived from the mean of the crossovers (i.e., the serum fentanyl concentrations of successive participants who responded and those who did not or vice versa). Ten and 11 independent crossover pairs were collected in the control and flurbiprofen groups, respectively, representing 42 of 62 enrolled patients. The mean (SD) fentanyl Cp50incision was less in the flurbiprofen group [0.84 (0.63) ng·mL(-1)] than in the control group [1.65 (1.15) ng·mL(-1)]; P = 0.007; however, there were no differences in BIS, blood pressure, or heart rate, between groups. Preoperative flurbiprofen axetil decreased the Cp50incision of fentanyl by 49% during propofol anesthesia without changing the BIS or hemodynamic variables.

Increase in Drug Overdose Deaths Involving Fentanyl-Rhode Island, January 2012-March 2014.

PubMed

Mercado, Melissa C; Sumner, Steven A; Spelke, M Bridget; Bohm, Michele K; Sugerman, David E; Stanley, Christina

2018-03-01

This study identified sociodemographic, substance use, and multiple opioid prescriber and dispenser risk factors among drug overdose decedents in Rhode Island, in response to an increase in overdose deaths (ODs) involving fentanyl. This cross-sectional investigation comprised all ODs reviewed by Rhode Island's Office of the State Medical Examiners (OSME) during January 2012 to March 2014. Data for 536 decedents were abstracted from OSME's charts, death certificates, toxicology reports, and Prescription Monitoring Program (PMP) databases. Decedents whose cause of death involved illicit fentanyl (N = 69) were compared with decedents whose causes of death did not involve fentanyl (other drug decedents; N = 467). Illicit-fentanyl decedents were younger than other drug decedents (P = 0.005). While more other-drug decedents than illicit fentanyl decedents had postmortem toxicological evidence of consuming heroin (31.9% vs 19.8%, P < 0.001) and various pharmaceutical substances (P = 0.002-0.027), third party reports indicated more recent heroin use among illicit fentanyl decedents (62.3% vs 45.6%, P = 0.002). Approximately 35% of decedents filled an opioid prescription within 90 days of death; of these, one-third had a mean daily dosage greater than 100 morphine milligram equivalents (MME/day). Most decedents' opioid prescriptions were filled at one to two dispensers (83.9%) and written by one to two prescribers (75.8%). Notably, 29.2% of illicit fentanyl and 10.5% of other drug decedents filled prescriptions for buprenorphine, which is used to treat opioid use disorders. Illicit-fentanyl deaths frequently involved other illicit drugs (e.g., cocaine, heroin). The proportion of all decedents acquiring greater than 100 MME/day prescription dosages written and/or filled by few prescribers and dispensers is concerning. To protect patients, prescribers and dispensers should review PMP records and substance abuse history prior to providing opioids.

Two Fatal Intoxications Involving Butyryl Fentanyl.

PubMed

Poklis, Justin; Poklis, Alphonse; Wolf, Carl; Hathaway, Cindie; Arbefeville, Elise; Chrostowski, Leszek; Devers, Kelly; Hair, Laura; Mainland, Mary; Merves, Michele; Pearson, Julia

2016-10-01

We present the case histories, autopsy findings and toxicology findings of two fatal intoxications involving the designer drug, butyryl fentanyl. The quantitative analysis of butyryl fentanyl in postmortem fluids and tissues was performed by an ultrahigh-performance liquid chromatography tandem mass spectrometry method. In the first case, butyryl fentanyl was the only drug detected with concentrations of 99 ng/mL in peripheral blood, 220 ng/mL in heart blood, 32 ng/mL in vitreous humor, 590 ng/mL in gastric contents, 93 ng/g in brain, 41 ng/g in liver, 260 ng/mL in bile and 64 ng/mL in urine. The cause of death was ruled fatal intoxication by butyryl fentanyl. In the second case, butyryl fentanyl was detected along with acetyl fentanyl, alprazolam and ethanol. The butyryl fentanyl concentrations were 3.7 ng/mL in peripheral blood, 9.2 ng/mL in heart blood, 9.8 ng/mL in vitreous humor, 4,000 ng/mL in gastric contents, 63 ng/g in brain, 39 ng/g in liver, 49 ng/mL in bile and 2 ng/mL in urine. The acetyl fentanyl concentrations were 21 ng/mL in peripheral blood, 95 ng/mL in heart blood, 68 ng/mL in vitreous humor, 28,000 ng/mL in gastric contents, 200 ng/g in brain, 160 ng/g in liver, 330 ng/mL in bile and 8 ng/mL in urine. In addition, the alprazolam concentration was 40 ng/mL and the ethanol concentration was 0.11 g/dL, both measured in peripheral blood. The cause of death in the second case was ruled a mixed drug intoxication. In both cases, the manner of death was accident. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Overdose Deaths Related to Fentanyl and Its Analogs - Ohio, January-February 2017.

PubMed

Daniulaityte, Raminta; Juhascik, Matthew P; Strayer, Kraig E; Sizemore, Ioana E; Harshbarger, Kent E; Antonides, Heather M; Carlson, Robert R

2017-09-01

Ohio is experiencing unprecedented loss of life caused by unintentional drug overdoses (1), with illicitly manufactured fentanyl (IMF) emerging as a significant threat to public health (2,3). IMF is structurally similar to pharmaceutical fentanyl, but is produced in clandestine laboratories and includes fentanyl analogs that display wide variability in potency (2); variations in chemical composition of these drugs make detection more difficult. During 2010-2015, unintentional drug overdose deaths in Ohio increased 98%, from 1,544 to 3,050.* In Montgomery County (county seat: Dayton), one of the epicenters of the opioid epidemic in the state, unintentional drug overdose deaths increased 40% in 1 year, from 249 in 2015 to 349 in 2016 (estimated unadjusted mortality rate = 57.7 per 100,000) (4). IMFs have not been part of routine toxicology testing at the coroner's offices and other types of medical and criminal justice settings across the country (2,3). Thus, data on IMF test results in the current outbreak have been limited. The Wright State University and the Montgomery County Coroner's Office/Miami Valley Regional Crime Laboratory (MCCO/MVRCL) collaborated on a National Institutes of Health study of fentanyl analogs and metabolites and other drugs identified in 281 unintentional overdose fatalities in 24 Ohio counties during January-February 2017. Approximately 90% of all decedents tested positive for fentanyl, 48% for acryl fentanyl, 31% for furanyl fentanyl, and 8% for carfentanil. Pharmaceutical opioids were identified in 23% of cases, and heroin in 6%, with higher proportions of heroin-related deaths in Appalachian counties. The majority of decedents tested positive for more than one type of fentanyl. Evidence suggests the growing role of IMFs, and the declining presence of heroin and pharmaceutical opioids in unintentional overdose fatalities, compared with 2014-2016 data from Ohio and other states (3-5). There is a need to include testing for IMFs as part of standard toxicology panels for biological specimens used in the medical, substance abuse treatment, and criminal justice settings.

Comparison of pain-relieving effects of fentanyl versus ketorolac after eye amputation surgery.

PubMed

Kim, Jin Hyung; Jang, Sun Young; Kim, Myung Jin; Lee, Sang Yeul; Yoon, Jin Sook

2013-08-01

To investigate the analgesic effect and incidence of postoperative nausea and vomiting (PONV) between the opioid fentanyl and the non-steroidal anti-inflammatory drug ketorolac in patients who underwent eye amputation surgery. Retrospective observational case series. Eighty-two patients underwent evisceration or enucleation surgery by one surgeon over a 2-year period. Fentanyl by intravenous patient-controlled analgesia (IV-PCA) at 20 µg/kg with 12 mg/kg ondansetron or intravenous ketorolac at 2 mg/kg/day was administered to patients at postoperative days 0, 1, and 2. The pain score was measured using an 11-point visual analog scale (VAS). The incidence of severe nausea requiring anti-emetics and the incidence of vomiting were reviewed. The mean postoperative VAS in the fentanyl group was significantly lower than that in the ketorolac group on the day of operation for both types of surgery (p = 0.001 and p = 0.004, respectively). At postoperative days 1 and 2, the mean VAS was not different between the two groups for either surgical type (p > 0.05 for both days). The mean VAS was significantly higher in eviscerated patients than in enucleated patients at postoperative days 0 and 1 in the fentanyl group (p = 0.023 and p = 0.016, respectively). However, this was not observed in the ketorolac group. The incidence of PONV was higher in the fentanyl group than in the ketorolac group, although this was not statistically significant for either surgical type (p > 0.05 for both groups). Fentanyl was more effective as an analgesic than was ketorolac on the day of operation for both surgical types. There was no difference between the two analgesics on postoperative day 1. The analgesic effect of fentanyl in enucleated patients was significantly higher than in eviscerated patients at postoperative days 0 and 1. The use of fentanyl by IV-PCA was associated with greater PONV despite co-administration with anti-emetics, although this finding was not significant.

Comparison of Pain-relieving Effects of Fentanyl versus Ketorolac after Eye Amputation Surgery

PubMed Central

Kim, Jin Hyung; Jang, Sun Young; Kim, Myung Jin; Lee, Sang Yeul

2013-01-01

Purpose To investigate the analgesic effect and incidence of postoperative nausea and vomiting (PONV) between the opioid fentanyl and the non-steroidal anti-inflammatory drug ketorolac in patients who underwent eye amputation surgery. Methods Retrospective observational case series. Eighty-two patients underwent evisceration or enucleation surgery by one surgeon over a 2-year period. Fentanyl by intravenous patient-controlled analgesia (IV-PCA) at 20 µg/kg with 12 mg/kg ondansetron or intravenous ketorolac at 2 mg/kg/day was administered to patients at postoperative days 0, 1, and 2. The pain score was measured using an 11-point visual analog scale (VAS). The incidence of severe nausea requiring anti-emetics and the incidence of vomiting were reviewed. Results The mean postoperative VAS in the fentanyl group was significantly lower than that in the ketorolac group on the day of operation for both types of surgery (p = 0.001 and p = 0.004, respectively). At postoperative days 1 and 2, the mean VAS was not different between the two groups for either surgical type (p > 0.05 for both days). The mean VAS was significantly higher in eviscerated patients than in enucleated patients at postoperative days 0 and 1 in the fentanyl group (p = 0.023 and p = 0.016, respectively). However, this was not observed in the ketorolac group. The incidence of PONV was higher in the fentanyl group than in the ketorolac group, although this was not statistically significant for either surgical type (p > 0.05 for both groups). Conclusions Fentanyl was more effective as an analgesic than was ketorolac on the day of operation for both surgical types. There was no difference between the two analgesics on postoperative day 1. The analgesic effect of fentanyl in enucleated patients was significantly higher than in eviscerated patients at postoperative days 0 and 1. The use of fentanyl by IV-PCA was associated with greater PONV despite co-administration with anti-emetics, although this finding was not significant. PMID:23908567

The rationale for intensity-modulated proton therapy in geometrically challenging cases

NASA Astrophysics Data System (ADS)

Safai, S.; Trofimov, A.; Adams, J. A.; Engelsman, M.; Bortfeld, T.

2013-09-01

Intensity-modulated proton therapy (IMPT) delivered with beam scanning is currently available at a limited number of proton centers. However, a simplified form of IMPT, the technique of field ‘patching’, has long been a standard practice in proton therapy centers. In field patching, different parts of the target volume are treated from different directions, i.e., a part of the tumor gets either full dose from a radiation field, or almost no dose. Thus, patching represents a form of binary intensity modulation. This study explores the limitations of the standard binary field patching technique, and evaluates possible dosimetric advantages of continuous dose modulations in IMPT. Specifics of the beam delivery technology, i.e., pencil beam scanning versus passive scattering and modulation, are not investigated. We have identified two geometries of target volumes and organs at risk (OAR) in which the use of field patching is severely challenged. We focused our investigations on two patient cases that exhibit these geometries: a paraspinal tumor case and a skull-base case. For those cases we performed treatment planning comparisons of three-dimensional conformal proton therapy (3DCPT) with field patching versus IMPT, using commercial and in-house software, respectively. We also analyzed the robustness of the resulting plans with respect to systematic setup errors of ±1 mm and range errors of ±2.5 mm. IMPT is able to better spare OAR while providing superior dose coverage for the challenging cases identified above. Both 3DCPT and IMPT are sensitive to setup errors and range uncertainties, with IMPT showing the largest effect. Nevertheless, when delivery uncertainties are taken into account IMPT plans remain superior regarding target coverage and OAR sparing. On the other hand, some clinical goals, such as the maximum dose to OAR, are more likely to be unmet with IMPT under large range errors. IMPT can potentially improve target coverage and OAR sparing in challenging cases, even when compared with the relatively complicated and time consuming field patching technique. While IMPT plans tend to be more sensitive to delivery uncertainties, their dosimetric advantage generally holds. Robust treatment planning techniques may further reduce the sensitivity of IMPT plans.

Dexmedetomidine in Attenuation of Haemodynamic Response and Dose Sparing Effect on Opioid and Anaesthetic Agents in Patients undergoing Laparoscopic Cholecystectomy- A Randomized Study

PubMed Central

Bhagat, Nandlal; Karim, Habib Md Reazaul; Hajong, Ranendra; Bhattacharyya, Prithwis; Singh, Manorama

2016-01-01

Introduction Perioperative procedures are stressful and lead to haemodynamic instability with potentially devastating consequences. Dexmedetomidine is found to have many of the desired characteristics that are required in perioperative period. Aim To evaluate the ability of pre and intraoperative dexmedetomidine to attenuate stress induced haemodynamic responses, quantifying the anaesthetic agents sparing as well as its cost-effectiveness in patients undergoing laparoscopic cholecystectomy. Materials and Methods The present single blind randomized study was conducted with 120 ASA I and II consented patients who underwent laparoscopic cholecystectomy. Patients were randomly divided into 2 groups (i.e., group D and group N). Prior to induction, group D received 1 μg/kg of Dexmedetomidine and group N received Normal saline infusion over 20 minutes. Group D also received maintenance Dexmedetomidine intraoperatively. Bispectral index and minimum alveolar concentration monitoring was done in both the groups. Haemodynamic parameters were noted till 100 minutes post laryngoscopy. Opioid and anaesthetic agent consumptions were also noted and cost analysis was done. Medcalc–Version 12.5.0.0 software was used for statistics and p <0.05 was considered significant. Results Dexmedetomidine attenuated the stress induced haemodynamics responses and produced stable, relatively non fluctuating haemodynamics throughout. The Minimum Alveolar Concentration (MAC) requirement and the consumptions of Fentanyl and Isoflurane were significantly less in the Dexmedetomidine group (p<0.0001). However, despite anaesthetic dose sparing effect the anaesthetic technique was not cost-effective. Conclusion Dexmedetomidine is effective in attenuating haemodynamic responses in laparoscopic surgery and having dose sparing effect on Fentanyl, Propofol and Isoflurane. However, overall this technique is not cost-effective. PMID:28050479

75 FR 37300 - Correction of Code of Federal Regulations: Removal of Temporary Listing of Benzylfentanyl and...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-29

... scheduled fentanyl compounds at the University of Michigan Medical School in Ann Arbor and at the Medical College of Virginia in Richmond. The studies indicated that while most of the fentanyl compounds had abuse... samples with other fentanyl analogues and were most likely unreacted intermediates in the synthesis of the...

Effect of Fentanyl Nasal Packing Treatment on Patients With Acute Postoperative Pain After Nasal Operation: A Randomized Double-Blind Controlled Trial.

PubMed

Kim, Kwan-Sub; Yeo, Nam-Kyung; Kim, Seong-Su; Park, Woong-Sub; Kwak, Su-Hyun; Cho, Sang-Hyeon; Sung, Gyu-Wan; Kim, Hae-Sook; Yi, Sang-Wook; Cho, Hae Jun

2018-05-01

Nasal packing is an option for bleeding control after endoscopic sinus surgery and septoplasty. Although new packing materials have been developed, patients still suffer from pain and require additional analgesics treatments. In this study, a prospective, randomized, and double-blind controlled trial was designed to evaluate the effect of fentanyl-soaked packing on pain after endoscopic sinus surgery and septoplasty. One hundred fifty-two patients who underwent nasal surgeries due to chronic rhinosinusitis or nasal septal deviation were enrolled in this study. At the end of operation, 50 mcg fentanyl-soaked biodegradable synthetic polyurethane foams packing Nasopore or Merocel were applied to a group of 79 patients, and saline-soaked ones were applied to another group of 73 patients. To evaluate the influence of fentanyl on postoperative nasal pain, patients' conditions were assessed via means of Numeric Rating Scale, patient satisfaction, and Ramsay Sedation Scale. In addition, symptoms of headache or sore throat and any signs of cardiopulmonary-relevant indicators were monitored. The fentanyl group had significantly decreased Numeric Rating Scale and increased patient satisfaction in every operation type for the majority of postoperative time periods ( P < .05) with reduced postoperative headache and sore throat compared to the control group. The fentanyl group showed a higher score on Ramsay Sedation Scale than the control group ( P < .05 in group including endoscopic sinus surgery). There were no significant differences in cardiopulmonary-relevant indicators between the 2 groups ( P > .05). Fentanyl group showed significantly reduced postoperative pain without serious adverse effects. We suggest that topical fentanyl application to nasal packs can be a useful method to reduce pain during the early postoperative period after endoscopic sinus surgery and septoplasty.

Direct-injection mass spectrometric method for the rapid identification of fentanyl and norfentanyl in postmortem urine of six drug-overdose cases.

PubMed

Peer, Cody J; Shakleya, Diaa M; Younis, Islam R; Kraner, James C; Callery, Patrick S

2007-10-01

A rapid mass spectrometric method was developed for the identification of fentanyl and its major hepatic metabolite norfentanyl in postmortem urine of six drug-overdose victims involving fentanyl use. To reduce matrix effects or ion suppression, sample preparation consisted of centrifugation and solid-phase extraction. Deuterium-labeled internal standards ((2)H(5)-fentanyl and (2)H(5)-norfentanyl) were used to compensate for instrument variation in signal, analyte recovery during sample preparation, and ion suppression. Structural information for fentanyl and norfentanyl were collected using mass spectrometry (MS) with electrospray ionization (ESI) operated in the positive ion mode. Fentanyl (m/z 337) was found in each of the six overdose cases by the appearance of the MS-MS daughter ion on both an ion trap and a triple-quadrupole MS resulting from the fragmentation pathway of fentanyl (m/z 337 --> 188). Norfentanyl was detected in all six cases by the appearance of the MH(+) ion, m/z 233, with a single-quadrupole MS and confirmed in an ion trap MS. Ion suppression, as determined by the comparison of ion intensities from spiked samples in water with postmortem urine from the cases, ranged from 18% to 98% in three ESI sources. The use of stable isotope-labeled internal standards obviates sample preparation because ratios of analyte/internal standard remain constant in the presence of extensive matrix effects. This MS method provided sufficient sensitivity and selectivity for the rapid identification of fentanyl and norfentanyl in urine at levels >/= 10 ng/mL without prior analyte resolution by chromatography and with a total analysis time of less than 1 h.

Risk of fentanyl-involved overdose among those with past year incarceration: Findings from a recent outbreak in 2014 and 2015.

PubMed

Brinkley-Rubinstein, Lauren; Macmadu, Alexandria; Marshall, Brandon D L; Heise, Andrew; Ranapurwala, Shabbar I; Rich, Josiah D; Green, Traci C

2018-04-01

Overdose is the leading cause of unintentional injury-related death. Rhode Island (RI) has the highest rate of illicit drug use nationally and the 5th highest overdose mortality rate. RI has experienced an outbreak of fentanyl-related overdoses. In incarcerated populations, risk of overdose is greatly elevated. However, little is known about fentanyl-related overdose post-release. In the current analyses, we identify changes in fentanyl-related fatal overdose among those who died in 2014 and 2015 who were incarcerated in the year before death. We linked data from the RI Office of the Medical Examiner with records from the RI Department of Corrections. We calculated risk ratios and 95% confidence intervals using log-binomial regression to compare risk of fentanyl-involved overdose death. We also compared median time to death since release, median sentence length, and median number of incarcerations in 2014 and 2015. Results indicate that the risk of dying of a fentanyl-related overdose increased (RR: 1.99 (95% CI: 1.11-3.57, p = 0.014)) from 2014 to 2015 among those with past year incarceration. This study is one of the first to describe fentanyl-related fatal overdose among those with past year incarceration. In 2015 the median sentence was longer among those with a fentanyl-related overdose death and the median time from release to death among all who had past year incarceration extended past 90 days. Access to medications for addiction treatment, overdose education, and naloxone should be available during community re-entry and extended beyond the early post-release period. Copyright © 2018. Published by Elsevier B.V.

Pharmacokinetics and transplacental distribution of fentanyl in epidural anesthesia for normal pregnant women.

PubMed

Moisés, Elaine Christine Dantas; de Barros Duarte, Luciana; de Carvalho Cavalli, Ricardo; Lanchote, Vera Lúcia; Duarte, Geraldo; da Cunha, Sérgio Pereira

2005-08-01

Fentanyl is an opioid drug widely used as a co-adjuvant in abdominal delivery, a fact that justifies its pharmacokinetic study under these conditions. Our objective was to investigate the pharmacokinetics and placental transfer of fentanyl in parturients whose pregnancies were resolved by cesarian section with epidural anesthesia. Ten clinically normal parturients who delivered at term received 5 ml of 2% lidocaine hydrochloride without a vasoconstrictor for skin and subcutaneous blockade, followed by epidural injection of 2 ml fentanyl citrate (0.05 mg/ml), 15 ml 0.5% bupivacaine hydrochloride with 1:200,000 epinephrine, and 10 ml 2% lidocaine hydrochloride without a vasoconstrictor. Maternal blood samples were collected at various times after injection (1--840 min), and the fentanyl plasma concentrations were determined by gas chromatography-mass spectrometry. Pharmacokinetic analysis was performed using the bi- or tri-compartmental model. The fetal/maternal ratio of the plasma fentanyl was determined at birth. The values of the pharmacokinetic parameters were: t(1/2)alpha=13.5 min, t(1/2)beta=192.5 min, t(1/2)gamma=620 min, AUC(0-infinity)=137.404 ng.min per milliliter, C(l)/f=464.984 ml/min, V(d)/f=299.974 l, C(l)/f/kg=6.875 ml/min per kilogram, and V(d)/f/kg=4.441 l/kg. The latency between drug administration and birth was 28.5 min, with a maternal and fetal plasma concentration of 0.310 and 0.245 ng/ml, respectively, at a median fetal/maternal ratio of 0.892. The study demonstrated a rapid passage of fentanyl from the epidural space to maternal blood and a significant transplacental transfer of maternal fentanyl of about 90%, which should serve as an alert to obstetricians.

Effect of different surgical procedures on the accuracy of prediction of the plasma concentration of fentanyl: comparison between mastectomy and laparoscopic prostatectomy.

PubMed

Fujita, Yoshihito; Yoshizawa, Saya; Hoshika, Maiko; Inoue, Koichi; Matsushita, Shoko; Oka, Hisao; Sobue, Kazuya

2017-01-01

The accuracy of simulation-predicted fentanyl concentration in different types of surgical procedure is not fully understood. We wished to estimate the effect of different types of surgical procedure on the accuracy of such simulations. Fifty patients who had undergone elective mastectomy or laparoscopic prostatectomy (American Society of Anesthesiologists physical status = I-II) were enrolled. Anesthesia was maintained throughout surgery with sevoflurane and a bolus infusion of fentanyl. A maintenance infusion was administered with 8 mL/kg/h Ringer's acetate solution from the start of anesthesia to completion of blood sampling. An infusion to compensate for blood loss was administered (one to two volumes of hydroxyethyl starch). A blood sample was drawn every 30 min during anesthesia.We measured the plasma concentration of fentanyl in 358 samples from 50 patients. The plasma concentration of fentanyl was correlated significantly with the simulated predicted fentanyl concentration ( r  = 0.734, P  < 0.01) but 36.0% of all samples had a difference greater than ±0.5 ng/mL. Approximately 0.3 ng/mL of a fixed bias was shown throughout mastectomy. During laparoscopic prostatectomy, the fixed bias gradually became negative from ≈0.3 to -0.3 ng/mL as the sampling stage proceeded. The predicted concentration of fentanyl was significantly correlated with the plasma concentration of fentanyl ( r  = 0.734). However, there were different patterns of a fixed bias between mastectomy and laparoscopic prostatectomy groups. We should pay attention to this tendency among different surgical procedures. UMIN000005110.

Pharmacokinetics, safety, and tolerability of rotigotine transdermal system in healthy Japanese and Caucasian subjects following multiple-dose administration.

PubMed

Cawello, Willi; Kim, Seong Ryul; Braun, Marina; Elshoff, Jan-Peer; Masahiro, Takeuchi; Ikeda, Junji; Funaki, Tomoo

2016-08-01

Rotigotine is a dopamine receptor agonist indicated for the treatment of Parkinson's disease and moderate-to-severe restless legs syndrome. Continuous transdermal delivery of rotigotine via a silicon-based patch maintains stable plasma concentrations over 24 h. The objective of the study was to evaluate the pharmacokinetics, safety, and tolerability of a multiple-dose schedule of rotigotine transdermal patch in Japanese and Caucasian subjects. In this open-label, repeated-dose, parallel-group study (ClinicalTrials.gov: NCT01854216), healthy male and female subjects of Japanese or Caucasian ethnic origin were matched by gender, body mass index, and age. Subjects underwent a 9-day patch application period. 12 Japanese and 12 Caucasian subjects were included in the pharmacokinetic analyses. Mean apparent doses (actual amount of drug delivered) increased proportionally with rotigotine nominal dosages (1, 2, and 4 mg/24 h) and were similar for both ethnic groups, with large inter-individual variability. Mean plasma concentration-time profiles for unconjugated rotigotine were similar in both ethnic groups at day 3 for each dosage. Peak concentrations (C max,ss) and area under the concentration-time curves from pre-dose to the concentration measured 24 h after administration of patch (AUC(0-24,ss)) showed similar exposure in both groups; higher values in Japanese subjects were explained by differences in body weight. For total rotigotine, C max,ss and AUC(0-24,ss) values were higher in Caucasian subjects and could be explained by small differences in apparent dose. Rotigotine was generally well tolerated following multiple applications up to 4 mg/24 h. These findings suggest similar dosage requirements for rotigotine transdermal system in Japanese and Caucasian populations.

Pharmacokinetic properties and tolerability of rotigotine transdermal patch after repeated-dose application in healthy korean volunteers.

PubMed

Kim, Bo-Hyung; Yu, Kyung-Sang; Jang, In-Jin; Soo Lim, Kyoung; Kim, Jung-Ryul; Elshoff, Jan-Peer; Andreas, Jens-Otto; Braun, Marina; Cawello, Willi

2015-04-01

Rotigotine, a nonergolinic dopamine receptor agonist, is a once-daily transdermal patch developed for the treatment of Parkinson's disease and restless legs syndrome. The objective of the present study was to determine the pharmacokinetic characteristics and tolerability of rotigotine transdermal patch after repeated-dose application in healthy male and female Korean subjects. In this randomized, double-blind, placebo-controlled, repeated-dose study, subjects were randomly assigned to receive either rotigotine or placebo (ratio, 20 rotigotine to 4 placebo, per sex). Rotigotine patches were applied once daily at a dose of 2 mg/24 h on days 1 to 3, followed by 4 mg/24 h on days 4 to 6. Serial blood and urine samples were collected on days 1 to 9 for the determination of the concentrations of rotigotine and its metabolites. Tolerability was evaluated by adverse events determined using physical examination, including vital signs with orthostatic measurements; ECG; and clinical laboratory testing. A total of 48 healthy Korean subjects were enrolled (24 men, 24 women; mean age, 24 years). Approximately 50% of the total drug content was delivered within 24 hours. The mean plasma concentration of unconjugated rotigotine increased proportionally with dose. At the 2 mg/24 h dose at steady state, the geometric mean AUC0-24h and Cmax values of unconjugated rotigotine were 5.88 ng·h/mL and 0.347 ng/mL, respectively; at the 4 mg/24 h dose, the corresponding values were 13.74 ng·h/mL and 0.838 ng/mL. The mean t½ of rotigotine was 4.96 hours. At the 2 mg/24 h dose at steady state, the geometric mean AUC0-24h and Cmax values of total rotigotine were 14.02 ng·h/mL and 0.776 ng/mL; at the 4-mg/24 h dose, 32.38 ng·h/mL and 1.867 ng/mL. Common adverse events reported in the rotigotine-treated subjects included nausea (17 subjects, 42.5%), headache (11, 27.5%), and dizziness (9, 22.5%). No clinically significant changes in blood pressure, ECG, or laboratory values were observed. The mean plasma exposures of unconjugated rotigotine increased proportionally with dose. Repeated daily application of the rotigotine patch was well tolerated in these healthy Korean volunteers. ClinicalTrials.gov identifier: NCT01964573. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Hydroxyisohexyl 3-cyclohexene carboxaldehyde- known as Lyral: quantitative aspects and risk assessment of an important fragrance allergen.

PubMed

Johansen, J D; Frosch, P J; Svedman, C; Andersen, K E; Bruze, M; Pirker, C; Menné, T

2003-06-01

Hydroxyisohexyl 3-cyclohexene carboxaldehyde, also known as Lyral, is a fragrance ingredient identified as the cause of contact allergic reactions in 2-3% of eczema patients undergoing patch testing. Lyral has been included in the standard patch test series in many clinics due to its importance as an allergen. It has been used without restrictions in cosmetic products, until now. In the present study, the dose-response relationship of Lyral contact allergy was studied with doses relevant for normal exposure in cosmetic products. 18 eczema patients, who previously had given a positive patch test to Lyral 5% petrolatum, were included along with 7 control subjects. All cases were tested with a serial dilution of Lyral in ethanol 6% to 6 p.p.m and subjected to a 2-week, repeated open application test with a low dose of Lyral in ethanol. In the case of no reaction, this was followed by another 2 weeks of testing with a higher dose. The test was performed at the volar aspect of the forearm. In 16 of 18 cases (89%), a positive use test developed, 11 reacting to the low and 5 to the high concentration. None reacted to the vehicle control of ethanol applied to the contralateral arm. All controls were negative to both the test solutions of Lyral and the ethanol control. The difference between the test and the control group was statistically significant (Fisher's test, P < 0.001). It is concluded that Lyral at the current usage levels is inducing sensitization in the community. The same levels were shown to elicit allergic contact dermatitis in almost all sensitized individuals. A significant reduction in usage concentrations is recommended to prevent contact allergic reactions.

Cost-effectiveness analysis of oral fentanyl formulations for breakthrough cancer pain treatment

PubMed Central

Cortesi, Paolo Angelo; D’Angiolella, Lucia Sara; Vellucci, Renato; Allegri, Massimo; Casale, Giuseppe; Favaretti, Carlo; Kheiraoui, Flavia; Cesana, Giancarlo; Mantovani, Lorenzo Giovanni

2017-01-01

Breakthrough cancer Pain (BTcP) has a high prevalence in cancer population. Patients with BTcP reported relevant health care costs and poor quality of life. The study assessed the cost-effectiveness of the available Oral Fentanyl Formulations (OFFs) for BTcP in Italy. A decision-analytical model was developed to estimate costs and benefits associated with treatments, from the Italian NHS perspective. Expected reductions in pain intensity per BTcP episodes were translated into, percentage of BTcP reduction, resource use and Quality-Adjusted-Life-Years (QALYs). Relative efficacy, resources used and unit costs data were derived from the literature and validated by clinical experts. Probabilistic and deterministic sensitivity analyses were performed. At base-case analysis, Sublingual Fentanyl Citrate (FCSL) compared to other oral formulations reported a lower patient’s cost (€1,960.8) and a higher efficacy (18.7% of BTcP avoided and 0.0507 QALYs gained). The sensitivity analyses confirmed the main results in all tested scenarios, with the highest impact reported by BTcP duration and health care resources consumption parameters. Between OFFs, FCSL is the cost-effective option due to faster reduction of pain intensity. However, new research is needed to better understand the economic and epidemiologic impact of BTcP, and to collect more robust data on economic and quality of life impact of the different fentanyl formulations. Different fentanyl formulations are available to manage BTcP in cancer population. The study is the first that assesses the different impact in terms of cost and effectiveness of OFFs, providing new information to better allocate the resources available to treat BTcP and highlighting the need of better data. PMID:28654672

Mid-latency auditory evoked potentials and circulatory response to loud sounds.

PubMed

Schwender, D; Haessler, R; Klasing, S; Madler, C; Pöppel, E; Peter, K

1994-03-01

We investigated in 60 patients scheduled for elective aorto-coronary bypass grafting if loud sounds by themselves can induce cardiovascular responses and if these could be related to mid-latency auditory evoked potentials (MLAEP). Anaesthesia was induced in group I (n = 20) with flunitrazepam-fentanyl 0.01 mg kg-1 and maintained with flunitrazepam-fentanyl 1.2 mg h-1. Patients in groups II (n = 20) and III (n = 20) received etomidate 0.25 mg kg-1 and fentanyl 0.005 mg kg-1 for induction and 0.6-1.2 vol% isoflurane and fentanyl 1.2 mg h-1, or propofol 4-8 mg kg-1 h-1 and fentanyl 1.2 mg h-1 for maintenance of general anaesthesia. After preparation of the sternum the operation was stopped for several minutes. Then, as a loud auditory stimulus, the sound of the running sternotomy saw was presented to the patients by putting the saw inverted on the sternum for several seconds. Heart rate (HR), arterial pressure (SAP), pulmonary capillary wedge pressure (PCWP), cardiac index, systemic vascular resistance and MLAEP were measured in the awake state, before and after presentation of the sound. Latencies of the peak V, Na, Pa, Nb and P1 were measured. In group I there were statistically significant increases in HR (63.5-70.2 beat min-1), SAP (123.9-146-5 mm Hg) and PCWP (9.2-11.7 mm Hg) after presentation of the sound. These haemodynamic changes were not observed in patients in groups II and III. In the awake state, AEP had high peak -to-peak amplitudes and a periodic waveform.(ABSTRACT TRUNCATED AT 250 WORDS)

Convolutional auto-encoder for image denoising of ultra-low-dose CT.

PubMed

Nishio, Mizuho; Nagashima, Chihiro; Hirabayashi, Saori; Ohnishi, Akinori; Sasaki, Kaori; Sagawa, Tomoyuki; Hamada, Masayuki; Yamashita, Tatsuo

2017-08-01

The purpose of this study was to validate a patch-based image denoising method for ultra-low-dose CT images. Neural network with convolutional auto-encoder and pairs of standard-dose CT and ultra-low-dose CT image patches were used for image denoising. The performance of the proposed method was measured by using a chest phantom. Standard-dose and ultra-low-dose CT images of the chest phantom were acquired. The tube currents for standard-dose and ultra-low-dose CT were 300 and 10 mA, respectively. Ultra-low-dose CT images were denoised with our proposed method using neural network, large-scale nonlocal mean, and block-matching and 3D filtering. Five radiologists and three technologists assessed the denoised ultra-low-dose CT images visually and recorded their subjective impressions of streak artifacts, noise other than streak artifacts, visualization of pulmonary vessels, and overall image quality. For the streak artifacts, noise other than streak artifacts, and visualization of pulmonary vessels, the results of our proposed method were statistically better than those of block-matching and 3D filtering (p-values < 0.05). On the other hand, the difference in the overall image quality between our proposed method and block-matching and 3D filtering was not statistically significant (p-value = 0.07272). The p-values obtained between our proposed method and large-scale nonlocal mean were all less than 0.05. Neural network with convolutional auto-encoder could be trained using pairs of standard-dose and ultra-low-dose CT image patches. According to the visual assessment by radiologists and technologists, the performance of our proposed method was superior to that of large-scale nonlocal mean and block-matching and 3D filtering.

A Review on Pharmacokinetic Modeling and the Effects of Environmental Stressors on Pharmacokinetics for Operational Medicine: Operational Pharmacokinetics

DTIC Science & Technology

2009-09-01

hypercholesterolemia Two-compartment model Ezzet, Krishna et al. 2001 Antilipemics Statins: simvastatin, rosuvastatin, atorvastatin Treatment of...Pharmacokinetic model* & rosuvastatin Scopus 14 3 PubMed 9 3 Pharmacokinetic model* & atorvastatin Scopus 49 4 Pharmacokinetic model* & zaleplon...Fentanyl & pharmacokinetic & heat 9 2 Fentanyl & pharmacokinetic & cold 4 0 Fentanyl & pharmacokinetic & blood loss 19 5 Atorvastatin

Fentanyl reduces desflurane-induced airway irritability following thiopental administration in children.

PubMed

Lee, J; Oh, Y; Kim, C; Kim, S; Park, H; Kim, H

2006-10-01

Airway irritation is a major drawback of desflurane anesthesia. This study was designed to evaluate the effect of intravenous fentanyl given before thiopental induction on airway irritation caused by a stepwise increase in desflurane in children. Eighty children (2-8 years) were enrolled in a randomized, double-blind study. Forty received saline and 40 received 2 microg/kg of fentanyl intravenously; this was followed by thiopental sodium 5 mg/kg in both groups. Patients were assistant-ventilated with desflurane 1%, which was then increased by 1% every six breaths up to 10%. During this period, cough, secretion, excitation and apnea were graded and the desflurane concentration at which airway irritation symptoms first occurred was recorded. The results were analyzed using Pearson's chi-squared test. The incidence of typical airway irritation events was lower with fentanyl than with saline (cough, 2.5% vs. 42.5%; secretion, 27.5% vs. 82.5%; excitation, 10% vs. 82.5%; apnea, 20% vs. 65%; P < 0.05). The mean expired desflurane concentration at which the first airway irritation symptom occurred was greater with fentanyl than with saline (7.3% vs. 5.5%, P < 0.05). Intravenous fentanyl in children reduces airway complications caused by desflurane.

Fentanyl Buccal Tablet for the Treatment of Breakthrough Pain: Pharmacokinetics of Buccal Mucosa Delivery and Clinical Efficacy

PubMed Central

Darwish, Mona; Hamed, Ehab; Messina, John

2010-01-01

The treatment of breakthrough pain (BTP), a transitory exacerbation of pain that occurs on a background of otherwise-controlled, persistent pain, requires an opioid formulation and/or method of administration that can provide rapid and extensive systemic exposure. Fentanyl buccal tablet (FBT; FENTORA®, Cephalon, Inc.) employs OraVescent® drug delivery technology, which enhances the rate and extent of fentanyl absorption. OraVescent technology enhances the oral dissolution and buccal absorption of fentanyl, which facilitates rapid uptake of fentanyl into the bloodstream, reducing gastrointestinal absorption and minimizing extensive first-pass metabolism. The resulting pharmacokinetic profile of FBT is characterized by greater bioavailability and a higher early systemic exposure compared with the earlier oral transmucosal fentanyl citrate formulation. In clinical studies of opioid-tolerant patients with cancer-related and noncancer-related BTP, FBT has provided consistent and clinically relevant improvements in pain intensity and pain relief relative to placebo, with a safety and tolerability profile that is generally typical of that observed with other potent opioids. The pharmacokinetic properties of FBT allow for meaningful clinical efficacy, with an onset of action that closely matches the onset of BTP. PMID:20634985

THERMAL SENSITIVITY ACROSS AGES AND DURING CHRONIC FENTANYL ADMINISTRATION IN RATS

PubMed Central

Mitzelfelt, Jeremiah D.; Carter, Christy S.; Morgan, Drake

2013-01-01

Rationale Chronic pain is becoming a more common medical diagnosis and is especially prevalent in older individuals. As such, prescribed use of opioids is on the rise, even though the efficacy for pain management in older individuals is unclear. Objectives Thus the present preclinical study assessed the effectiveness of chronic fentanyl administration to produce antinociception in aging rats (16, 20, 24 months). Methods Animals were tested in a thermal sensitivity procedure known to involve neural circuits implicated in chronic pain in humans. Sensitivity to heat and cold thermal stimulation was assessed during 28 days of fentanyl administration (1.0 mg/kg/day), and 28 days of withdrawal. Results Fentanyl resulted in decreased thermal sensitivity to heat but not cold stimulation indicated by more time spent in the hot compartment relative to time spent in the cold or neutral compartments. Unlike previous findings using a hot-water tail withdrawal procedure, tolerance did not develop to the antinociceptive effects of fentanyl over a 28-day period of drug administration. The oldest animals were least sensitive, and the youngest animals most sensitive to the locomotor-stimulating effects of fentanyl. The effect on the antinociceptive response to fentanyl in the oldest group of rats was difficult to interpret due to profound changes in the behavior of saline-treated animals. Conclusions Overall, aging modifies the behavioral effects of opioids, a finding that may inform future studies for devising appropriate treatment strategies. PMID:23900640

Effect of preoperative incentive spirometry on fentanyl-induced cough: a prospective, randomized, controlled study.

PubMed

Goyal, Vipin Kumar; Bhargava, Suresh Kumar; Baj, Birbal

2017-10-01

Fentanyl-induced cough (FIC) has a reported incidence of 13-65% on induction of anesthesia. Incentive spirometry (IS) creates forceful inspiration, while stretching pulmonary receptors. We postulated that spirometry just before the fentanyl (F) bolus would decrease the incidence and severity of FIC. This study enrolled 200 patients aged 18-60 years and with American Society of Anesthesiologists status I or II. The patients were allocated to two groups of 100 patients each depending on whether they received preoperative incentive spirometry before fentanyl administration. Patients in the F+IS group performed incentive spirometry 10 times just before an intravenous bolus of 3 µg/kg fentanyl in the operating room. The onset time and number of coughs after fentanyl injection were recorded as primary outcomes. Any significant changes in blood pressure, heart rate, or adverse effects of the drug were recorded as secondary outcomes. Patients in the F+IS group had a significantly lower incidence of FIC than in the F group (6% vs. 26%) (P < 0.05). The severity of cough in the F+IS group was also significantly lower than that in group F (mild, 5 vs. 17; moderate 1 vs. 7; severe, 0 vs. 2) (P < 0.05). The median onset time was comparable in both groups (9 s [range: 6-12 s] in both groups). Preoperative incentive spirometry significantly reduces the incidence and severity of FIC when performed just before fentanyl administration.

Effect of preoperative incentive spirometry on fentanyl-induced cough: a prospective, randomized, controlled study

PubMed Central

Bhargava, Suresh Kumar; Baj, Birbal

2017-01-01

Background Fentanyl-induced cough (FIC) has a reported incidence of 13–65% on induction of anesthesia. Incentive spirometry (IS) creates forceful inspiration, while stretching pulmonary receptors. We postulated that spirometry just before the fentanyl (F) bolus would decrease the incidence and severity of FIC. Methods This study enrolled 200 patients aged 18–60 years and with American Society of Anesthesiologists status I or II. The patients were allocated to two groups of 100 patients each depending on whether they received preoperative incentive spirometry before fentanyl administration. Patients in the F+IS group performed incentive spirometry 10 times just before an intravenous bolus of 3 µg/kg fentanyl in the operating room. The onset time and number of coughs after fentanyl injection were recorded as primary outcomes. Any significant changes in blood pressure, heart rate, or adverse effects of the drug were recorded as secondary outcomes. Results Patients in the F+IS group had a significantly lower incidence of FIC than in the F group (6% vs. 26%) (P < 0.05). The severity of cough in the F+IS group was also significantly lower than that in group F (mild, 5 vs. 17; moderate 1 vs. 7; severe, 0 vs. 2) (P < 0.05). The median onset time was comparable in both groups (9 s [range: 6–12 s] in both groups). Conclusions Preoperative incentive spirometry significantly reduces the incidence and severity of FIC when performed just before fentanyl administration. PMID:29046775

Administration order of midazolam/fentanyl for moderate dental sedation.

PubMed

Lobb, Douglas; Clarke, Alix; Lai, Hollis

2018-02-01

The purpose of this study is to investigate the effects of administration order when a sedative drug (midazolam) and an opioid analgesic drug (fentanyl) is applied for moderate intravenous (IV) sedation in dentistry. A retrospective chart review was conducted in one dental clinic during its transition from a midazolam-first to a fentanyl-first protocol for dental procedures requiring moderate IV sedation. Physiological parameters, drug administration times, patient recovery times, drug dosages, and patient recall and satisfaction were investigated for differences. A total of 76 charts (40 midazolam-first and 36 fentanyl-first administrations), were used in the analysis. Administering midazolam first resulted in an average 4.38 min (52%) decrease in administration times (P < 0.001), and a decrease in procedural recollection immediately following the procedure (P = 0.03), and 24 to 48 hours later (P = 0.009). Administering fentanyl first required an average of 2.43 mg (29%) less midazolam (P < 0.001). No significant differences were found for change in vital signs, minimum oxygen saturation levels, recovery times, and patient satisfaction (P > 0.05). Oxygen saturation levels did not drop below 90% for either group; however, 5 cases in the fentanyl-first group fell to between 90% and 92%, compared with 0 cases in the midazolam-first group. The administration order of fentanyl and midazolam may have different effects on patients and the sedation procedure. Findings from this study should be used to facilitate discussion among dental practitioners and to guide additional research investigating this topic.

[Competitive study of the effects of naloxone and of almitrine on fentanyl analgesia in the anesthetized dog: effects on the muzzle opening reflex and blood gases].

PubMed

Dauthier, C; Gaudy, J H; Willer, J C

1980-01-01

The search for a technique making it possible to dissociate the analgesia and ventilatory depression of central analgesics led to a comparison of the effects of naloxone, a specific morphinomimetic antagonist, with almitrine, a ventilatory stimulant with a peripheral action, on muzzle opening reflex and blood gases. Five male dogs (Beagles, aged one year), anaesthetised with Alfetesine were treated separately with the two drugs used alone and after fentanyl analgesia (injection of fractionnated doses up to the threshold of apnoea). The association of the two drugs was also tested in tyhe dog after analgesia. The parameters studied were muzzle opening reflex, as an indication of analgesia, and blood gases, and were observed for 45 minutes, including 15 minutes control. 1 - The intravenous injection of 1,2 mg of naloxone had the effect of increasing the surface area of muscle potentials with a maximum of 7 per cent (p 0.001) at the 15 th minute. By contrast, no significant change in blood gases was seen. In the same dogs given fentanyl analgesia, naloxone not only reversed respiratory depression but had a stimulatory effect on MOR reaching 7 per cent (p 0.001) at the 30 th minute. 2 - The effects of 1 mg.kg-1 of almitrine were characterised by a fall in MOR for a period equal to that of the study and a minimum of 7.8 per cent (p 0.001) at the 20 th minute. At the same time, marked ventilatory stimulation was seen. PO2 rose by 22.7 per cent (p 0.02) at the 5 th minute. PCO2 fell during the 30 minutes studied with a minimum of 39.6 per cent (p 0.01) at the 20 th minute. Almitrine did not antagonise the depression of MOR caused by fentanyl but reversed the respiratory depression of the analgesic, increasing PO2 by 26 per cent (p 0.01) and decreasing PCO2 by 25.7 per cent (p 0.01). 3 - The combination of both drugs cancelled out the abolition of the reflex by fentanyl then facilitated it up to 24.7 per cent (p 0.001) in comparison with the animal not receiving any analgesic. By contrast, the ventilatory action of almitrine was not potentialised by naloxone. In view of these data, and in the absence of any emergency, the choice of naloxone as an antagonist of ventilatory depression of central analgesics should not be preferential in order to avoid the rebound effect.

The safety and effectiveness of a long-acting transdermal fentanyl solution compared with oxymorphone for the control of postoperative pain in dogs: a randomized, multicentered clinical study

PubMed Central

Martinez, S A; Wilson, M G; Linton, D D; Newbound, G C; Freise, K J; Lin, T-L; Clark, T P

2014-01-01

A prospective, double-blinded, positive-controlled, multicenter, noninferiority study was conducted to evaluate the safety and effectiveness of transdermal fentanyl solution (TFS) compared with oxymorphone for the control of postoperative pain in dogs. Five hundred and two (502) client-owned dogs were assigned to a single dose of TFS (2.7 mg/kg) applied 2–4 h prior to surgery or oxymorphone hydrochloride (0.22 mg/kg) administered subcutaneously 2–4 h prior to surgery and q6h through 90 h. Pain was evaluated over 4 days by blinded observers using a modified Glasgow composite pain scale, and the a priori criteria for treatment failure was a pain score ≥8 or adverse event necessitating withdrawal. Four TFS- and eight oxymorphone-treated dogs were withdrawn due to lack of pain control. Eighteen oxymorphone-treated, but no TFS-treated dogs were withdrawn due to severe adverse events. The one-sided upper 95% confidence interval of the difference between TFS and oxymorphone treatment failure rates was −5.3%. Adverse events associated with oxymorphone were greater in number and severity compared with TFS. It was concluded that a single administration of TFS was safe and noninferior to repeated injections of oxymorphone for the control of postoperative pain over 4 days at the dose rates of both formulations used in this study. PMID:24344787

Development and validation of a highly sensitive gas chromatographic-mass spectrometric screening method for the simultaneous determination of nanogram levels of fentanyl, sufentanil and alfentanil in air and surface contamination wipes.

PubMed

Van Nimmen, Nadine F J; Veulemans, Hendrik A F

2004-05-07

A highly sensitive gas chromatographic-mass spectrometric (GC-MS) analytical method for the determination of the opioid narcotics fentanyl, alfentanil, and sufentanil in industrial hygiene personal air samples and surface contamination wipes was developed and comprehensively validated. Sample preparation involved a single step extraction of the samples with methanol, fortified with a fixed amount of the penta-deuterated analogues of the opioid narcotics as internal standard. The GC-MS analytical procedure using selected ion monitoring (SIM) was shown to be highly selective. Linearity was shown for levels of extracted wipe and air samples corresponding to at least 0.1-2 times their surface contamination limit (SCL) and accordingly to 0.1-2 times their time weighted average occupational exposure limit (OEL-TWA) based on a full shift 9601 air sample. Extraction recoveries were determined for spiked air samples and surface wipes and were found to be quantitative for both sampling media in the entire range studied. The air sampling method's limit of detection (LOD) was determined to be 0.4 ng per sample for fentanyl and sufentanil and 1.6 ng per sample for alfentanil, corresponding to less than 1% of their individual OEL for a full shift air sample (9601). The limit of quantification (LOQ) was found to be 1.4, 1.2, and 5.0 ng per filter for fentanyl, sufentanil, and alfentanil, respectively. The wipe sampling method had LODs of 4 ng per wipe for fentanyl and sufentanil and 16 ng per wipe for alfentanil and LOQs of respectively, 14, 12, and 50 ng per wipe. The analytical intra-assay precision of the air sampling and wipe sampling method, defined as the coefficient of variation on the analytical result of six replicate spiked media was below 10 and 5%, respectively, for all opioids at all spike levels. Accuracy expressed as relative error was determined to be below 10%, except for alfentanil at the lowest spike level (-13.1%). The stability of the opioids during simulated air sampling was investigated. For fentanyl and sufentanil a quantitative recovery was observed at all spike levels, while for alfentanil recoveries ranged from 60.3 to 85.4%. When spiked air samples were stored at ambient temperature and at -15 degrees C quantitative recovery was found for fentanyl and sufentanil after 7 and 14 days. For alfentanil a slight loss seemed to occur upon storage during 7 days, being more explicit after 14 days. Ambient storage of spiked wipes seemed to lead to significant losses of all opioids studied, yielding recoveries of 37.7-88.3%. Upon storage of similar wipes at -15 degrees C a significantly higher recovery was found ranging from 77.3 to 88.3%. The developed analytical and sampling procedures have been recently applied in an explorative field study of which the results of surface contamination wipe sampling are presented in this paper. To our knowledge, this is the first study addressing the development and validation of analytical procedures for the assessment of external occupational exposure to potent opioid narcotics.

Reversal of overdose on fentanyl being illicitly sold as heroin with naloxone nasal spray: A case report.

PubMed

Fareed, Ayman; Buchanan-Cummings, Ann Marie; Crampton, Kelli; Grant, Angela; Drexler, Karen

2015-08-01

This is a case report describing a reversal of fentanyl overdose with naloxone nasal spray. The patient was not aware that he overdosed on fentanyl being sold as heroin. The Veterans Health Administration (VHA) has implemented an initiative to provide education for veterans, their families, friends and significant others about opioid overdose and use of naloxone reversal kits. The Atlanta VA Medical Center adopted this program to reduce the risk of opioid overdose in high risk patients. Over the past year, we provided educational sessions for 63 veterans and their families. We also prescribed 41 naloxone kits. We have received three reports of opioid overdose reversal with use of naloxone kits prescribed by the Atlanta VA Medical Center. The authors recommend that public health administrators and policy makers advocate for the implementation of these programs to reduce the rising number of overdose death in the United States and worldwide. © American Academy of Addiction Psychiatry.

Comparing the Effect of Adding Fentanyl, Sufentanil, and Placebo with Intrathecal Bupivacaine on Duration of Analgesia and Complications of Spinal Anesthesia in Patients Undergoing Cesarean Section

PubMed Central

Farzi, Farnoush; Mirmansouri, Ali; Naderi Nabi, Bahram; Atrkar Roushan, Zahra; Ghazanfar Tehran, Samaneh; Nematollahi Sani, Mona; Makhlooghi Azad, Soodabe; Nemati, Maryam

2017-01-01

Background Spinal anesthesia is the method of choice for most elective and emergency Cesarean sections. To increase the duration of anesthesia and improve the quality of analgesia during and after surgery, intrathecal opioids, as adjuvant drugs, are used in combination with local anesthetics. Methods This was a double-blind clinical trial performed on 99 patients. Women were divided into 3 groups of fentanyl, sufentanil, and placebo. For fentanyl group, 12.5 mg of bupivacaine and 25 micrograms of fentanyl; for sufentanil group, 12.5 mg of bupivacaine and 2.5 micrograms of sufentanil; and for placebo group, 12.5 mg of bupivacaine and a half mL of normal saline were injected in subarachnoid space. The sensory and motor block, hemodynamic status (mean blood pressure and heart rate), and probable complications were assessed. Results There was no significant difference between the groups in demographic characteristics. Durations of analgesia were, respectively, 314 ± 42.95, 312.5 ± 34.44, and 116.1 ± 42.24 minutes in the fentanyl, sufentanil, and placebo groups (P = 0.0001). Duration of sensory and motor block was higher in fentanyl and sufentanil groups compared with the placebo group. The highest duration of sensory and motor block was noted in sufentanil group (P = 0.0001). No significant difference was found between the groups in the hemodynamic parameters (P > 0.05). The frequency of itching in the fentanyl group was higher than sufentanil and placebo groups (P = 0.003). Also, shivering was higher in the placebo group compared with other groups (P = 0.036). Conclusions According to the results, adding 25 microgram fentanyl or 2.5 microgram sufentanil to intrathecal bupivacaine increased the duration of analgesia and provided hemodynamic stability with no major complication. As administering intrathecal fentanyl had a similar duration of analgesia like sufentanil with faster return of motor block and ambulation, it seems that it is a preferred additive for Cesarean section surgery. PMID:29696107

Thermography as an early predictive measurement for evaluating epidural and femoral-sciatic block success in dogs.

PubMed

Küls, Nina; Blissitt, Karen J; Shaw, Darren J; Schöffmann, Gudrun; Clutton, Richard E

2017-09-01

To evaluate skin temperature increase as an early predictive measure for evaluating epidural and femoral-sciatic block success in dogs. Prospective clinical trial. A total of 29 dogs undergoing orthopaedic surgery on one hindlimb. Dogs were anaesthetized and placed into lateral recumbency with the affected limb uppermost and the coat was clipped. Baseline infrared thermographic images (T0) of the affected limb, of the paw pad of the affected leg and of the ipsilateral paw pad were taken. Subsequently, dogs were administered either an epidural (EPI; n=11) or a femoral-sciatic block (FS; n=18) using bupivacaine 1 mg kg -1 . Then, 2 minutes after placement of the block, thermographic images were obtained every 3 minutes for a total of four measurements (T1-T4) and surgery was commenced. Rescue analgesia consisting of fentanyl 1 μg kg -1 was administered if needed. A regional block was considered successful if the dose of fentanyl administered was less than the lower 95% confidence interval of the geometric mean of the total fentanyl used in each group. A ≥ 1 °C increase of skin temperature was considered as the minimum increase required for detection of a successful block. A total of 12 out of 18 blocks in the FS and eight of 11 in the EPI group were considered successful based on fentanyl consumption. Out of these, only four of 12 in the FS and one of eight in the EPI group developed an increase in temperature of ≥ 1 °C. Contrarily, four of six of the nonsuccessful cases in the FS and three of three in the EPI group developed an increase in temperature of ≥ 1 °C. Contrary to reports in humans, thermography did not indicate regional block success prior to surgery in dogs. However further studies under more controlled conditions are needed to determine whether thermography can be used to indicate failure of regional blockade. Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.

Transdermal patches: history, development and pharmacology

PubMed Central

Pastore, Michael N; Kalia, Yogeshvar N; Horstmann, Michael; Roberts, Michael S

2015-01-01

Transdermal patches are now widely used as cosmetic, topical and transdermal delivery systems. These patches represent a key outcome from the growth in skin science, technology and expertise developed through trial and error, clinical observation and evidence-based studies that date back to the first existing human records. This review begins with the earliest topical therapies and traces topical delivery to the present-day transdermal patches, describing along the way the initial trials, devices and drug delivery systems that underpin current transdermal patches and their actives. This is followed by consideration of the evolution in the various patch designs and their limitations as well as requirements for actives to be used for transdermal delivery. The properties of and issues associated with the use of currently marketed products, such as variability, safety and regulatory aspects, are then described. The review concludes by examining future prospects for transdermal patches and drug delivery systems, such as the combination of active delivery systems with patches, minimally invasive microneedle patches and cutaneous solutions, including metered-dose systems. PMID:25560046

A novel tri-layered buccal mucoadhesive patch for drug delivery: assessment of nicotine delivery.

PubMed

Rao, Shasha; Song, Yunmei; Peddie, Frank; Evans, Allan M

2011-06-01

The aim of this study was to assess the potential of a novel delivery device for administering drugs that suffer from a high degree of first-pass metabolism. A tri-layered buccal mucoadhesive patch, comprising a medicated dry tablet adhered to a mucoadhesive film, was prepared and characterized by its physicochemical properties and mucoadhesive strength. Nicotine was used as a model drug for the characterization of drug release and drug permeation. The influence of different adsorbents on the release of nicotine base from the patches was evaluated in vitro. Different molecular forms of nicotine (base and complex salt) were evaluated for their effect on release performance and permeation in vitro. Results demonstrated acceptable physicochemical and mucoadhesive properties for the tri-layered patch. Rapid release of nicotine was observed when nicotine base was incorporated with calcium sulfate dihydrate as the adsorbent. Patches incorporating nicotine base showed distinct advantages over those containing nicotine polacrilex, in terms of drug release (complete drug release achieved at 30 vs 60 min) and transmucosal permeation (37.28 ± 4.25 vs 2.87 ± 0.26% of the dose permeating through mucosa within 120 min). The novel tri-layered patch can effectively adhere to, and deliver an active ingredient through the buccal mucosa, confirming its potential for buccal mucoadhesive drug delivery. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

Opioid doses required for pain management in lung cancer patients with different cholesterol levels: negative correlation between opioid doses and cholesterol levels.

PubMed

Huang, Zhenhua; Liang, Lining; Li, Lingyu; Xu, Miao; Li, Xiang; Sun, Hao; He, Songwei; Lin, Lilong; Zhang, Yixin; Song, Yancheng; Yang, Man; Luo, Yuling; Loh, Horace H; Law, Ping-Yee; Zheng, Dayong; Zheng, Hui

2016-03-08

Pain management has been considered as significant contributor to broad quality-of-life improvement for cancer patients. Modulating serum cholesterol levels affects analgesia abilities of opioids, important pain killer for cancer patients, in mice system. Thus the correlation between opioids usages and cholesterol levels were investigated in human patients with lung cancer. Medical records of 282 patients were selected with following criteria, 1) signed inform consent, 2) full medical records on total serum cholesterol levels and opioid administration, 3) opioid-naïve, 4) not received/receiving cancer-related or cholesterol lowering treatment, 5) pain level at level 5-8. The patients were divided into different groups basing on their gender and cholesterol levels. Since different opioids, morphine, oxycodone, and fentanyl, were all administrated at fixed low dose initially and increased gradually only if pain was not controlled, the percentages of patients in each group who did not respond to the initial doses of opioids and required higher doses for pain management were determined and compared. Patients with relative low cholesterol levels have larger percentage (11 out of 28 in female and 31 out of 71 in male) to not respond to the initial dose of opioids than those with high cholesterol levels (0 out of 258 in female and 8 out of 74 in male). Similar differences were obtained when patients with different opioids were analyzed separately. After converting the doses of different opioids to equivalent doses of oxycodone, significant correlation between opioid usages and cholesterol levels was also observed. Therefore, more attention should be taken to those cancer patients with low cholesterol levels because they may require higher doses of opioids as pain killer.

A Primer on Heroin and Fentanyl.

PubMed

Worley, Julie

2017-06-01

Heroin and fentanyl use have reached epidemic proportions in the United States and are now blamed for the majority of drug-related overdose deaths. Both drugs are produced primarily in South America and Asia and enter the United States illegally. One result of smoking or injecting heroin or fentanyl is the development of a substance use disorder (SUD), which causes changes in brain chemistry and function. These changes result in negative behaviors and an inability to stop use. Yet, treatments are available and recovery is possible. Nurses have the potential to impact the heroin and fentanyl epidemic through developing therapeutic relationships with patients who are at risk or already have a SUD. Strategies for effective communication include maintaining a supportive, nonjudgmental attitude and incorporating motivational interviewing. All patients should be screened for opioid use and referred for treatment if indicated. It is important for nurses to be knowledgeable about heroin and fentanyl and available treatments. [Journal of Psychosocial Nursing and Mental Health Services, 55(6), 16-20.]. Copyright 2017, SLACK Incorporated.

Report of Increasing Overdose Deaths that include Acetyl Fentanyl in Multiple Counties of the Southwestern Region of the Commonwealth of Pennsylvania in 2015-2016.

PubMed

Dwyer, Jessica B; Janssen, Jennifer; Luckasevic, Todd M; Williams, Karl E

2018-01-01

Acetyl fentanyl is a Schedule I controlled synthetic opioid that is becoming an increasingly detected "designer drug." Routine drug screening procedures in local forensic toxicology laboratories identified a total of 41 overdose deaths associated with acetyl fentanyl within multiple counties of the southwestern region of the state of Pennsylvania. The range, median, mean, and standard deviation of blood acetyl fentanyl concentrations for these 41 cases were 0.13-2100 ng/mL, 11 ng/mL, 169.3 ng/mL, and 405.3 ng/mL, respectively. Thirty-six individuals (88%) had a confirmed history of substance abuse, and all but one case (96%) were ruled multiple drug toxicities. This report characterizes this localized trend of overdose deaths associated with acetyl fentanyl and provides further evidence supporting an alarmingly concentrated opiate and opioid epidemic of both traditional and novel drugs within this region of the United States. © 2017 American Academy of Forensic Sciences.

U.S. Army War College Key Strategic Issues List 2013-2014

DTIC Science & Technology

2013-09-24

of a fentanyl cocktail by Russian special forces in October 2002 to end a hostage crisis in the Dubrovka Theater by Chechen 47 extremists brought...the crisis. In December 2011, the European Court of Human Rights found the Russian government not-guilty regarding the use of the fentanyl cocktail...and development into fentanyls and other pharmaceuticals by CWC signatory countries. While these chemicals are deemed incapacitants, under certain

Stress, Predictability, and Oral Fentanyl Self-Administration in Female and Male Rats

DTIC Science & Technology

1995-03-09

naloxone. When dissolved in water, fentanyl hydrochloride (Hel) is less bitter-tasting than morphine and it is readily self- administered by rats...and for assessment of the biochemical effects of the stressor. Drugs Fentanyl- hydrochloride (HCI) (NIDA, Baltimore, MD), in a concentration of 50...responses despite lower opioid SA, treatment for men might focus on pharmacologic replacement therapies, such as methadone maintenance programs. The

Effects of Parecoxib and Fentanyl on nociception-induced cortical activity

PubMed Central

2010-01-01

Background Analgesics, including opioids and non-steroid anti-inflammatory drugs reduce postoperative pain. However, little is known about the quantitative effects of these drugs on cortical activity induced by nociceptive stimulation. The aim of the present study was to determine the neural activity in response to a nociceptive stimulus and to investigate the effects of fentanyl (an opioid agonist) and parecoxib (a selective cyclooxygenase-2 inhibitor) on this nociception-induced cortical activity evoked by tail pinch. Extracellular recordings (electroencephalogram and multi-unit signals) were performed in the area of the anterior cingulate cortex while intracellular recordings were made in the primary somatosensory cortex. The effects of parecoxib and fentanyl on induced cortical activity were compared. Results Peripheral nociceptive stimulation in anesthetized rats produced an immediate electroencephalogram (EEG) desynchronization resembling the cortical arousal (low-amplitude, fast-wave activity), while the membrane potential switched into a persistent depolarization state. The induced cortical activity was abolished by fentanyl, and the fentanyl's effect was reversed by the opioid receptor antagonist, naloxone. Parecoxib, on the other hand, did not significantly affect the neural activity. Conclusion Cortical activity was modulated by nociceptive stimulation in anesthetized rats. Fentanyl showed a strong inhibitory effect on the nociceptive-stimulus induced cortical activity while parecoxib had no significant effect. PMID:20089200

Noninvasive treatment of keloid using customized Re-188 skin patch.

PubMed

Bhusari, Priya; Shukla, Jaya; Kumar, Munish; Vatsa, Rakhee; Chhabra, Anupriya; Palarwar, Kanchan; Rathore, Yogesh; De, Dipanker; Kumaran, Sendhil; Handa, Sanjeev; Mittal, B R

2017-09-01

Keloids are developed as fibrotic scar at the site of surgery or trauma and often enlarge beyond the original scar margins. Re-188 colloid coated customized patch was superficially fixed onto the lesion for 3 hrs. The same patch was reapplied on the lesion on third day for 3 hrs. The patients were followed up at 1, 3,6 and 12 months post treatment. The size and elevation of the keloid lesion was reduced after treatment. The total radiation dose from the patch (day-1 and day-3) was 100 Gy/mCi of Re-188. The radioactive patch treatment of keloids is noninvasive, painless and safe with prolonged outcome. © 2017 Wiley Periodicals, Inc.

Recommendation to increase the test concentration of methylchloroisothiazolinone/methylisothiazolinone in the European baseline patch test series - on behalf of the European Society of Contact Dermatitis and the European Environmental and Contact Dermatitis Research Group.

PubMed

Bruze, Magnus; Goossens, An; Isaksson, Marléne

2014-07-01

Methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI) in aqua is present in the European baseline patch test series at 100 ppm, whereas 200 ppm has been used in Sweden since 1986, in Spain in the late 1980s, and, in recent years, also in the United Kingdom and Ireland. With regard to MCI/MI, to investigate the data on contact allergy rates in dermatitis patients, the frequencies of allergic contact dermatitis in the same group, and adverse reactions, particularly patch test sensitization in tested dermatitis patients, and to find the optimal patch test concentration as dose in mg/cm(2) . We performed a survey of the literature found via the National Library of Medicine (PubMed, http://www.ncbi.nlm.nih.gov/pubmed, last accessed 20 February 2014). MCI/MI at 200 ppm aq. diagnosis substantially more contact allergy and allergic contact dermatitis, without any registered increase in patch test sensitization, than the presently used concentration of 100 ppm. MCI/MI at 200 ppm aq. is recommended to be included in the European baseline patch test series. To avoid patch test sensitization, a dose of 0.006 mg/cm(2) must not be exceeded, which means a volume of 15 µl for Finn Chambers(®) (Ø 8 mm). © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Syndrome surveillance of fentanyl-laced heroin outbreaks: Utilization of EMS, Medical Examiner and Poison Center databases.

PubMed

Moore, P Quincy; Weber, Joseph; Cina, Steven; Aks, Steven

2017-11-01

Describe surveillance data from three existing surveillance systems during an unexpected fentanyl outbreak in a large metropolitan area. We performed a retrospective analysis of three data sets: Chicago Fire Department EMS, Cook County Medical Examiner, and Illinois Poison Center. Each included data from January 1, 2015 through December 31, 2015. EMS data included all EMS responses in Chicago, Illinois, for suspected opioid overdose in which naloxone was administered and EMS personnel documented other criteria indicative of opioid overdose. Medical Examiner data included all deaths in Cook County, Illinois, related to heroin, fentanyl or both. Illinois Poison Center data included all calls in Chicago, Illinois, related to fentanyl, heroin, and other prescription opioids. Descriptive statistics using Microsoft Excel® were used to analyze the data and create figures. We identified a spike in opioid-related EMS responses during an 11-day period from September 30-October 10, 2015. Medical Examiner data showed an increase in both fentanyl and mixed fentanyl/heroin related deaths during the months of September and October, 2015 (375% and 550% above the median, respectively.) Illinois Poison Center data showed no significant increase in heroin, fentanyl, or other opioid-related calls during September and October 2015. Our data suggests that EMS data is an effective real-time surveillance mechanism for changes in the rate of opioid overdoses. Medical Examiner's data was found to be valuable for confirmation of EMS surveillance data and identification of specific intoxicants. Poison Center data did not correlate with EMS or Medical Examiner data. Copyright © 2017 Elsevier Inc. All rights reserved.

Administration order of midazolam/fentanyl for moderate dental sedation

PubMed Central

2018-01-01

Background The purpose of this study is to investigate the effects of administration order when a sedative drug (midazolam) and an opioid analgesic drug (fentanyl) is applied for moderate intravenous (IV) sedation in dentistry. Methods A retrospective chart review was conducted in one dental clinic during its transition from a midazolam-first to a fentanyl-first protocol for dental procedures requiring moderate IV sedation. Physiological parameters, drug administration times, patient recovery times, drug dosages, and patient recall and satisfaction were investigated for differences. Results A total of 76 charts (40 midazolam-first and 36 fentanyl-first administrations), were used in the analysis. Administering midazolam first resulted in an average 4.38 min (52%) decrease in administration times (P < 0.001), and a decrease in procedural recollection immediately following the procedure (P = 0.03), and 24 to 48 hours later (P = 0.009). Administering fentanyl first required an average of 2.43 mg (29%) less midazolam (P < 0.001). No significant differences were found for change in vital signs, minimum oxygen saturation levels, recovery times, and patient satisfaction (P > 0.05). Oxygen saturation levels did not drop below 90% for either group; however, 5 cases in the fentanyl-first group fell to between 90% and 92%, compared with 0 cases in the midazolam-first group. Conclusions The administration order of fentanyl and midazolam may have different effects on patients and the sedation procedure. Findings from this study should be used to facilitate discussion among dental practitioners and to guide additional research investigating this topic. PMID:29556559

Demonstration of analgesic effect of intranasal ketamine and intranasal fentanyl for postoperative pain after pediatric tonsillectomy.

PubMed

Yenigun, Alper; Yilmaz, Sinan; Dogan, Remzi; Goktas, Seda Sezen; Calim, Muhittin; Ozturan, Orhan

2018-01-01

Tonsillectomy is one of the oldest and most commonly performed surgical procedure in otolaryngology. Postoperative pain management is still an unsolved problem. In this study, our aim is to demonstrate the efficacy of intranasal ketamine and intranasal fentanyl for postoperative pain relief after tonsillectomy in children. This randomized-controlled study was conducted to evaluate the effects of intranasal ketamine and intranasal fentanyl in children undergoing tonsillectomy. Tonsillectomy performed in 63 children were randomized into three groups. Group I received: Intravenous paracetamol (10 mg/kg), Group II received intranasal ketamine (1.5 mg/kg ketamine), Group III received intranasal fentanyl (1.5 mcg/kg). The Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) and Wilson sedation scale scores were recorded at 15, 30, 60 min, 2 h, 6hr, 12 h and 24 h postoperatively. Patients were interviewed on the day after surgery to assess the postoperative pain, nightmares, hallucinations, nausea, vomiting and bleeding. Intranasal ketamine and intranasal fentanyl provided significantly stronger analgesic affects compared to intravenous paracetamol administration at postoperative 15, 30, 60 min and at 2, 6, 12 and 24 h in CHEOPS (p < 0.05). Sedative effects were observed in three patients in the intranasal ketamine administration group. No such sedative effect was seen in the groups that received intranasal fentanyl and intravenous paracetamol in Wilson Sedation Scale (p < 0.05). Cognitive impairment, constipation, nausea, vomiting and bleeding were not observed in any of the groups. This study showed that either intranasal ketamine and intranasal fentanyl were more effective than paracetamol for postoperative analgesia after pediatric tonsillectomy. Sedative effects were observed in three patients with the group of intranasal ketamine. There was no significant difference in the efficacy of IN Ketamine and IN Fentanyl for post-tonsillectomy pain. Copyright © 2017 Elsevier B.V. All rights reserved.

Contribution of Central μ-Receptors to Switching Pulmonary C-Fibers-Mediated Rapid Shallow Breathing into An Apnea by Fentanyl in Anesthetized Rats

PubMed Central

Zhang, Zhenxiong; Zhang, Cancan; Zhuang, Jianguo; Xu, Fadi

2012-01-01

Our previous study has shown that activating peripheral μ-receptors is necessary for switching the bronchopulmonary C-fibers (PCFs)-mediated rapid shallow breathing (RSB) into an apnea by systemic administration of fentanyl. The brainstem nuclei, such as the medial nucleus tractus solitarius (mNTS) and the Pre-Botzinger Complex (PBC), are required for completing the PCF-mediated respiratory reflexes. Moreover, these areas contain abundant μ-receptors and their activation prolongs expiratory duration (TE). Thus, we asked if central μ-receptors, especially those in the mNTS and PBC, are involved in fully expressing this RSB-apnea switch by fentanyl. In anesthetized rats, the cardiorespiratory responses to right atrial injection of phenylbiguanide (PBG, 3–6 μg/kg) were repeated after: 1) fentanyl (iv), a μ-receptor agonist, alone (8 μg/kg, iv); 2) fentanyl following microinjection of naloxone methiodide (NXM, an opioid receptor antagonist) into the cisterna magna (10 μg/4 μl); 3) the bilateral mNTS (10 mM, 20 nl); or 4) PBC (10 mM, 20 nl). Our results showed that PBG shortened TE by 37 ± 6 % (RSB, from 0.41 ± 0.05 to 0.26 ± 0.03 s, P < 0.01), but it markedly prolonged TE by 5.8-fold (an apnea, from 0.50 ± 0.04 s to 2.9 ± 0.57 s, P < 0.01) after fentanyl (iv). Pretreatment with NXM injected into the cisterna magna or the PBC, but not the mNTS, prevented the fentanyl-induced switch. This study, along with our previous results mentioned above, suggests that although peripheral μ-receptors are essential for triggering the fentanyl-induced switch, central μ-receptors, especially those in the PBC, are required to fully exhibit such switch. PMID:22759907

Fatalities Involving Carfentanil and Furanyl Fentanyl: Two Case Reports.

PubMed

Swanson, Dina M; Hair, Laura S; Strauch Rivers, Selly R; Smyth, Brianna C; Brogan, Sara C; Ventoso, Alexis D; Vaccaro, Samantha L; Pearson, Julia M

2017-07-01

Carfentanil is a fentanyl analog frequently used in large animal veterinary medicine. Recently, carfentanil has been discovered in postmortem and antemortem cases throughout the United States in the heroin supply either alone or mixed with heroin and/or other fentanyl analogs. The potency of carfentanil is ~10,000 times greater than morphine and 100 times greater than fentanyl. In two recent cases, carfentanil was identified and ruled to be the cause of death, either alone or in combination with other drugs. Case 1 involved a known heroin user. He was discovered slumped over in a running van blocking the bays of a carwash. Two syringes, a spoon with cotton and residue and a yellow baggie of powder were found in the van. Case 2 involved a man living in a tent in a park with his mother. He was last heard from by a sister via phone who stated he sounded very intoxicated and by his mother who noted him to be "itching all over" and upset over his girlfriend. When the mother returned from work, she discovered him unresponsive with a small baggie of brown powder next to him. Routine drug and volatile screening tests were performed on heart blood using headspace gas chromatography, immunoassay and gas chromatography mass spectrometry methods. Results from initial testing on both cases did not have any significant toxicological findings. However, due to the history, scene photos, toxicological findings in blood and urine and analysis of the drug paraphernalia on one of the cases which identified carfentanil and furanyl fentanyl, fentanyl analogues were suspected. Heart blood was sent to a reference laboratory for carfentanil and furanyl fentanyl analysis. Case 1 had a carfentanil concentration of 1.3 ng/mL and a furanyl fentanyl concentration of 0.34 ng/mL. Case 2 had a carfentanil concentration of 0.12 ng/mL. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Mechanism-based PK/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers.

PubMed

Yassen, A; Olofsen, E; Romberg, R; Sarton, E; Teppema, L; Danhof, M; Dahan, A

2007-01-01

The objective of this study was to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of buprenorphine and fentanyl for the respiratory depressant effect in healthy volunteers. Data on the time course of the ventilatory response at a fixed P(ET)CO(2) of 50 mm Hg and P(ET)O(2) of 110 mm Hg following intravenous administration of buprenorphine and fentanyl were obtained from two phase I studies (50 volunteers received buprenorphine: 0.05-0.6 mg/70 kg and 24 volunteers received fentanyl: 0.075-0.5 mg/70 kg). The PK/PD correlations were analyzed using nonlinear mixed effects modeling. A two- and three-compartment pharmacokinetic model characterized the time course of fentanyl and buprenorphine concentration, respectively. Three structurally different PK/PD models were evaluated for their appropriateness to describe the time course of respiratory depression: (1) a biophase distribution model with a fractional sigmoid E(max) pharmacodynamic model, (2) a receptor association/dissociation model with a linear transduction function, and (3) a combined biophase distribution-receptor association/dissociation model with a linear transduction function. The results show that for fentanyl hysteresis is entirely determined by the biophase distribution kinetics, whereas for buprenorphine hysteresis is caused by a combination of biophase distribution kinetics and receptor association/dissociation kinetics. The half-time values of biophase equilibration (t(1/2, k(eo))) were 16.4 and 75.3 min for fentanyl and buprenorphine, respectively. In addition, for buprenorphine, the value of k(on) was 0.246 ml/ng/min and the value of k(off) was 0.0102 min(-1). The concentration-effect relationship of buprenorphine was characterized by a ceiling effect at higher concentrations (intrinsic activity alpha=0.56, 95% confidence interval (CI): 0.50-0.62), whereas fentanyl displayed full respiratory depressant effect (alpha=0.91, 95% CI: 0.19-1.62).

Combination of Continuous Dexmedetomidine Infusion with Titrated Ultra-Low-Dose Propofol-Fentanyl for an Awake Craniotomy

PubMed Central

Das, Samaresh; Al-Mashani, Ali; Suri, Neelam; Salhotra, Neeraj; Chatterjee, Nilay

2016-01-01

An awake craniotomy is a continuously evolving technique used for the resection of brain tumours from the eloquent cortex. We report a 29-year-old male patient who presented to the Khoula Hospital, Muscat, Oman, in 2016 with a two month history of headaches and convulsions due to a space-occupying brain lesion in close proximity with the left motor cortex. An awake craniotomy was conducted using a scalp block, continuous dexmedetomidine infusion and a titrated ultra-low-dose of propofolfentanyl. The patient remained comfortable throughout the procedure and the intraoperative neuropsychological tests, brain mapping and tumour resection were successful. This case report suggests that dexmedetomidine in combination with titrated ultra-low-dose propofolfentanyl are effective options during an awake craniotomy, ensuring optimum sedation, minimal disinhibition and a rapid recovery. To the best of the authors’ knowledge, this is the first awake craniotomy conducted successfully in Oman. PMID:27606116

Effective Use of Naloxone by Law Enforcement in Response to Multiple Opioid Overdoses.

PubMed

Kitch, Bryan B; Portela, Roberto C

2016-01-01

Growing rates of opioid abuse and overdose throughout the nation have lead some community organizations to develop naloxone administration programs. In Pitt County North Carolina, two of our law enforcement agencies were trained in the identification of opioid overdose and use of naloxone therapy. Attributed partially to introduction of fentanyl into the illicit drug market, our community experienced a 48-hour period in which officers successfully deployed five doses of antagonist medication to four individuals. This article presents case descriptions demonstrating the feasibility and safety of law enforcement naloxone programs.

The Role of Pituitary Beta-Endorphin in the Attenuation of Nociception

DTIC Science & Technology

1986-08-28

204 X TABLES Table # Title 1 Effects of naloxone, fentanyl , diazepam and placebo on plasma norepinephrine levels (pgjml). 2 Lack of...the clinical CRH study. 4 Experimental design and sampling schedule for the clinical dexamethasone study. 5 Effects of naloxone (NAL), fentanyl ...FEN), diazepam (DZP) and placebo (PLBO) on circulating levels of iB-END. 6 7 8 9 10 11 12 Effects of naloxone (NAL), fentanyl (FEN), diazepam

Development of a conformational search strategy for flexible ligands: A study of the potent μ-selective opioid analgesic fentanyl

NASA Astrophysics Data System (ADS)

Cometta-Morini, Chiara; Loew, Gilda H.

1991-08-01

An extensive conformational search of the potent opioid analgesic, fentanyl, was performed using the semiempirical quantum mechanical method AM1 and the CHARMm potential energy function. A combination of two procedures was used to search the conformational space for fentanyl, which included nested dihedral scans, geometry optimization and molecular dynamics simulation at different temperatures. In addition, the effect of a continuum solvent environment was taken into account by use of appropriate values for the dielectric constant in the CHARMm computations. The results of the conformational search allowed the determination of the probable conformation of fentanyl in polar and nonpolar solvents and of three candidate conformers for its bioactive form.

Clonidine versus ketamine to prevent tourniquet pain during intravenous regional anesthesia with lidocaine.

PubMed

Gorgias, N K; Maidatsi, P G; Kyriakidis, A M; Karakoulas, K A; Alvanos, D N; Giala, M M

2001-01-01

Both clonidine and ketamine have been found to prolong the action of local anesthetics through a peripheral mechanism. Our study compares the efficacy of a low dose of clonidine or ketamine separately added to intravenous regional anesthesia (IVRA) with lidocaine to prevent tourniquet pain. We conducted a prospective randomized double-blinded study in 45 patients undergoing hand or forearm surgery, with anticipated duration exceeding 1 hour under IVRA. Proximal cuff inflation of a double tourniquet was followed by administration of 40 mL of lidocaine 0.5% and either saline, 1 microg/kg clonidine, or 0.1 mg/kg ketamine. When anesthesia was established, the inflation of the proximal and distal cuff was interchanged. Thereafter, tourniquet pain was rated on a visual analog scale (VAS) every 10 minutes. Intraoperatively, boluses of 25 microg fentanyl were provided for tourniquet pain treatment when required, and total fentanyl consumption was recorded. Patients receiving plain lidocaine persistently reported the highest pain scores among groups (P <.001) 20 minutes after distal cuff inflation. Differences between the groups with additional treatment were noted 50 minutes after distal cuff inflation and until the end of the observation, with significantly lower VAS ratings (P <.001 to P <.01) in ketamine-treated patients. Total fentanyl consumption was significantly decreased by ketamine (70.00 +/- 25.35 microg) or clonidine (136.67 +/- 39.94 microg) compared with the plain lidocaine group (215.33 +/- 52.33 microg) (P <.001 between all groups). The addition of clonidine 1 microg/kg or ketamine 0.1 mg/kg to lidocaine for IVRA delays the onset of unbearable tourniquet pain and decreases analgesic consumption for tourniquet pain relief, although ketamine has a more potent effect.

Plasma Membrane Permeabilization by 60- and 600-ns Electric Pulses Is Determined by the Absorbed Dose

PubMed Central

Ibey, Bennett L.; Xiao, Shu; Schoenbach, Karl H.; Murphy, Michael R.; Pakhomov, Andrei G.

2008-01-01

We explored how the effect of plasma membrane permeabilization by nanosecond-duration electric pulses (nsEP) depends on the physical characteristics of exposure. The resting membrane resistance (Rm) and membrane potential (MP) were measured in cultured GH3 and CHO cells by conventional whole-cell patch-clamp technique. Intact cells were exposed to a single nsEP (60 or 600 ns duration, 0-22 kV/cm), followed by patch-clamp measurements after a 2-3 min delay. Consistent with earlier findings, nsEP caused long-lasting Rm decrease, accompanied by the loss of MP. The threshold for these effects was about 6 kV/cm for 60 ns pulses, and about 1 kV/cm for 600 ns pulses. Further analysis established that it was neither pulse duration nor the E-field amplitude per se, but the absorbed dose that determined the magnitude of the biological effect. In other words, exposure to nsEP at either pulse duration caused equal effects if the absorbed doses were equal. The threshold absorbed dose to produce plasma membrane effects in either GH3 or CHO cells at either pulse duration was found to be at or below 10 mJ/g. Despite being determined by the dose, the nsEP effect clearly is not thermal, as the maximum heating at the threshold dose is less than 0.01 °C. The use of the absorbed dose as a universal exposure metric may help to compare and quantify nsEP sensitivity of different cell types and of cells in different physiological conditions. The absorbed dose may also prove to be a more useful metric than the incident E-field in determining safety limits for high peak, lowaverage power EMF emissions. PMID:18839412

Assessing the Potential Cost-Effectiveness of Microneedle Patches in Childhood Measles Vaccination Programs: The Case for Further Research and Development.

PubMed

Adhikari, Bishwa B; Goodson, James L; Chu, Susan Y; Rota, Paul A; Meltzer, Martin I

2016-12-01

Currently available measles vaccines are administered by subcutaneous injections and require reconstitution with a diluent and a cold chain, which is resource intensive and challenging to maintain. To overcome these challenges and potentially increase vaccination coverage, microneedle patches are being developed to deliver the measles vaccine. This study compares the cost-effectiveness of using microneedle patches with traditional vaccine delivery by syringe-and-needle (subcutaneous vaccination) in children's measles vaccination programs. We built a simple spreadsheet model to compute the vaccination costs for using microneedle patch and syringe-and-needle technologies. We assumed that microneedle vaccines will be, compared with current vaccines, more heat stable and require less expensive cool chains when used in the field. We used historical data on the incidence of measles among communities with low measles vaccination rates. The cost of microneedle vaccination was estimated at US$0.95 (range US$0.71-US$1.18) for the first dose, compared with US$1.65 (range US$1.24-US$2.06) for the first dose delivered by subcutaneous vaccination. At 95 % vaccination coverage, microneedle patch vaccination was estimated to cost US$1.66 per measles case averted (range US$1.24-US$2.07) compared with an estimated cost of US$2.64 per case averted (range US$1.98-US$3.30) using subcutaneous vaccination. Use of microneedle patches may reduce costs; however, the cost-effectiveness of patches would depend on the vaccine recipients' acceptability and vaccine effectiveness of the patches relative to the existing conventional vaccine-delivery method. This study emphasizes the need to continue research and development of this vaccine-delivery method that could boost measles elimination efforts through improved access to vaccines and increased vaccination coverage.

Development of an Injectable Salmon Fibrinogen-Thrombin Matrix to Enhance Healing of Compound Fractures of Extremities

DTIC Science & Technology

2012-09-01

first responder. Many factors may contribute to non-union of fractures, including nutritional or hormonal status, age of the patient, and presence of...of transdermal 420 fentanyl (100 µg/h) in Yucatan minipigs, plasma fentanyl concentration peaked within 48 hours, 421 with peak concentrations...3rd, Morse BC. 2001. Evaluation of a transdermal fentanyl system in 612 yucatan miniature pigs. Contemp Top Lab Anim Sci 40:12-16. 613 50. Wolfe

Aerosol Stable Peptide-Coated Liposome Nanoparticles: A Proof-of-Concept Study with Opioid Fentanyl in Enhancing Analgesic Effects and Reducing Plasma Drug Exposure

PubMed Central

HOEKMAN, JOHN D; SRIVASTAVA, PRAMOD; HO, RODNEY J Y

2014-01-01

Previous we reported a novel pressurized olfactory drug (POD) delivery device that deposit aerosolized drug preferentially to upper nasal cavity. This POD device provided sustained CNS levels of soluble morphine analgesic effects. However, analgesic onset of less soluble fentanyl was more rapid but brief, likely due to hydrophobic fentanyl redistribution readily back to blood. To determine whether fentanyl incorporated into an aerosol stable liposome that binds to nasal epithelial cells will enhance CNS drug exposure and analgesic effects and reduce plasma exposure, we constructed RGD liposomes anchored with acylated integrin binding peptides (palmitoyl-GRGDS). The RGD liposomes, which assume gel-phase membrane structure at 25°C were stable under the stress of aerosolization as only 2.2 ± 0.5 % calcein leakage detected. The RGD mediated integrin binding of liposome is also verified to be unaffected by aerosolization. Rats treated with fentanyl in RGD-liposome and POD device exhibited greater analgesic effect, compared to the free drug counterpart (AUCeffect = 1387.l vs. 760.1 %MPE*min); while ~20% reduced plasma drug exposure was noted (AUC0-120 = 208.2 vs 284.8 ng*min/ml). Collectively, fentanyl incorporated in RGD-liposomes are physically and biologically stable under aerosolization, enhanced the overall analgesic effects and reduced plasma drug exposure for the first 2 hours. PMID:24909764

Fentanyl

MedlinePlus

... a sublingual (underneath the tongue) tablet (Abstral), a film (Onsolis), and a buccal (between the gum and ... still have pain 30 minutes after using fentanyl films (Onsolis), your doctor may tell you to use ...

Transdermal patches: history, development and pharmacology.

PubMed

Pastore, Michael N; Kalia, Yogeshvar N; Horstmann, Michael; Roberts, Michael S

2015-05-01

Transdermal patches are now widely used as cosmetic, topical and transdermal delivery systems. These patches represent a key outcome from the growth in skin science, technology and expertise developed through trial and error, clinical observation and evidence-based studies that date back to the first existing human records. This review begins with the earliest topical therapies and traces topical delivery to the present-day transdermal patches, describing along the way the initial trials, devices and drug delivery systems that underpin current transdermal patches and their actives. This is followed by consideration of the evolution in the various patch designs and their limitations as well as requirements for actives to be used for transdermal delivery. The properties of and issues associated with the use of currently marketed products, such as variability, safety and regulatory aspects, are then described. The review concludes by examining future prospects for transdermal patches and drug delivery systems, such as the combination of active delivery systems with patches, minimally invasive microneedle patches and cutaneous solutions, including metered-dose systems. © 2015 The British Pharmacological Society.

[Effect of remifentanil on urine output during gynecological laparoscopic surgery].

PubMed

Yago, Yasuko; Tajiri, Osamu; Ito, Hiroyuki; Kanazawa, Masashi; Tateda, Takeshi

2009-05-01

We retrospectively examined the effect of remifentanil on urine output during gynecological laparoscopic surgery under general anesthesia performed from April 2006 to July 2007. Forty six patients undergoing gynecological laparoscopic surgery under general anesthesia were divided into 2 groups. In group C (n=23), anesthesia was performed using sevoflurane and/or propofol with intermittent fentanyl. In group R (n=23), remifentanil was additionally used with the method of group C. Patient's demography was not different between the two groups. Intraoperative conditions were compatible in both groups. In group R, total dose of fentanyl is significantly lower than group C. BP and HR measured at 20 min after pneumoperitoneum were significantly lower in group R. Intraoperative urine output was significantly greater in group R than group C. A decrease in urine output is commonly seen particularly in laparoscopic surgery. Increased stress hormonal responses due to pneumoperitoneum have been explained as one of the causes of this phenomenon. Remifentanil has been reported to maintain urine output as well as to blunt hormonal responses in CABG surgery. Although we did not measure hormonal responses in the present study, increased urine output could be attributed to decreased catecholamine levels by remifentanil.

Compliance with occlusion therapy for childhood amblyopia.

PubMed

Wallace, Michael P; Stewart, Catherine E; Moseley, Merrick J; Stephens, David A; Fielder, Alistair R

2013-09-17

Explore compliance with occlusion treatment of amblyopia in the Monitored and Randomized Occlusion Treatment of Amblyopia Studies (MOTAS and ROTAS), using objective monitoring. Both studies had a three-phase protocol: initial assessment, refractive adaptation, and occlusion. In the occlusion phase, participants were instructed to dose for 6 hours/day (MOTAS) or randomized to 6 or 12 hour/day (ROTAS). Dose was monitored continuously using an occlusion dose monitor (ODM). One hundred and fifty-two patients (71 male, 81 female; 122 Caucasian, 30 non-Caucasian) of mean ± SD age 68 ± 18 months participated. Amblyopia was defined as an interocular acuity difference of at least 0.1 logMAR and was associated with anisometropia in 50, strabismus in 44, and both (mixed) in 58. Median duration of occlusion was 99 days (interquartile range 72 days). Mean compliance was 44%, mean proportion of days with no patch worn was 42%. Compliance was lower (39%) on weekends compared with weekdays (46%, P = 0.04), as was the likelihood of dosing at all (52% vs. 60%, P = 0.028). Compliance was lower when attendance was less frequent (P < 0.001) and with prolonged treatment duration (P < 0.001). Age, sex, amblyopia type, and severity were not associated with compliance. Mixture modeling suggested three subpopulations of patch day doses: less than 30 minutes; doses that achieve 30% to 80% compliance; and doses that achieve around 100% compliance. This study shows that compliance with patching treatment averages less than 50% and is influenced by several factors. A greater understanding of these influences should improve treatment outcome. (ClinicalTrials.gov number, NCT00274664).

Use of sodium nitroprusside in neurosurgical cases during anesthesia with enflurane.

PubMed

Vandesteene, A; Mouawad, E; Noterman, J; Deloof, T; Ewalenko, P; Genette, F

1980-01-01

In patients operated for cerebral aneurysm or angioma, the same basic method of anesthesia has been used. Premedication consisted of Thalamonal or diazepam. After induction with thiopentone, curarisation with pancuronium and tracheal intubation, anesthesia was maintained with N2O 70%, O2 30% and enflurane 1%. Small doses of fentanyl or Thalamonal were given at the beginning of anesthesia, but no more within 30 minutes before starting controlled hypotension. Adjuvant drugs and methods to reduce intracranial pressure were also used, such as dexamethasone, mannitol and cerebro-spinal fluid subtraction. The approach and dissection of the vascular lesion was done under controlled hypotension with sodium nitroprusside 0.01% solution. The mean dose of sodium nitroprusside to maintain a mean blood pressure at about 50 Torr was 1.37 mcg/kg/min.

Nitrate Attenuation Pathways and Capacity in Urban Wetlands of Phoenix, Arizona.

NASA Astrophysics Data System (ADS)

Handler, A. M.; Suchy, A. K.; Grimm, N. B.; Palta, M.; Childers, D. L.; Stromberg, J. C.

2016-12-01

In the urban Salt River channel of Phoenix, Arizona, stormwater pipes collect urban runoff that drains directly into the dry river bed, providing a new water source that sustains perennial wetlands. Water delivered by storm drains is enriched in nitrogen, particularly nitrate (NO3-), a common surface-water pollutant. However, these systems are not planned nor are they actively managed to reduce nitrogen loads. We investigated the microbial capacity of these wetlands to reduce nitrate concentrations by examining surface-water (SW) and subsurface porewater (PW) chemistry and conducting soil incubations from dominant wetland vegetation patches. Nitrate was higher in SW than PW (mean ± S.E.: 0.23 ± 0.05 vs. 0.03 ± 0.01 ppm N-NO3-) while ammonium (NH4+) was the opposite (0.11 ± 0.02 vs. 0.47 ± 0.10 ppm N-NH4+). Dissolved organic carbon (DOC) was abundant throughout the wetland (6.0 ± 0.9 ppm), but was significantly higher in vegetated patches compared to non-vegetated patches (t-test: p=0.04). These data indicate conditions that support microbial NO3- reduction persists, especially in vegetated patches. Laboratory incubations of wetland soil treated with a high (7 ppm) and low (1 ppm) dose of NO3- consumed 0.191 ± 0.022 and 0.019 ± 0.005 mg N-NO3- hr-1 kg wet soil-1, respectively. A best-fit model showed incubations with a higher starting NO3- concentration had a higher NO3- loss rate (standardized β=0.10 ± 0.01, p<0.001) and incubations from vegetated patches had a higher NO3- loss rate than those from open patches (β=0.02 ± 0.01, p=0.003). Across patches, NH4+ increased in the high treatment incubations (t-test: p<0.001), potentially indicating the presence of dissimilatory nitrate reduction to ammonium (DNRA). These results suggest the wetlands have the capacity to both remove nitrogen via denitrification and retain it via DNRA. This study indicates unplanned, unmanaged urban wetland systems have a high capacity to attenuate NO3- delivered from the urban landscape.

Multicenter Patch Testing With Methylchloroisothizoline/Methylisothiazolinone in 100 and 200 ppm Within the International Contact Dermatitis Research Group.

PubMed

Engfeldt, Malin; Ale, Iris; Andersen, Klaus E; Elsner, Peter; Goh, Chee-Leok; Goossens, An; Jerajani, Hemangi; Matsunaga, Kayoko; Bruze, Magnus

The preservative methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) is a well-known contact sensitizer. Historically, there have been different opinions on the optimal patch test concentration of MCI/MI, and both 0.01% and 0.02% aqueous (aq.) have been proposed. In 2011, based on literature reviews, it was recommended that the concentration of 0.02% aq. should be used in the international baseline series. The aim of this study was to verify the recommendation from 2011 by comparing the patch test results from consecutive patch testing with MCI/MI 0.01% and 0.02% in clinics representing countries around the world. Two thousand seven hundred three consecutive patients with dermatitis in 8 dermatology clinics representing 8 countries were patch tested with MCI/MI 0.01% aq. and, in parallel with MCI/MI 0.02% aq., provisionally included in the baseline series. Contact allergy to MCI/MI at 0.01% and 0.02% was found in 3.7% and 5.6% of the patients, respectively (P < 0.001). Methylchloroisothiazolinone/MI 0.02% aq. (dose, 6 μg/cm) diagnoses significantly more contact allergy than 0.01% (dose, 3 μg/cm), without resulting in more adverse reactions. Methylchloroisothiazolinone/MI at 0.02% aq. should therefore be continuously used in the international baseline series.

Analysis of Novel Synthetic Opioids U-47700, U-50488 and Furanyl Fentanyl by LC-MS/MS in Postmortem Casework.

PubMed

Mohr, Amanda L A; Friscia, Melissa; Papsun, Donna; Kacinko, Sherri L; Buzby, David; Logan, Barry K

2016-11-01

Following series of synthetic cannabinoid and synthetic cathinone derivatives, the illicit drug market has begun to see increased incidence of synthetic opioids including fentanyl and its derivatives, and other chemically unrelated opioid agonists including AH-7921 and MT-45. Among the most frequently encountered compounds in postmortem casework have been furanyl fentanyl (N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylfuran-2-carboxamide, Fu-F) and U-47700 (trans-3,4-dichloro-N-(2-(dimethylamino)cyclohexyl)-N-methylbenzamide). Both drugs have been reported to be present in the heroin supply and to be gaining popularity among recreational opioid users, but were initially developed by pharmaceutical companies in the 1970s as candidates for development as potential analgesic therapeutic agents. A method was developed and validated for the analysis of U-47700, U-50488 and furanyl fentanyl in blood specimens. A total of 20 postmortem cases, initially believed to be heroin or other opioid-related drug overdoses, were submitted for quantitative analysis. The analytical range for U-47770 and U-50488 was 1-500 and 1-100 ng/mL for furanyl fentanyl. The limit of detection was 0.5 ng/mL for all compounds. Within the scope of the method, U-47700 was the only confirmed drug in 11 of the cases, 5 cases were confirmed for both U-47700 and furanyl fentanyl, and 3 cases were confirmed only for furanyl fentanyl. The mean and median blood concentrations for U-47700 were 253 ng/mL (±150) and 247 ng/mL, respectively, range 17-490 ng/mL. The mean and median blood concentrations for furanyl fentanyl were 26 ng/mL (±28) and 12.9 ng/mL, respectively, range 2.5-76 ng/mL. Given the widespread geographical distribution and increase in prevalence in postmortem casework, toxicology testing should be expanded to include testing for "designer opioids" in cases with histories consistent with opioid overdose but with no traditional opioids present or insufficient quantities to account for death. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Efficacy and Safety of Remifentanil as an Alternative Labor Analgesic

PubMed Central

Devabhakthuni, Sandeep

2013-01-01

The objective of this review was to evaluate the clinical efficacy and safety of remifentanil in the management of labor pain. Although neuraxial analgesia is the best option during labor, alternative analgesic options are needed for patients with contraindications. Using a systematic literature search, clinical outcomes of remifentanil for labor pain have been summarized. Also, comparisons of remifentanil to other options including meperidine, epidural analgesia, fentanyl, and nitrous oxide are provided. Based on the literature review, remifentanil is associated with high overall maternal satisfaction and favorable side-effect profile. However, due to the low reporting of adverse events, large, randomized controlled trials are needed to evaluate maternal and neonatal safety adequately and determine the optimal dosing needed to provide effective analgesia. While remifentanil is a feasible alternative for patients who cannot or do not want to receive epidural analgesia, administration should be monitored closely for potential adverse effects. PMID:24665213

Breakthrough cancer pain – still a challenge

PubMed Central

Margarit, Cesar; Juliá, Joaquim; López, Rafael; Anton, Antonio; Escobar, Yolanda; Casas, Ana; Cruz, Juan Jesús; Galvez, Rafael; Mañas, Ana; Zaragozá, Francisco

2012-01-01

Breakthrough cancer pain is defined as transient pain exacerbation in patients with stable and controlled basal pain. Although variable, the prevalence of breakthrough cancer pain is high (33%–95%). According to the American Pain Foundation, breakthrough pain is observed in 50%–90% of all hospitalized cancer patients, in 89% of all patients admitted to homes for the elderly and terminal-patient care centers, and in 35% of all ambulatory care cancer patients. The management of breakthrough cancer pain should involve an interdisciplinary and multimodal approach. The introduction of new fentanyl formulations has represented a great advance and has notably improved treatment. Among these, the pectin-based intranasal formulation adjusts very well to the profile of breakthrough pain attacks, is effective, has a good toxicity profile, and allows for convenient dosing – affording rapid and effective analgesia with the added advantage of being easily administered by caregivers when patients are unable to collaborate. PMID:23204865

Data Overview: Overview of an Epidemic

MedlinePlus

... the Epidemic Commonly Used Terms Prescription Opioids Heroin Fentanyl Data Opioid Data Analysis Drug Overdose Death Data ... Overdose Data Heroin Overdose Data Synthetic Opioid Data Fentanyl Encounters Data Overdose Prevention Improve Opioid Prescribing Prevent ...

Identification of Chemical Attribution Signatures of Fentanyl Syntheses Using Multivariate Statistical Analysis of Orthogonal Analytical Data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mayer, B. P.; Mew, D. A.; DeHope, A.

Attribution of the origin of an illicit drug relies on identification of compounds indicative of its clandestine production and is a key component of many modern forensic investigations. The results of these studies can yield detailed information on method of manufacture, starting material source, and final product - all critical forensic evidence. In the present work, chemical attribution signatures (CAS) associated with the synthesis of the analgesic fentanyl, N-(1-phenylethylpiperidin-4-yl)-N-phenylpropanamide, were investigated. Six synthesis methods, all previously published fentanyl synthetic routes or hybrid versions thereof, were studied in an effort to identify and classify route-specific signatures. 160 distinct compounds and inorganicmore » species were identified using gas and liquid chromatographies combined with mass spectrometric methods (GC-MS and LCMS/ MS-TOF) in conjunction with inductively coupled plasma mass spectrometry (ICPMS). The complexity of the resultant data matrix urged the use of multivariate statistical analysis. Using partial least squares discriminant analysis (PLS-DA), 87 route-specific CAS were classified and a statistical model capable of predicting the method of fentanyl synthesis was validated and tested against CAS profiles from crude fentanyl products deposited and later extracted from two operationally relevant surfaces: stainless steel and vinyl tile. This work provides the most detailed fentanyl CAS investigation to date by using orthogonal mass spectral data to identify CAS of forensic significance for illicit drug detection, profiling, and attribution.« less

A phase III study evaluating the efficacy and safety of remimazolam (CNS 7056) compared with placebo and midazolam in patients undergoing colonoscopy.

PubMed

Rex, Douglas K; Bhandari, Raj; Desta, Taddese; DeMicco, Michael; Schaeffer, Cynthia; Etzkorn, Kyle; Barish, Charles; Pruitt, Ronald; Cash, Brooks D; Quirk, Daniel; Tiongco, Felix; Sullivan, Shelby; Bernstein, David

2018-04-30

Remimazolam is an ultrashort-acting benzodiazepine. We performed a randomized double-blind comparison of remimazolam to placebo for outpatient colonoscopy. This study design was a requirement of the U.S. Food and Drug Administration. An additional group was randomized to open-label midazolam administered according to its package insert instructions (randomization ratio for remimazolam:placebo:midazolam was 30:6:10). Study medications were administered under the supervision of the endoscopist, without any involvement of an anesthesia specialist. Patients were given 50 to 75 μg of fentanyl before receiving study medications. Patients who failed to achieve adequate sedation in any arm were rescued with midazolam dosed at the investigator's discretion. The primary endpoint was a composite that required 3 criteria be met: completion of the colonoscopy, no need for rescue medication, and ≤5 doses of remimazolam or placebo in any 15-minute interval (≤3 doses of midazolam in any 12-minute interval in the open-label midazolam arm). There were 461 randomized patients in 12 U.S. sites. The primary endpoint was met for remimazolam, placebo, and midazolam in 91.3%, 1.7%, and 25.2% of patients, respectively (P< 0.0001 for remimazolam vs placebo). Patients administered remimazolam received less fentanyl, had faster recovery of neuropsychiatric function, were ready for discharge faster, and felt back to normal faster than patients with both placebo and midazolam. Hypotension was less frequent with remimazolam and hypoxia occurred in 1% of subjects with remimazolam or midazolam. There were no treatment-emergent serious adverse events. Remimazolam can be safely administered under the supervision of endoscopists for outpatient colonoscopy and allows faster recovery of neuropsychiatric function compared with placebo (midazolam rescue) and midazolam. Copyright © 2018 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

Effective treatment of laparoscopic cholecystectomy pain with intravenous followed by oral COX-2 specific inhibitor.

PubMed

Joshi, Girish P; Viscusi, Eugene R; Gan, Tong J; Minkowitz, Harold; Cippolle, Mark; Schuller, Rienhard; Cheung, Raymond Y; Fort, John G

2004-02-01

In this multicenter, double-blinded, randomized, placebo-controlled study we evaluated the analgesic and opioid-sparing efficacy of a preoperative dose of i.v. parecoxib followed by oral valdecoxib in treating pain associated with elective laparoscopic cholecystectomy. Patients were randomized to receive a single i.v. dose of parecoxib 40 mg (n = 134) or placebo (n = 129) 30-45 min before induction of anesthesia. Six to 12 h after the i.v. dose, the parecoxib group received a single oral dose of valdecoxib 40 mg, followed by valdecoxib 40 mg qd on postoperative days 1-4, then 40 mg qd prn days 5-7. The placebo i.v. group received oral placebo on an identical schedule. All patients were allowed supplemental i.v. fentanyl as needed during the first 4 h postoperatively (T0-240 min) followed by hydrocodone 5 mg/acetaminophen 500 mg (Vicodin(R); 1-2 tablets orally every 4-6 h as needed). Patients taking parecoxib used 21% less fentanyl than those receiving placebo (P = 0.011). The mean area under the curve of pain intensity (PI) scores over time from T0-240 min was 55.2 for parecoxib and 61.2 for placebo (P = 0.083). At T180 and T240 min, mean PI score was 7.0 and 7.6 points lower in the parecoxib group, respectively (P < 0.02). Fewer patients on valdecoxib required supplemental analgesics (P < 0.05) after discharge. At T240 min and at day 7, Patient's and Physician's/Nurse's Global Evaluations were significantly better in the parecoxib/valdecoxib group (P < 0.05). Incidences of adverse events, adverse events causing withdrawal, and serious adverse events were less for parecoxib/valdecoxib than for placebo. The authors conclude that preoperative parecoxib is a valuable opioid-sparing adjunct to the standard of care for treating pain after laparoscopic cholecystectomy, and subsequent treatment with oral valdecoxib extends this clinical benefit. Parecoxib 40 mg i.v., 30-45 min preoperatively followed by oral valdecoxib 40 mg qd reduced opioid requirements and provided superior pain relief as well as improved patient global evaluation after laparoscopic cholecystectomy.

Epidural Dexamethasone Influences Postoperative Analgesia after Major Abdominal Surgery.

PubMed

Hong, Jeong-Min; Kim, Kyung-Hoon; Lee, Hyeon Jeong; Kwon, Jae-Young; Kim, Hae-Kyu; Kim, Hyae-Jin; Cho, Ah-Reum; Do, Wang-Seok; Kim, Hyo Sung

2017-05-01

Epidurally administered dexamethasone might reduce postoperative pain. However, the effect of epidural administration of dexamethasone on postoperative epidural analgesia in major abdominal surgery has been doubtful. To investigate the effects and optimal dose of epidural dexamethasone on pain after major abdominal surgery. A prospective randomized, double-blind study. University hospital. One hundred twenty ASA physical status I and II men, scheduled for gastrectomy, were enrolled. Patients were randomly assigned to receive one of 3 treatment regimens (n = 40 in each group): dexamethasone 5 mg (1 mL) with normal saline (1 mL) (group D) or dexamethasone 10 mg (2 mL) (group E) or 2 mL of normal saline (group C) mixed with 8 mL of 0.375% ropivacaine as a loading dose. After the surgery, 0.2% ropivacaine - fentanyl 4 ?g/mL was epidurally administered for analgesia. The infusion was set to deliver 4 mL/hr of the PCEA solution, with a bolus of 2 mL per demand and 15 minutes lockout time. The infused volume of PCEA, intensity of postoperative pain using visual analogue scale (VAS) during rest and coughing, incidence of postoperative nausea and vomiting (PONV), usage of rescue analgesia and rescue antiemetic, and side effects such as respiratory depression, urinary retention, and pruritus were recorded at 2, 6, 12, 24, and 48 hours after the end of surgery. The resting and effort VAS was significantly lower in group E compared to group C at every time point through the study period. On the contrary, only the resting VAS in group D was lower at 2 hours and 6 hours after surgery. Total fentanyl consumption of group E was significantly lower compared to other groups. There was no difference in adverse effect such as hypotension, bradycardia, PONV, pruritis, and urinary retention among groups. Use of epidural PCA with basal rate might interrupt an accurate comparison of dexamethasone effect. Hyperglycemia and adrenal suppression were not evaluated. Epidural dexamethasone was effective for reducing postoperative pain. Especially, an epidural dexamethasone dose of 10 mg was more effective than a lower dose in patients undergoing gastrectomy which was associated with moderate to severe postoperative pain.

A Dictionary Learning Approach with Overlap for the Low Dose Computed Tomography Reconstruction and Its Vectorial Application to Differential Phase Tomography

PubMed Central

Mirone, Alessandro; Brun, Emmanuel; Coan, Paola

2014-01-01

X-ray based Phase-Contrast Imaging (PCI) techniques have been demonstrated to enhance the visualization of soft tissues in comparison to conventional imaging methods. Nevertheless the delivered dose as reported in the literature of biomedical PCI applications often equals or exceeds the limits prescribed in clinical diagnostics. The optimization of new computed tomography strategies which include the development and implementation of advanced image reconstruction procedures is thus a key aspect. In this scenario, we implemented a dictionary learning method with a new form of convex functional. This functional contains in addition to the usual sparsity inducing and fidelity terms, a new term which forces similarity between overlapping patches in the superimposed regions. The functional depends on two free regularization parameters: a coefficient multiplying the sparsity-inducing norm of the patch basis functions coefficients, and a coefficient multiplying the norm of the differences between patches in the overlapping regions. The solution is found by applying the iterative proximal gradient descent method with FISTA acceleration. The gradient is computed by calculating projection of the solution and its error backprojection at each iterative step. We study the quality of the solution, as a function of the regularization parameters and noise, on synthetic data for which the solution is a-priori known. We apply the method on experimental data in the case of Differential Phase Tomography. For this case we use an original approach which consists in using vectorial patches, each patch having two components: one per each gradient component. The resulting algorithm, implemented in the European Synchrotron Radiation Facility tomography reconstruction code PyHST, has proven to be efficient and well-adapted to strongly reduce the required dose and the number of projections in medical tomography. PMID:25531987

A dictionary learning approach with overlap for the low dose computed tomography reconstruction and its vectorial application to differential phase tomography.

PubMed

Mirone, Alessandro; Brun, Emmanuel; Coan, Paola

2014-01-01

X-ray based Phase-Contrast Imaging (PCI) techniques have been demonstrated to enhance the visualization of soft tissues in comparison to conventional imaging methods. Nevertheless the delivered dose as reported in the literature of biomedical PCI applications often equals or exceeds the limits prescribed in clinical diagnostics. The optimization of new computed tomography strategies which include the development and implementation of advanced image reconstruction procedures is thus a key aspect. In this scenario, we implemented a dictionary learning method with a new form of convex functional. This functional contains in addition to the usual sparsity inducing and fidelity terms, a new term which forces similarity between overlapping patches in the superimposed regions. The functional depends on two free regularization parameters: a coefficient multiplying the sparsity-inducing L1 norm of the patch basis functions coefficients, and a coefficient multiplying the L2 norm of the differences between patches in the overlapping regions. The solution is found by applying the iterative proximal gradient descent method with FISTA acceleration. The gradient is computed by calculating projection of the solution and its error backprojection at each iterative step. We study the quality of the solution, as a function of the regularization parameters and noise, on synthetic data for which the solution is a-priori known. We apply the method on experimental data in the case of Differential Phase Tomography. For this case we use an original approach which consists in using vectorial patches, each patch having two components: one per each gradient component. The resulting algorithm, implemented in the European Synchrotron Radiation Facility tomography reconstruction code PyHST, has proven to be efficient and well-adapted to strongly reduce the required dose and the number of projections in medical tomography.

Efficiency of electronically monitored amblyopia treatment between 5 and 16 years of age: new insight into declining susceptibility of the visual system.

PubMed

Fronius, Maria; Cirina, Licia; Ackermann, Hanns; Kohnen, Thomas; Diehl, Corinna M

2014-10-01

The notion of a limited, early period of plasticity of the visual system has been challenged by more recent research demonstrating functional enhancement even into adulthood. In amblyopia ("lazy eye") it is still unclear to what extent the reduced effect of treatment after early childhood is due to declining plasticity or lower compliance with prescribed patching. The aim of this study was to determine the dose-response relationship and treatment efficiency from acuity gain and electronically recorded patching dose rates, and to infer from these parameters on a facet of age dependence of functional plasticity related to occlusion for amblyopia. The Occlusion Dose Monitor was used to record occlusion in 27 participants with previously untreated strabismic and/or anisometropic amblyopia aged between 5.4 and 15.8 (mean 9.2) years during 4months of conventional treatment. Group data showed improvement of acuity throughout the age span, but significantly more in patients younger than 7years despite comparable patching dosages. Treatment efficiency declined with age, with the most pronounced effects before the age of 7years. Thus, electronic recording allowed this first quantitative insight into occlusion treatment spanning the age range from within to beyond the conventional age for patching. Though demonstrating improvement in over 7year old patients, it confirmed the importance of early detection and treatment of amblyopia. Treatment efficiency is presented as a tool extending insight into age-dependent functional plasticity of the visual system, and providing a basis for comparisons of effects of patching vs. emerging alternative treatment approaches for amblyopia. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effects of chronic fentanyl administration on physical performance of aged rats

PubMed Central

Mitzelfelt, Jeremiah D.; DuPree, Jameson P.; Seo, Dong-oh; Carter, Christy S.; Morgan, Drake

2010-01-01

There is growing concern over the increasing use of opioids to treat chronic pain in the elderly primarily because of the potential increased sensitivity to the adverse side effects. Here, we use a preclinical model (male Brown Norway X F344 rats aged 12, 18, 24, and 30 months) to describe the outcome of chronic fentanyl administration (1.0 mg/kg/day) on various physiological and behavioral measures. Continuous fentanyl administration resulted in an initial decrease in food consumption, followed by the development of tolerance to this effect over a 4-week period and a subsequent increase in food consumption during withdrawal. This change in food consumption was associated with decreases in body weight (predominantly due to a loss of fat mass) that was maintained through early withdrawal. After one month of withdrawal, only the 12-month old animals had fully regained body weight. Fentanyl administration resulted in a decrease in grip strength and an increase in locomotor activity that did not differ across age groups. There was no effect of fentanyl administration on rotarod performance. These results demonstrate that while there is a delayed recovery of body mass with age, the observed changes in behavioral responses are uniform across ages. PMID:20951790

[Evaluation of postoperative pain intensity after ear, nose, and throat surgery--the effect of intraoperative fentanyl use].

PubMed

Mizota, Toshiyuki; Suzuki, Haruyo; Daijo, Hiroki; Tanaka, Tomoharu; Fukuda, Kazuhiko

2014-11-01

This study was designed to determine postoperative pain levels after ear, nose, and throat (ENT) surgery, and also to examine whether intraoperative fentanyl use during ENT surgery enhances the quality of postoperative pain control. The distribution of pain scores and rescue analgesic requirements among 198 patients undergoing ENT surgery were examined. Multivariate logistic regression analysis was performed to identify independent factors associated with moderate to severe postoperative pain (maximal pain score ≥ 5 on the numerical rating scale) and postoperative nausea and vomiting (PONV). 27.8% of patients experienced moderate to severe postoperative pain after ENT surgery. The distribution of postoperative pain levels was similar among procedures performed on different anatomical regions. Intraoperative fentanyl use was not associated with moderate to severe postoperative pain (adjusted odds ratio (95% confidence interval) :1.03 (0.51-2.13))]. On the other hand, intraoperative fentanyl use was independently associated with PONV [3.10 (1.25-8.92); P = 0.0138]. Prevalence of moderate to severe postoperative pain after ENT surgery was approximately 28%. Intraoperative fentanyl use was not associated with a decreased incidence of moderate to severe postoperative pain, but was significantly associated with PONV.

[Analgesic effect of intra-artcular fentanyl in knee arthroscopy to treat patellofemoral lateral hyperpressure syndrome].

PubMed

Gutiérrez-Mendoza, Israel; Pérez-Correa, José J; Serna-Vela, Francisco; Góngora-Ortega, Javier; Vilchis-Huerta, Ventura; Pérez-Guzmán, Carlos; Hernández-Garduño, Eduardo; Vidal-Rodríguez, Francisco Alberto

2009-01-01

During arthroscopy for the treatment of patellofemoral lateral hyper-pressure syndrome (LHS), intra-articular morphine or its derivatives (fentanyl) may reduce postoperative pain when combined with anesthetics. We therefore decided to determine whether adding fentanyl to epinephrine and bupivacaine produced an increased analgesia. We randomly distributed 40 patients into two groups. The experimental group (n=20) was given 0.5% bupivacaine (2 mg/kg), epinephrine (100 microg) and fentanyl (2.5 microg/kg). The control group (n=20) received 0.5% bupivacaine (2 mg/kg) and epinephrine (100 microg). Patients underwent chondroplasty and retinacular release, and we assessed pain, time of analgesia and postoperative range of motion at postoperative hours 6 and 24. The age and the grade of patellofemoral chondromalacia (PFC) were similar in both groups (p > 0.05). No differences were found in pain and ranges of motion intraoperatively and at postoperative hours 6 and 24 (p > 0.05) between both groups. The postoperative analgesia time was similar (p > 0.05). Adding intra-articular fentanyl to the combination of epinephrine plus bupivacaine did not decrease pain, and did not increase neither the analgesia time nor the range of motion in patients with LHS undergoing knee arthroscopy.

77 FR 16262 - Importer of Controlled Substances; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-20

... Enforcement Administration (DEA) to be registered as an importer of Fentanyl (9801), a basic class of... import of Fentanyl (9801), the authorization for the import of this basic class of controlled substance...

A novel male contraceptive pill-patch combination: oral desogestrel and transdermal testosterone in the suppression of spermatogenesis in normal men.

PubMed

Hair, W M; Kitteridge, K; O'Connor, D B; Wu, F C

2001-11-01

This study investigated the effect of transdermal T and oral desogestrel on the reproductive axis of healthy men. Twenty-three men were randomized to 1 of 3 treatment groups and received a daily transdermal T patch plus oral desogestrel at a dose of 75, 150, or 300 microg/d for 24 wk. Baseline blood and semen samples were obtained and then every 4 wk thereafter for 32 wk. The outcome measures were sperm density and plasma levels of FSH, LH, total and free T. The results show a dose-dependent suppression of spermatogenesis and gonadotropins. Seven of the 17 subjects became azoospermic. Desogestrel (300 microg daily) in combination with 5 mg daily transdermal T was the most effective (57% azoospermic), whereas a dose of 75 microg was ineffective (0% azoospermic). Total and free plasma T were reduced by approximately 30%. High density lipoprotein cholesterol was significantly reduced. No serious side-effects were encountered. We conclude that daily self-administered desogestrel with transdermal T is capable of suppressing the male reproductive axis, although the efficacy was less marked and less consistent than injectable regimens. The lower efficacy is likely to be due to failure of the transdermal T system to maintain circulating T levels consistently in the required range.

Sweat testing for the detection of atomoxetine from paediatric patients with attention deficit/ hyperactivity disorder: application to clinical practice.

PubMed

Marchei, Emilia; Papaseit, Esther; Garcia-Algar, Oscar; Bilbao, Amaia; Farré, Magí; Pacifici, Roberta; Pichini, Simona

2013-03-01

Atomoxetine (ATX) is a selective norepinephrine reuptake inhibitor approved since 2002 for the treatment of attention deficit hyperactivity disorder (ADHD) in children, adolescents, and adults as an alternative treatment to methylphenidate. Within the framework of a project evaluating the use of alternative biological matrices for therapeutic monitoring of psychoactive drugs in paediatric and non-paediatric individuals, the excretion of ATX and its principal metabolites has been recently studied in oral fluid and hair. The aim of this study was to describe the excretion profile of ATX and its metabolites 4-hydroxyatomoxetine (4-OH-ATX) and N-desmethylatomoxetine (N-des-ATX) in sweat following the administration of different dosage regimens (60, 40, 35, and 18 mg/day) of ATX to six paediatric patients. Sweat patches were applied to the back of each participant and removed at timed intervals. ATX and its metabolites were measured in patches using a previously validated liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. Independently from the administered dose, ATX appeared in the sweat patches 1 h post administration and reached its maximum concentration generally at 24 h. Peak ATX concentrations ranged between 2.31 and 40.4 ng/patch and did not correlate with the administered drug dose, or with body surface area. Total ATX excreted in sweat ranged between 0.008 and 0.121 mg, corresponding to 0.02 and 0.3% of the administered drug. Neither 4-OH-ATX, nor N-des-ATX was detected in either of the collected sweat patches. Measuring ATX in sweat patches can provide information on cumulative drug use from patch application until removal. Copyright © 2012 John Wiley & Sons, Ltd.

Pharmacokinetics of a granisetron transdermal system for the treatment of chemotherapy-induced nausea and vomiting.

PubMed

Howell, Julian; Smeets, Jean; Drenth, Henk-Jan; Gill, David

2009-12-01

To determine the pharmacokinetic (PK) profile of granisetron transdermal formulation and examine its possible relationship with age, gender, and renal function. This article describes a Phase I PK study and a post hoc pooled population PK analysis. The Phase I study was a randomized, cross-over study that assessed PK parameters of three granisetron patch sizes and oral granisetron. The pooled population PK analysis included data from three trials in healthy subjects (n = 48) and from Phase II and III studies in patients with cancer (n = 793). The population PK model was used to investigate granisetron exposure and its possible relationship with age, gender, and renal function. Following oral dosing, plasma granisetron concentration was quantifiable at 1 h, and maximal mean concentration (4.7 ng/mL) was reached 2 h after administration. With transdermal application, maximal concentration was reached 48 h post-application; t(1/2) was 36 h. With oral dosing, overall exposure after 5 days was 306 ng/mL.h, and C(avg) 2.6 ng/mL. This corresponded to an AUC(0-infinity) for the 52 cm(2) patch of 420 ng/mL.h and C(avg) 2.2 ng/mL over 6 days. Clearance was not affected by age, gender, weight, or renal function. The 52 cm( 2) granisetron patch achieves a similar exposure to that of a 2 mg oral dose and provides continuous delivery of granisetron over 6 days. The patch may have utility in treating chemotherapy-induced nausea and vomiting where prolonged drug delivery is advantageous. No dose adjustments would be needed based on age or renal function.

Effects of fentanyl administration before induction of anesthesia and placement of the Laryngeal Mask Airway: a randomized, placebo-controlled trial.

PubMed

Joshi, Girish P; Kamali, Amin; Meng, Jin; Rosero, Eric; Gasanova, Irina

2014-03-01

To assess the effects of fentanyl administered before induction of anesthesia on movement and airway responses during desflurane anesthesia via the Laryngeal Mask Airway (LMA). Randomized, double-blinded, controlled trial. Tertiary-care academic center. 100 adult, ASA physical status 1, 2, and 3 patients undergoing ambulatory surgery. Patients were administered fentanyl 1 μg/kg (n=51) or saline (n=49) 3 to 5 minutes before induction with propofol 2-2.5 mg/kg intravenously (IV), followed by LMA placement. Anesthesia was maintained with desflurane titrated to a bispectral index (BIS) of 50-60 and 50% nitrous oxide in oxygen, and fentanyl 25 μg boluses were titrated to respiratory rate. Apnea occurrence and duration of manual ventilation, as well as frequency and severity of movement, coughing, breath holding, and laryngospasm were recorded. Two patients in each group were excluded from analysis. The fentanyl pretreatment group had a higher frequency of apnea (94% vs 64%; P=0.0003) and longer duration of manual ventilation (3 [interquartile range (IQR), 1.5-5] min vs 1 [0-1.5] min; P<0.0001) at induction. In contrast, the fentanyl pretreatment group had a lower frequency of movements (16% vs 51%;P=0.0001). The rates of intraoperative breath holding (6.1% vs 8.5%) and laryngospasm (2% vs 4.3%) in the two groups were similar. All subjects experiencing laryngospasm were smokers. Adjusting for smoking status did not affect the differences noted in apnea, duration of manual ventilation, or movement between groups; however, coughing occurrence was statistically higher in the placebo group (P=0.043). Preinduction fentanyl increased the frequency of apnea at induction and duration of manual ventilation, but reduced the frequency of movements. In addition, it reduced intraoperative coughing in smokers. Copyright © 2014 Elsevier Inc. All rights reserved.

Fatality due to fentanyl-cocaine intoxication resulting in a fall.

PubMed

Ferrara, S D; Snenghi, R; Tedeschi, L

1994-01-01

This is the first report of fatal intoxication by fentanyl and cocaine outside the USA. The case involved a fall caused by toxic psychosis. The circumstantial, clinical, anatomical, histopathological and toxicological frame-work is interpreted.

Exposure to time varying magnetic fields associated with magnetic resonance imaging reduces fentanyl-induced analgesia in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Teskey, G.C.; Prato, F.S.; Ossenkopp, K.P.

The effects of exposure to clinical magnetic resonance imaging (MRI) on analgesia induced by the mu opiate agonist, fentanyl, was examined in mice. During the dark period, adult male mice were exposed for 23.2 min to the time-varying (0.6 T/sec) magnetic field (TVMF) component of the MRI procedure. Following this exposure, the analgesic potency of fentanyl citrate (0.1 mg/kg) was determined at 5, 10, 15, and 30 min post-injection, using a thermal test stimulus (hot-plate 50 degrees C). Exposure to the magnetic-field gradients attenuated the fentanyl-induced analgesia in a manner comparable to that previously observed with morphine. These results indicatemore » that the time-varying magnetic fields associated with MRI have significant inhibitory effects on the analgesic effects of specific mu-opiate-directed ligands.« less

Opioid Deaths in Milwaukee County, Wisconsin 2013-2017: The Primacy of Heroin and Fentanyl.

PubMed

Peterson, Brian L; Schreiber, Sara; Fumo, Nicole; Brooke Lerner, E

2018-04-23

Heroin and fentanyl are the overwhelming and increasing cause of opioid deaths in Milwaukee County, Wisconsin. We reviewed all drug and opioid deaths from 2013 to 2017 to delineate the specific opioid drugs involved and changes in their incidence. From 2013 to 2017, 980 deaths were due to opioids, rising from 184 in 2013 to 337 in 2017. In 2017, opioid deaths exceeded combined non-natural deaths from homicide and suicide. Illicit heroin and fentanyl/analogs caused 84% of opioid deaths and 80% of drug deaths, with no increase in deaths due to oral prescription drugs such as oxycodone and hydrocodone. Any approach to decreasing this dramatic increase in opioid deaths should first focus on interdicting the supply and cheap availability of these illicit opioids. Fentanyl and its analogs represent the most deadly opioids and the greatest threat to human life in our population. © 2018 American Academy of Forensic Sciences.

Long-term Pulmonary Responses to Quadweekly Intermittent Intratracheal Spray Instillations of Magnetite (Fe3O4) Nanoparticles for 52 Weeks in Fischer 344 Rats.

PubMed

Tada, Yukie; Yano, Norio; Takahashi, Hiroshi; Yuzawa, Katsuhiro; Ando, Hiroshi; Kubo, Yoshikazu; Nagasawa, Akemichi; Inomata, Akiko; Ogata, Akio; Nakae, Dai

2013-12-01

Information about potential risks of iron nanomaterials is still limited, while a wide variety of applications are expected. We recently reported acute phase responses of male and female Fischer 344 rats after a single intratracheal spray instillation of Fe3O4 nanoparticles (magnetite), clearly showing dose-dependent pulmonary inflammatory changes (Tada et al., J Toxicol Pathol 25, 233-239, 2012). The present study assessed long-term responses of male and female Fischer 344 rats to multiple administrations of magnetite. Ten-week-old male and female Fischer 344 rats (n=20/group) were exposed to a total of 13 quadweekly intermittent intratracheal spray instillations of magnetite during the experimental period of 52 weeks, at doses of 0, 0.2 (low), 1.0 (medium) and 5.0 (high-dose) mg/kg body weight per administration. Absolute and relative lung weights of the high-dose group were significantly higher than those of the control group. Macroscopically, slight enlargement and scattered black patches were recognized in the lungs and the lung-associated lymph nodes of the high-dose group. Histopathologically, infiltration of macrophages phagocytosing magnetite (all dose groups) and of chronic inflammatory cells (medium- and high-dose males and high-dose females), alveolar bronchiolization and granuloma (high-dose group) were observed. In addition, alveolar hyperplasias were observed in some rats of the high-dose group, and cytoplasmic overexpression of β-catenin protein was immunohistochemically found in such lesions. The present results clearly show that instilled magnetite causes chronic inflammatory responses in the lung. These responses occur in a dose-dependent manner without apparent differences among sexes.

Chemical Attribution of Fentanyl Using Multivariate Statistical Analysis of Orthogonal Mass Spectral Data

DOE PAGES

Mayer, Brian P.; DeHope, Alan J.; Mew, Daniel A.; ...

2016-03-24

Attribution of the origin of an illicit drug relies on identification of compounds indicative of its clandestine production and is a key component of many modern forensic investigations. Here, the results of these studies can yield detailed information on method of manufacture, starting material source, and final product, all critical forensic evidence. In the present work, chemical attribution signatures (CAS) associated with the synthesis of the analgesic fentanyl, N-(1-phenylethylpiperidin-4-yl)-N-phenylpropanamide, were investigated. Six synthesis methods, all previously published fentanyl synthetic routes or hybrid versions thereof, were studied in an effort to identify and classify route-specific signatures. A total of 160 distinctmore » compounds and inorganic species were identified using gas and liquid chromatographies combined with mass spectrometric methods (gas chromatography/mass spectrometry (GC/MS) and liquid chromatography–tandem mass spectrometry-time of-flight (LC–MS/MS-TOF)) in conjunction with inductively coupled plasma mass spectrometry (ICPMS). The complexity of the resultant data matrix urged the use of multivariate statistical analysis. Using partial least-squares-discriminant analysis (PLS-DA), 87 route-specific CAS were classified and a statistical model capable of predicting the method of fentanyl synthesis was validated and tested against CAS profiles from crude fentanyl products deposited and later extracted from two operationally relevant surfaces: stainless steel and vinyl tile. Finally, this work provides the most detailed fentanyl CAS investigation to date by using orthogonal mass spectral data to identify CAS of forensic significance for illicit drug detection, profiling, and attribution.« less

Chemical Attribution of Fentanyl Using Multivariate Statistical Analysis of Orthogonal Mass Spectral Data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mayer, Brian P.; DeHope, Alan J.; Mew, Daniel A.

Attribution of the origin of an illicit drug relies on identification of compounds indicative of its clandestine production and is a key component of many modern forensic investigations. Here, the results of these studies can yield detailed information on method of manufacture, starting material source, and final product, all critical forensic evidence. In the present work, chemical attribution signatures (CAS) associated with the synthesis of the analgesic fentanyl, N-(1-phenylethylpiperidin-4-yl)-N-phenylpropanamide, were investigated. Six synthesis methods, all previously published fentanyl synthetic routes or hybrid versions thereof, were studied in an effort to identify and classify route-specific signatures. A total of 160 distinctmore » compounds and inorganic species were identified using gas and liquid chromatographies combined with mass spectrometric methods (gas chromatography/mass spectrometry (GC/MS) and liquid chromatography–tandem mass spectrometry-time of-flight (LC–MS/MS-TOF)) in conjunction with inductively coupled plasma mass spectrometry (ICPMS). The complexity of the resultant data matrix urged the use of multivariate statistical analysis. Using partial least-squares-discriminant analysis (PLS-DA), 87 route-specific CAS were classified and a statistical model capable of predicting the method of fentanyl synthesis was validated and tested against CAS profiles from crude fentanyl products deposited and later extracted from two operationally relevant surfaces: stainless steel and vinyl tile. Finally, this work provides the most detailed fentanyl CAS investigation to date by using orthogonal mass spectral data to identify CAS of forensic significance for illicit drug detection, profiling, and attribution.« less

77 FR 31388 - Importer of Controlled Substances; Notice of Registration; Capricorn Pharma, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-25

... importer of Fentanyl (9801), a basic class of controlled substance listed in schedule II. The company plans... manufactured FDF to foreign markets. In reference to the import of Fentanyl (9801), the authorization for the...

Single- and multiple-dose pharmacokinetics of a novel tetramethylpyrazine reservoir-type transdermal patch versus tetramethylpyrazine phosphate oral tablets in healthy normal volunteers, and in vitro/in vivo correlation.

PubMed

Shen, Teng; Xu, Huinan; Weng, Weiyu; Zhang, Jianfang

2013-01-01

A novel reservoir-type transdermal system of 2,3,5,6-tetramethylpyrazine (TMP) was developed containing eucalyptus oil as a penetration enhancer. The single and multiple-dose pharmacokinetic profiles of TMP administrated by TMP transdermal patch were characterized in healthy volunteers using an in vivo, randomized, open-label, two-way crossover design. 2,3,5,6-Tetramethylpyrazine phosphate (TMPP) oral tablets were chosen as reference. Following single/multiple oral administration of 200/100 mg TMPP tablets, a TMP C(max) of 1284/613.5 ng/mL was observed within 0.75 h. Single/multiple applications of the TMP patch yielded mean C(max) of 309/325 ng/mL at a median T(max) of 5/4 h, with steady state achieved at second application. The mean C(min) of the patch was 131±30.38 ng/mL, contrasting to nearly zero for the tablet. Multiple applications of patch produced an accumulative effect over single application. At steady state 250 mg/20 cm(2) TMP patch given daily provided comparable exposure to 100 mg TMPP tablets three times daily (3753.91 versus 3563.67 ng·h/mL). TMP tablets and patch yielded similar steady-state plasma concentrations: C(av) (148.48±51.27, 156.41±40.31 ng/mL). The results demonstrated that TMP patch can achieve a therapeutic effect that is comparable to oral administration, exhibited prolonged and sustained plasma levels, fewer drug fluctuations, lower adverse effects, more convenience, and improved patient compliance. In-vitro permeation through human skin demonstrated zero-order kinetics with the flux of 364 µg/cm(2)/h. The predicted C(av) (163.9 ng/mL) was in agreement with the observed C(av) (156.4 ng/mL).

Pharmacokinetic overview of ethinyl estradiol dose and bioavailability using two transdermal contraceptive systems and a standard combined oral contraceptive

PubMed Central

Hofmann, Birte; Reinecke, Isabel; Schuett, Barbara; Merz, Martin; Zurth, Christian

2014-01-01

Objective: To determine the relative bioavailability of ethinyl estradiol (EE) and gestodene (GSD) after application of a novel transdermal contraceptive patch vs. a standard combined oral contraceptive (COC) pill (study 1), and to evaluate the pharmacokinetics (PK) of EE after application of the EE/GSD patch compared with an EE/norelgestromin (NGMN) patch (study 2). Materials: Participants were healthy, non-obese women aged 18 – 45 years (study 1) or 18 – 35 years (study 2). Compositions of study treatments were as follows: 0.55 mg EE/2.1 mg GSD (EE/GSD patch); 0.02 mg EE/0.075 mg GSD (standard COC); 0.6 mg EE/6 mg NGMN (EE/NGMN patch). Methods: In study 1, which consisted of 3 treatment periods (each followed by 7 patch- or pill-free days), treatments were administered in one of two randomized orders: either P–M–E (EE/GSD patch (P) every 7 days for 28 days → COC (M) once-daily for 21 days → two 7-day patch-wearing periods followed by one 10-day patch-wearing phase (E)), or the same treatments administered in sequence M–P–E. For study 2, participants received either the EE/GSD patch or EE/NGMN patch for seven treatment cycles (one patch per week for 3 weeks followed by a 7-day patch-free interval). Results: In study 1, average daily exposure to EE was similar for treatments P and M; the mean daily area under the concentration-time curve (AUC) ratio of treatment P vs. treatment M for EE was 1.06 (90% confidence interval (CI): 0.964 – 1.16), indicating average daily delivery similar to oral administration of 0.019 – 0.023 mg EE. For unbound GSD, average daily exposure was lower for treatment P vs. treatment M. The mean AUC ratio of treatment P vs. treatment M for unbound GSD was 0.820 (90% CI: 0.760 – 0.885), indicating average daily delivery from the patch of 0.057 – 0.066 mg GSD. Prolonged patch wearing did not result in a distinct decline in GSD and EE serum concentrations. In study 2, AUC at steady state (AUC0–168,ss), average steady-state serum concentration, and maximum steady-state serum concentration for EE was 2.0 – 2.7-fold higher for the EE/NGMN patch vs. the EE/GSD patch. The EE/GSD patch was well tolerated in both studies. Conclusions: Based on the 90% CI of the AUC ratio of oral treatment vs. patch application for unbound GSD and EE, the daily doses of GSD and EE released from the EE/GSD patch over the 7-day application period provided the same systemic exposure as those recorded after daily oral administration of a COC containing 0.02 mg EE and 0.06 mg GSD. The EE/GSD patch showed reduced EE exposure compared with the EE/NGMN patch. Together with its good tolerability, these properties support the EE/GSD patch as an effective and well-tolerated alternative to available transdermal and oral contraceptives. PMID:25295716

Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications

PubMed Central

Vardanyan, Ruben S; Hruby, Victor J

2014-01-01

Fentanyl and its analogs have been mainstays for the treatment of severe to moderate pain for many years. In this review, we outline the structural and corresponding synthetic strategies that have been used to understand the structure–biological activity relationship in fentanyl-related compounds and derivatives and their biological activity profiles. We discuss how changes in the scaffold structure can change biological and pharmacological activities. Finally, recent efforts to design and synthesize novel multivalent ligands that act as mu and delta opioid receptors and NK-1 receptors are discussed. PMID:24635521

Postoperative analgesia in children when using clonidine in addition to fentanyl with bupivacaine given caudally.

PubMed

Jarraya, Anouar; Elleuch, Sahar; Zouari, Jawhar; Smaoui, Mohamed; Laabidi, Sofiene; Kolsi, Kamel

2016-01-01

The aim of the study was to evaluate the efficacy of clonidine in association with fentanyl as an additive to bupivacaine 0.25% given via single shot caudal epidural in pediatric patients for postoperative pain relief. In the present prospective randomized double blind study, 40 children of ASA-I-II aged 1-5 years scheduled for infraumblical surgical procedures were randomly allocated to two groups to receive either bupivacaine 0.25% (1 ml/kg) with fentanyl 1 μg/kg and clonidine 1μg/kg (group I) or bupivacaine 0.25% (1 ml/kg) with fentanyl 1 μg/kg (group II). Caudal block was performed after the induction of general anesthesia. Postoperatively patients were observed for analgesia, sedation, hemodynamic parameters, and side effects or complications. Both the groups were similar with respect to patient and various block characteristics. Heart rate and blood pressure were not different in 2 groups. Significantly prolonged duration of post-operative analgesia was observed in group I (P<0.05). Side effects such as respiratory depression, vomiting and bradycardia were similar in both groups. The adjunction of clonidine to fentanyl as additives to bupivacaine in single shot caudal epidural in children may provide better and longer analgesia after infraumblical surgical procedures.

Analysis of fentanyl in urine by DLLME-GC-MS.

PubMed

Gardner, Michael A; Sampsel, Sheena; Jenkins, Werner W; Owens, Janel E

2015-03-01

Fentanyl is a synthetic narcotic anesthetic ∼80-100 times more potent than morphine. Owing to the potential for its abuse, the drug may be included in a forensic toxicology work-up, which requires fast, precise and accurate measurements. Here, the stability of fentanyl was assessed when stored at three different temperatures (-20, 4 and 25°C) in synthetic urine. Stability at those three temperatures was demonstrated over 12 weeks upon analysis by gas chromatography-mass spectrometry with a deuterated internal standard (fentanyl-D5) utilizing three different extraction techniques: liquid-liquid extraction (LLE), solid-phase extraction and dispersed liquid-liquid microextraction (DLLME). The DLLME method was then optimized before use in the analysis of fentanyl in urine samples obtained from autopsy cases at the El Paso County Coroner's Office. Accuracy of the DLLME method was assessed by completing spike and recovery studies at three different fortification levels (10, 100 and 250 ng/mL) with excellent recovery (89.9-102.6%). The excellent comparability between DLLME and LLE is demonstrated (Bland-Altman difference plot with a mean difference of 4.9 ng/mL) and the use of this methodology in the analysis of forensically relevant samples is discussed. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Increased Hyperalgesia and Proinflammatory Cytokines in the Spinal Cord and Dorsal Root Ganglion After Surgery and/or Fentanyl Administration in Rats

PubMed Central

Chang, Lu; Ye, Fang; Luo, Quehua; Tao, Yuanxiang

2018-01-01

BACKGROUND: Perioperative fentanyl has been reported to induce hyperalgesia and increase postoperative pain. In this study, we tried to investigate behavioral hyperalgesia, the expression of proinflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and the activation of microglia in the spinal cord and dorsal root ganglion (DRG) in a rat model of surgical plantar incision with or without perioperative fentanyl. METHODS: Four groups of rats (n = 32 for each group) were subcutaneously injected with fentanyl at 60 μg/kg or normal saline for 4 times with 15-minute intervals. Plantar incisions were made to rats in 2 groups after the second drug injection. Mechanical and thermal nociceptive thresholds were assessed by the tail pressure test and paw withdrawal test on the day before, at 1, 2, 3, 4 hours, and on the days 1–7 after drug injection. The lumbar spinal cord, bilateral DRG, and cerebrospinal fluid of 4 rats in each group were collected to measure IL-1β, IL-6, and TNF-α on the day before, at the fourth hour, and on the days 1, 3, 5, and 7 after drug injection. The lumbar spinal cord and bilateral DRG were removed to detect the ionized calcium-binding adapter molecule 1 on the day before and on the days 1 and 7 after drug injection. RESULTS: Rats injected with normal saline only demonstrated no significant mechanical or thermal hyperalgesia or any increases of IL-1β, IL-6, and TNF-α in the spinal cord or DRG. However, injection of fentanyl induced analgesia within as early as 4 hours and a significant delayed tail mechanical and bilateral plantar thermal hyperalgesia after injections lasting for 2 days, while surgical plantar incision induced a significant mechanical and thermal hyperalgesia lasting for 1–4 days. The combination of fentanyl and incision further aggravated the hyperalgesia and prolonged the duration of hyperalgesia. The fentanyl or surgical incision upregulated the expression of IL-1β, IL-6, and TNF-α in the spinal cord and bilateral DRG for more than 7 days and increase of ionized calcium-binding adapter molecule 1 in the spinal cord. The combination of fentanyl and incision resulted in higher increase of IL-1β, IL-6, and TNF-α in the spinal cord and bilateral DRG. CONCLUSIONS: The surgical plantar incision with or without perioperative fentanyl induced significant mechanical and thermal hyperalgesia, an increased expression of IL-1β, IL-6, TNF-α in the spinal cord and DRG, and activation of microglia in the spinal cord. PMID:29135586

Increased Hyperalgesia and Proinflammatory Cytokines in the Spinal Cord and Dorsal Root Ganglion After Surgery and/or Fentanyl Administration in Rats.

PubMed

Chang, Lu; Ye, Fang; Luo, Quehua; Tao, Yuanxiang; Shu, Haihua

2018-01-01

Perioperative fentanyl has been reported to induce hyperalgesia and increase postoperative pain. In this study, we tried to investigate behavioral hyperalgesia, the expression of proinflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and the activation of microglia in the spinal cord and dorsal root ganglion (DRG) in a rat model of surgical plantar incision with or without perioperative fentanyl. Four groups of rats (n = 32 for each group) were subcutaneously injected with fentanyl at 60 μg/kg or normal saline for 4 times with 15-minute intervals. Plantar incisions were made to rats in 2 groups after the second drug injection. Mechanical and thermal nociceptive thresholds were assessed by the tail pressure test and paw withdrawal test on the day before, at 1, 2, 3, 4 hours, and on the days 1-7 after drug injection. The lumbar spinal cord, bilateral DRG, and cerebrospinal fluid of 4 rats in each group were collected to measure IL-1β, IL-6, and TNF-α on the day before, at the fourth hour, and on the days 1, 3, 5, and 7 after drug injection. The lumbar spinal cord and bilateral DRG were removed to detect the ionized calcium-binding adapter molecule 1 on the day before and on the days 1 and 7 after drug injection. Rats injected with normal saline only demonstrated no significant mechanical or thermal hyperalgesia or any increases of IL-1β, IL-6, and TNF-α in the spinal cord or DRG. However, injection of fentanyl induced analgesia within as early as 4 hours and a significant delayed tail mechanical and bilateral plantar thermal hyperalgesia after injections lasting for 2 days, while surgical plantar incision induced a significant mechanical and thermal hyperalgesia lasting for 1-4 days. The combination of fentanyl and incision further aggravated the hyperalgesia and prolonged the duration of hyperalgesia. The fentanyl or surgical incision upregulated the expression of IL-1β, IL-6, and TNF-α in the spinal cord and bilateral DRG for more than 7 days and increase of ionized calcium-binding adapter molecule 1 in the spinal cord. The combination of fentanyl and incision resulted in higher increase of IL-1β, IL-6, and TNF-α in the spinal cord and bilateral DRG. The surgical plantar incision with or without perioperative fentanyl induced significant mechanical and thermal hyperalgesia, an increased expression of IL-1β, IL-6, TNF-α in the spinal cord and DRG, and activation of microglia in the spinal cord.

Respiratory depression in the intoxicated trauma patient: are opioids to blame?

PubMed

Shenk, Eleni; Barton, Cassie A; Mah, Nathan D; Ran, Ran; Hendrickson, Robert G; Watters, Jennifer

2016-02-01

Providing effective pain management to acutely intoxicated trauma patients represents a challenge of balancing appropriate pain management with the risk of potential respiratory depression from opioid administration. The objective of this study was to quantify the incidence of respiratory depression in trauma patients acutely intoxicated with ethanol who received opioids as compared with those who did not and identify potential risk factors for respiratory depression in this population. Retrospective medical record review was conducted for subjects identified via the trauma registry who were admitted as a trauma activation and had a detectable serum ethanol level upon admission. Risk factors and characteristics compared included demographics, Injury Severity Score, Glasgow Coma Score, serum ethanol level upon arrival, urine drug screen results, incidence of respiratory depression, and opioid and other sedative medication use. A total of 233 patients were included (78.5% male). Patients who received opioids were more likely to have a higher Injury Severity Score and initial pain score on admission as compared with those who did not receive opioids. Blood ethanol content was higher in patients who did not receive opioids (0.205 vs 0.237 mg/dL, P = .015). Patients who did not receive opioids were more likely to be intubated within 4 hours of admission (1.7% vs 12.1%, P = .02). Opioid administration was not associated with increased risk of respiratory depression (19.7% vs 22.4%, P = .606). Increased cumulative fentanyl dose was associated with increased risk of respiratory depression. Increased cumulative fentanyl dose, but not opioid administration alone, was found to be a risk factor for respiratory depression. Copyright © 2015 Elsevier Inc. All rights reserved.

Pharmacogenomics and Patient Treatment Parameters to Opioid Treatment in Chronic Pain: A Focus on Morphine, Oxycodone, Tramadol, and Fentanyl.

PubMed

Lloyd, Renae A; Hotham, Elizabeth; Hall, Catherine; Williams, Marie; Suppiah, Vijayaprakash

2017-12-01

Opioids are one of the most commonly prescribed medicines for chronic pain. However, their use for chronic pain has been controversial. The objective of this literature review was to identify the role of genetic polymorphisms on patient treatment parameters (opioid dose requirements, response, and adverse effects) for opioids used in malignant and nonmalignant chronic pain. The opioids that this review focuses on are codeine, morphine, oxycodone, tramadol, and fentanyl. A literature search of databases Medline and Embase was carried out, and studies up to April 2016 were included in this review. Studies were included based on a combination of key words: chronic pain and related terms, pharmacogenetics and related terms, and opioids and related terms. Among the 1,408 individual papers retrieved from the search in Medline and Embase, 32 original articles were included in this review, with none related to codeine. The 32 papers reported various study designs, opioids, and polymorphisms being studied for associations with treatment outcomes. This literature review reveals that variants in ABCB1, OPRM1, and COMT have been replicated for opioid dosing and variants in ABCB1 have been replicated for both treatment response and adverse effects. Currently, there are few validated studies to form a strong evidence base to support pharmacogenomics testing when initiating opioid therapy. However, the field of pharmacogenomics in chronic pain is likely to expand over the coming years, with the increasing number of treatment options available and larger cohorts being assembled in order to identify true associations. © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Low dose CT image restoration using a database of image patches

NASA Astrophysics Data System (ADS)

Ha, Sungsoo; Mueller, Klaus

2015-01-01

Reducing the radiation dose in CT imaging has become an active research topic and many solutions have been proposed to remove the significant noise and streak artifacts in the reconstructed images. Most of these methods operate within the domain of the image that is subject to restoration. This, however, poses limitations on the extent of filtering possible. We advocate to take into consideration the vast body of external knowledge that exists in the domain of already acquired medical CT images, since after all, this is what radiologists do when they examine these low quality images. We can incorporate this knowledge by creating a database of prior scans, either of the same patient or a diverse corpus of different patients, to assist in the restoration process. Our paper follows up on our previous work that used a database of images. Using images, however, is challenging since it requires tedious and error prone registration and alignment. Our new method eliminates these problems by storing a diverse set of small image patches in conjunction with a localized similarity matching scheme. We also empirically show that it is sufficient to store these patches without anatomical tags since their statistics are sufficiently strong to yield good similarity matches from the database and as a direct effect, produce image restorations of high quality. A final experiment demonstrates that our global database approach can recover image features that are difficult to preserve with conventional denoising approaches.

Epidural volume extension: A novel technique and its efficacy in high risk cases

PubMed Central

Tiwari, Akhilesh Kumar; Singh, Rajeev Ratan; Anupam, Rudra Pratap; Ganguly, S.; Tomar, Gaurav Singh

2012-01-01

We present a unique case series restricting ourselves only to the high-risk case of different specialities who underwent successful surgery in our Institute by using epidural volume extension's technique using 1 mL of 0.5% ropivacaine and 25 μg of fentanyl. PMID:25885627

Defined daily doses (DDD) do not accurately reflect opioid doses used in contemporary chronic pain treatment.

PubMed

Nielsen, Suzanne; Gisev, Natasa; Bruno, Raimondo; Hall, Wayne; Cohen, Milton; Larance, Briony; Campbell, Gabrielle; Shanahan, Marian; Blyth, Fiona; Lintzeris, Nicholas; Pearson, Sallie; Mattick, Richard; Degenhardt, Louisa

2017-05-01

To assess how well the defined daily dose (DDD) metric reflects opioid utilisation among chronic non-cancer pain patients. Descriptive, cross-sectional study, utilising a 7-day medication diary. Community-based treatment settings, Australia. A sample of 1101 people prescribed opioids for chronic non-cancer pain. Opioid dose data was collected via a self-completed 7-day medication diary capturing names, strengths and doses of each medication taken in the past week. Median daily dose was calculated for each opioid. Comparisons were made to the World Health Organization's (WHO) DDD metric. WHO DDDs ranged from 0.6 to 7.1 times the median opioid doses used by the sample. For transdermal fentanyl and oral hydromorphone, the median dose was comparable with the DDD. The DDD for methadone was 0.6 times lower than the median doses used by this sample of chronic pain patients. In contrast, the DDD for oxycodone and transdermal buprenorphine, the most commonly used strong opioids for chronic pain in Australia, was two to seven times higher than actual doses used. For many opioids, there are key differences between the actual doses used in clinical practice and the WHO's DDDs. The interpretation of opioid utilisation studies using population-level DDDs may be limited, and a recalibration of the DDD for many opioids or the reporting of opioid utilisation in oral morphine equivalent doses is recommended. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Rational use of opioids.

PubMed

Mastronardi, P; Cafiero, T

2001-04-01

The role of analgesia and sedation in intensive care units (ICU) is ancillary to other intensive care strategies, nevertheless they permit that every other diagnostic and therapeutic procedure is safely performed by keeping the patient pain-free, anxiety-free and cooperative. Commonly used opioids in ICU include morphine, fentanyl, sufentanil and remifentanil. The choice among opioid drugs relies on their pharmacokinetics and their pharmacodynamic effects. Cardiovascular stability observed with fentanyl and sufentanil indicates their use in hemodynamically compromised patients. Short-acting remifentanil offers several advantages in patients requiring prolonged infusions. The organ-independent metabolism of this newer molecule may be valuable in patients with multiple organ failure. The main indications for opioid analgesia and sedation in ICU include: 1) Anxiety, pain and agitation: in turn, they can increase cardiac workload, myocardial oxygen consumption and rate of dysarrhythmias; 2) immediate postoperative period after major surgery; 3) short-term invasive procedures. Potential advantages offered by opioids in the ICU setting also include: a) Cardiac protection: in animal models, it has been observed that delta-opiate receptor stimulation confers a preconditioning-like protective effects against myocardial ischemia; b) Neuroprotection: recent studies suggest that mu- and kappa-opiate receptors are involved in ischemic preconditioning against seizures in the brain. During opioid therapy in the ICU, drug tolerance and withdrawal symptoms should be anticipated and the dose adjusted accordingly.

Hydrotalcite composites for an effective fluoride buccal administration: a new technological approach.

PubMed

Perioli, Luana; Nocchetti, Morena; Giannelli, Paola; Pagano, Cinzia; Bastianini, Maria

2013-09-15

The aim of this work was to develop new mucoadhesive buccal patches containing an inorganic fluorinated compound, MgAl-F, intended for decay prevention. Firstly MgAl-F was synthesized and characterized, then the patches were prepared starting from a physical blend of mucoadhesive polymers (NaCMC and polycarbophil) in which MgAl-F was dispersed in different amounts in order to obtain the films. The prepared mucoadhesive patches were characterized in terms of swelling capacity, mucoadhesion force and time, surface morphology and in vitro release studies. Moreover, the organoleptic properties and acceptability have been evaluated by in vivo application. The performed studies demonstrated that the proposed formulations are practical, manageable, flexible and adaptable to the biological substrate showing, at the same time, good organoleptic properties. Moreover, the presence of the MgAl-F is able to decrease the strong adhesion of the employed polymers, reducing pain and irritations resulting in a high patient acceptability. Data obtained from release studies revealed that the application of small patch portions is enough able to release, for a prolonged time, an amount of fluoride ions able to reach the efficacious dose. These observations suggest the applicability of such formulations for buccal administration of different active ingredients. Copyright © 2013 Elsevier B.V. All rights reserved.

Pharmacokinetic Evaluation of Two Nicotine Patches in Smokers.

PubMed

Rasmussen, Scott; Horkan, Kathleen Halabuk; Kotler, Mitchell

2018-02-02

Smoking continues to be a major preventable cause of early mortality worldwide, and nicotine replacement therapy has been demonstrated to increase rates of abstinence among smokers attempting to quit. Nicotine transdermal systems (also known as nicotine patches) attach to the skin via an adhesive layer composed of a mixture of different-molecular-weight polyisobutylenes (PIBs) in a specific ratio. This randomized, single-dose, 2-treatment, crossover pharmacokinetic (PK) trial assessed the bioequivalence of nicotine patches including a replacement PIB adhesive (test) compared with the PIB adhesive historically used on marketed patches (reference). The test and reference patches were bioequivalent, as determined by the PK parameters of C max and AUC 0-t . In addition, the parameters T max and t 1/2 did not significantly differ between the 2 patches, supporting the bioequivalence finding from the primary analysis. The tolerability profiles of the patches containing the replacement and previously used PIB adhesives were similar; application-site adverse events did not significantly differ between test and reference patches. Overall, these data establish the bioequivalence of the nicotine patch with the replacement PIB adhesive formulation and the previously utilized PIB adhesive formulation. © 2018 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

The effect of spinal hyperbaric bupivacaine-fentanyl or hyperbaric bupivacaine on uterine tone and fetal heart rate in labouring women: a randomised controlled study.

PubMed

Kuberan, A; Jain, K; Bagga, R; Makkar, J K

2018-07-01

The mechanism for fetal heart rate abnormalities following spinal opioids remains controversial. We evaluated uterine tone, using an intra-uterine pressure catheter, and fetal heart rate abnormalities in 30 women in spontaneous labour with cervical dilation of 3-5 cm having combined spinal-epidural analgesia. Women were randomly assigned to receive a spinal with 2.0 mg hyperbaric bupivacaine plus 15 μg fentanyl, or 2.5 mg hyperbaric bupivacaine. The primary outcome measure was an increase > 10 mmHg in baseline uterine tone in the 30-min period following spinal injection. Only three (20%) women who had a bupivacaine-fentanyl spinal showed a > 10 mmHg increase in baseline tone vs. none who had bupivacaine (p = 0.63). The mean (SD) baseline uterine tone after the spinal injection was 13.3 (7.0) mmHg in the bupivacaine-fentanyl group and 7.7 (2.5) mmHg in the bupivacaine group (p = 0.01). Seven (47%) in the bupivacaine-fentanyl group showed new onset fetal heart rate changes during the 30-min period after the spinal, compared with two (13%) in the bupivacaine group (p = 0.04); however, these were transient and responded to intra-uterine resuscitation. Pain scores, sensory and motor block as well as neonatal outcomes were comparable between the groups. We found that raised baseline uterine tone was not more frequent when using bupivacaine-fentanyl rather than bupivacaine in the spinal component of combined spinal-epidural, although absolute values of baseline tone were higher, and fetal heart rate changes more frequent, in the former group. © 2018 The Association of Anaesthetists of Great Britain and Ireland.

On the Road to Development of an in Vitro Permeation Test (IVPT) Model to Compare Heat Effects on Transdermal Delivery Systems: Exploratory Studies with Nicotine and Fentanyl.

PubMed

Shin, Soo Hyeon; Ghosh, Priyanka; Newman, Bryan; Hammell, Dana C; Raney, Sam G; Hassan, Hazem E; Stinchcomb, Audra L

2017-09-01

At elevated temperatures, the rate of drug release and skin permeation from transdermal delivery systems (TDS) may be higher than at a normal skin temperature. The aim of this study was to compare the effect of heat on the transdermal delivery of two model drugs, nicotine and fentanyl, from matrix-type TDSs with different formulations, using in vitro permeation tests (IVPT). IVPT experiments using pig skin were performed on two nicotine and three fentanyl TDSs. Both continuous and transient heat exposures were investigated by applying heat either for the maximum recommended TDS wear duration or for short duration. Continuous heat exposure for the two nicotine TDSs resulted in different effects, showing a prolonged heat effect for one product but not the other. The J max enhancement ratio due to the continuous heat effect was comparable between the two nicotine TDS, but significantly different (p < 0.05) among the three fentanyl TDSs. The J max enhancement ratios due to transient heat exposure were significantly different for the two nicotine TDSs, but not for the three fentanyl TDSs. Furthermore, the transient heat exposure affected the clearance of drug from the skin depot after TDS removal differently for two drugs, with fentanyl exhibiting a longer heat effect. This exploratory work suggests that an IVPT study may be able to discriminate differences in transdermal drug delivery when different TDS are exposed to elevated temperatures. However, the clinical significance of IVPT heat effects studies should be further explored by conducting in vivo clinical studies with similar study designs.

5-Hydroxytryptamine 1A/7 and 4alpha receptors differentially prevent opioid-induced inhibition of brain stem cardiorespiratory function.

PubMed

Wang, Xin; Dergacheva, Olga; Kamendi, Harriet; Gorini, Christopher; Mendelowitz, David

2007-08-01

Opioids evoke respiratory depression, bradycardia, and reduced respiratory sinus arrhythmia, whereas serotonin (5-HT) agonists stimulate respiration and cardiorespiratory interactions. This study tested whether serotonin agonists can prevent the inhibitory effects of opioids on cardiorespiratory function. Spontaneous and rhythmic inspiratory-related activity and gamma-aminobutyric acid (GABA) neurotransmission to premotor parasympathetic cardioinhibitory neurons in the nucleus ambiguus were recorded simultaneously in an in vitro thick slice preparation. The mu-opioid agonist fentanyl inhibited respiratory frequency. The 5-hydroxytryptamine 1A/7 receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin increased respiratory frequency by itself and also prevented the fentanyl-induced respiratory depression. The 5-hydroxytryptamine 4alpha agonist BIMU-8 did not by itself change inspiratory activity but prevented the mu-opioid-mediated respiratory depression. Both spontaneous and inspiratory-evoked GABAergic neurotransmission to cardiac vagal neurons were inhibited by fentanyl. 8-Hydroxy-2-(di-n-propylamino)tetralin inhibited spontaneous but not inspiratory-evoked GABAergic activity to parasympathetic cardiac neurons. However, 8-hydroxy-2-(di-n-propylamino)tetralin differentially altered the opioid-mediated depression of inspiratory-evoked GABAergic activity but did not change the opioid-induced reduction in spontaneous GABAergic neurotransmission. In contrast, BIMU-8 did not alter GABAergic neurotransmission to cardiac vagal neurons by itself but prevented the fentanyl depression of both spontaneous and inspiratory-elicited GABAergic neurotransmission to cardiac vagal neurons. In the presence of tetrodotoxin, the inhibition of GABAergic inhibitory postsynaptic currents with fentanyl is prevented by coapplication of BIMU-8, indicating that BIMU-8 acts at presynaptic GABAergic terminals to prevent fentanyl-induced depression. These results suggest that activation of 5-hydroxytryptamine receptors, particularly 5-hydroxytryptamine 4alpha agonists, may be a useful therapeutic approach in preventing opioid-evoked cardiorespiratory depression.

Impact of allergic rhinitis and its treatment on the pharmacokinetics of nasally administered fentanyl.

PubMed

Perelman, Michael; Fisher, Anthony N; Smith, Alan; Knight, Alastair

2013-05-01

Fentanyl pectin nasal spray (FPNS, Lazanda® in the US and PecFent® in Europe and Australia) is a novel analgesic approved for the management of breakthrough pain in cancer patients. Given that the fentanyl is nasally administered, it is important to understand whether concomitant allergic rhinitis, or its treatment with a vasoconstrictor, would affect its absorption and, potentially, its efficacy or safety. Subjects with a history of allergic rhinitis were screened to identify subjects who developed at least moderate rhinitis symptoms on exposure to pollen allergen (either ragweed or tree) in an environmental exposure chamber (EEC). These were entered into a randomized, three-way crossover study in which each subject received 100 μg of FPNS under three exposure conditions; Control (no rhinitis), Rhinitis (symptomatic without decongestant), Treated (symptomatic with concomitant oxymetazoline). Blood samples for fentanyl were collected over a 24-hour period. A total of 132 subjects was screened to identify 54 for inclusion in the study; 31 were evaluable for pharmacokinetics. Measures of fentanyl absorption (mean or median) were similar between Control and Rhinitis conditions: Cmax 453.0 vs. 467.8 pg/ml; AUCt 1,292.3 vs. 1,325.4 pg×h/ml, AUC0-∞ 1,430.6 vs. 1,387 pg×h/ml and tmax 20 vs. 17 minutes. When oxymetazoline was co-administered, overall fentanyl absorption was slightly reduced (AUC0-∞ 1,362.4 pg×h/ml); but, more clinically relevant were the delayed rate of absorption (tmax 53 minutes) and reduced Cmax (235.3 pg/ml). Patients treated with FPNS will be unaffected by the development of allergic rhinitis; but, if oxymetazoline is prescribed, the patient would benefit from added supervision when oxymetazoline is started and stopped.

Ligand-induced μ opioid receptor internalization in enteric neurons following chronic treatment with the opiate fentanyl.

PubMed

Anselmi, Laura; Jaramillo, Ingrid; Palacios, Michelle; Huynh, Jennifer; Sternini, Catia

2013-06-01

Morphine differs from most opiates its poor ability to internalize μ opioid receptors (μORs). However, chronic treatment with morphine produces adaptational changes at the dynamin level, which enhance the efficiency of acute morphine stimulation to promote μOR internalization in enteric neurons. This study tested the effect of chronic treatment with fentanyl, a μOR-internalizing agonist, on ligand-induced endocytosis and the expression of the intracellular trafficking proteins, dynamin and β-arrestin, in enteric neurons using organotypic cultures of the guinea pig ileum. In enteric neurons from guinea pigs chronically treated with fentanyl, μOR immunoreactivity was predominantly at the cell surface after acute exposure to morphine with a low level of μOR translocation, slightly higher than in neurons from naïve animals. This internalization was not due to morphine's direct effect, because it was also observed in neurons exposed to medium alone. By contrast, D-Ala2-N-Me-Phe4-Gly-ol5-enkephalin (DAMGO), a potent μOR-internalizing agonist, induced pronounced and rapid μOR endocytosis in enteric neurons from animals chronically treated with fentanyl or from naïve animals. Chronic fentanyl treatment did not alter dynamin or β-arrestin expression. These findings indicate that prolonged activation of μORs with an internalizing agonist such as fentanyl does not enhance the ability of acute morphine to trigger μOR endocytosis or induce changes in intracellular trafficking proteins, as observed with prolonged activation of μORs with a poorly internalizing agonist such as morphine. Cellular adaptations induced by chronic opiate treatment might be ligand dependent and vary with the agonist efficiency to induce receptor internalization. Copyright © 2013 Wiley Periodicals, Inc.

Efficacy of transverse abdominis plane block in reduction of postoperation pain in laparoscopic cholecystectomy.

PubMed

Saliminia, Alireza; Azimaraghi, Omid; Babayipour, Shiva; Ardavan, Kamelia; Movafegh, Ali

2015-12-01

Transversus abdominis plane (TAP) block is a recently introduced regional anesthesia technique that is used for postoperative pain reduction in some abdominal surgeries. The present study evaluated the efficacy of the TAP block on the post laparoscopic cholecystectomy pain intensity and analgesic consumption. Fifty-four patients were enrolled in three groups: TAP block with normal saline (Group 1, n = 18); TAP block with bupivacaine (Group 2, n = 18); and TAP block with bupivacaine plus sufentanil (Group 3, n = 18). The time to the first fentanyl request, fentanyl consumption in the 24 hours following surgery, and postoperative pain intensity at 30 minutes, 1 hour, 6 hours, 12 hours, and 24 hours following discharge for recovery were measured and recorded. The total amount of 24-hour fentanyl consumption was higher in Group 1 (877.8 ± 338.8 μg) than either Group 2 (566.7 ± 367.8 μg) or Group 3 (555.5 ± 356.8 μg; p = 0.03). Postoperative pain score was higher in Group 1 than intervention groups (p = 0.006); however, there was no significant difference in intervention groups. The time to the first fentanyl request in Group 1 (79.44 ± 42.2) was significantly lower than Group 3 (206.38 ± 112.7; p = 0.001). The present study demonstrated that bilateral TAP block with 0.5% bupivacaine reduces post laparoscopic cholecystectomy pain intensity and fentanyl request and prolongs time to the first analgesic request. Adding sufentanil to the block solution reduced neither pain intensity nor fentanyl further consumption. Copyright © 2015. Published by Elsevier B.V.

Comparison between intravenous paracetamol and fentanyl for intraoperative and postoperative pain relief in dilatation and evacuation: Prospective, randomized interventional trial.

PubMed

Ali, Muhammad Asghar; Shamim, Faisal; Chughtai, Shakaib

2015-01-01

Dilatation and Evacuation procedure involves pain, for which pain control measures need to be undertaken. The purpose of this study was to compare paracetamol with fentanyl for pain relief in dilatation and curettage procedures. Sixty female patients were randomly included during the period from March 1, 2012 to February 28, 2013. All patients had received oral midazolam 7.5 mg as a premedication 30 min before procedure in the ward. Group P had received intravenous (IV) paracetamol 15 mg/kg in the waiting area of the operating room 15 min before starting the procedure. Group F had received IV fentanyl 2 ug/kg/min at induction of anesthesia. Pain scores on a numerical rating scale at 5, 15, and 30 min intervals after surgery were recorded. Mild pain was commonly observed in both groups, an insignificant difference between groups. The study demonstrates the usefulness of IV paracetamol which may be as effective as fentanyl in dilation and curettage procedures.

A Case Report on Dyskinesia Following Rivastigmine Patch 13.3 mg/24 hours for Alzheimer's Disease

PubMed Central

Diaz, Maria Cristina B.; Rosales, Raymond L.

2015-01-01

Abstract Current reports on movement disorder adverse effects of acetylcholinesterase inhibitors only include extrapyramidal symptoms and myoclonus. Here is a case of an 81-year-old female Filipino with dementia who presented with first-onset generalized choreiform movements. The etiology of the clinical finding of dyskinesia was investigated through laboratories, neuroimaging, and electroencephalogram, all of which yielded negative results. Review of her medications included the rivastigmine (Exelon) patch, which had just been increased to 13.3 mg/24-hour-dose 3 months prior. With all other possible causes excluded, a trial discontinuation of rivastigmine, showed decreased frequency of the dyskinesia 48 hours after, with complete resolution after 6 days, and no recurrence since then. This case thus presents a probable association or causality between the choreiform movement and rivastigmine at 13.3 mg/24-hour-dose patch because of clear temporal proximity, lack of alternative explanations, and a reversal of the dyskinesia upon medicament discontinuation. PMID:26313774

TU-AB-BRA-02: An Efficient Atlas-Based Synthetic CT Generation Method

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han, X

2016-06-15

Purpose: A major obstacle for MR-only radiotherapy is the need to generate an accurate synthetic CT (sCT) from MR image(s) of a patient for the purposes of dose calculation and DRR generation. We propose here an accurate and efficient atlas-based sCT generation method, which has a computation speed largely independent of the number of atlases used. Methods: Atlas-based sCT generation requires a set of atlases with co-registered CT and MR images. Unlike existing methods that align each atlas to the new patient independently, we first create an average atlas and pre-align every atlas to the average atlas space. When amore » new patient arrives, we compute only one deformable image registration to align the patient MR image to the average atlas, which indirectly aligns the patient to all pre-aligned atlases. A patch-based non-local weighted fusion is performed in the average atlas space to generate the sCT for the patient, which is then warped back to the original patient space. We further adapt a PatchMatch algorithm that can quickly find top matches between patches of the patient image and all atlas images, which makes the patch fusion step also independent of the number of atlases used. Results: Nineteen brain tumour patients with both CT and T1-weighted MR images are used as testing data and a leave-one-out validation is performed. Each sCT generated is compared against the original CT image of the same patient on a voxel-by-voxel basis. The proposed method produces a mean absolute error (MAE) of 98.6±26.9 HU overall. The accuracy is comparable with a conventional implementation scheme, but the computation time is reduced from over an hour to four minutes. Conclusion: An average atlas space patch fusion approach can produce highly accurate sCT estimations very efficiently. Further validation on dose computation accuracy and using a larger patient cohort is warranted. The author is a full time employee of Elekta, Inc.« less

The efficacy and resource utilization of remifentanil and fentanyl in fast-track coronary artery bypass graft surgery: a prospective randomized, double-blinded controlled, multi-center trial.

PubMed

Cheng, D C; Newman, M F; Duke, P; Wong, D T; Finegan, B; Howie, M; Fitch, J; Bowdle, T A; Hogue, C; Hillel, Z; Pierce, E; Bukenya, D

2001-05-01

We compared (a) the perioperative complications; (b) times to eligibility for, and actual time of the following: extubation, less intense monitoring, intensive care unit (ICU), and hospital discharge; and (c) resource utilization of nursing ratio for patients receiving either a typical fentanyl/isoflurane/propofol regimen or a remifentanil/isoflurane/propofol regimen for fast-track cardiac anesthesia in 304 adults by using a prospective randomized, double-blinded, double-dummy trial. There were no differences in demographic data, or perioperative mortality and morbidity between the two study groups. The mini-mental status examination at postoperative Days 1 to 3 were similar between the two groups. The eligible and actual times for extubation, less intense monitoring, ICU discharge, and hospital discharge were not significantly different. Further analyses revealed no differences in times for extubation and resource utilization after stratification by preoperative risk scores, age, and country. The nurse/patient ratio was similar between the remifentanil/isoflurane/propofol and fentanyl/isoflu-rane/propofol groups during the initial ICU phase and less intense monitoring phase. Increasing preoperative risk scores and older age (>70 yr) were associated with longer times until extubation (eligible), ICU discharge (eligible and actual), and hospital discharge (eligible and actual). Times until extubation (eligible and actual) and less intense monitoring (eligible) were significantly shorter in Canadian patients than United States' patients. However, there was no difference in hospital length of stay in Canadian and United States' patients. We conclude that both anesthesia techniques permit early and similar times until tracheal extubation, less intense monitoring, ICU and hospital discharge, and reduced resource utilization after coronary artery bypass graft surgery. An ultra-short opioid technique was compared with a standard fast-track small-dose opioid technique in coronary artery bypass graft patients in a prospective randomized, double-blinded controlled study. The postoperative recovery and resource utilization, including stratification of preoperative risk score, age, and country, were analyzed.

A structural study of fentanyl by DFT calculations, NMR and IR spectroscopy

NASA Astrophysics Data System (ADS)

Asadi, Zahra; Esrafili, Mehdi D.; Vessally, Esmail; Asnaashariisfahani, Manzarbanou; Yahyaei, Saeideh; Khani, Ali

2017-01-01

N-(1-(2-phenethyl)-4-piperidinyl-N-phenyl-propanamide (fentanyl) is synthesized and characterized by FT-IR, 1H NMR, 13C NMR, mass spectroscopy and elemental analyses. The geometry optimization is performed using the B3LYP and M06 density functionals with 6-311 + G(d) and 6-311++G(d,p) basis sets. The complete assignments are performed on the basis of the potential energy distribution (PED) of the all vibrational modes. Almost a nice correlation is found between the calculated 13C chemical shifts and experimental data. The frontier molecular orbitals and molecular electrostatic potential of fentanyl are also obtained.

Alfentanil and memory function. A comparison with fentanyl for day case termination of pregnancy.

PubMed

Kennedy, D J; Ogg, T W

1985-06-01

Two groups of 20 patients undergoing day case vaginal termination of pregnancy received either methohexitone and alfentanil 7.5 micrograms/kg or methohexitone and fentanyl 1.5 micrograms/kg. Their recovery times and memory function at 1 and 2 hours after surgery were compared. No difference in the recovery of the 2 groups was noted but at 2 hours after operation the alfentanil group showed impairment of memory for new facts compared with pre-operative memory function testing. This was not evident in the fentanyl group. Apart from this finding alfentanil was adjudged to be a suitable agent for day case anaesthesia.

High-dose estradiol improves cognition for women with AD: results of a randomized study.

PubMed

Asthana, S; Baker, L D; Craft, S; Stanczyk, F Z; Veith, R C; Raskind, M A; Plymate, S R

2001-08-28

To characterize the cognitive and neuroendocrine response to treatment with a high dose of estrogen for postmenopausal women with AD. Twenty postmenopausal women with AD were randomized to receive either 0.10 mg/day of 17 beta-estradiol by skin patch or a placebo patch for 8 weeks. Subjects were evaluated at baseline, at weeks 3, 5, and 8 during treatment, and again 8 weeks after treatment termination. During each visit, cognition was assessed with a battery of neuropsychological tests, and blood samples were collected to measure plasma estradiol as well as several other neuroendocrine markers of interest. Significant effects of estrogen treatment were observed on attention (Stroop Color Word Interference Test), verbal memory (Buschke Selective Reminding Test), and visual memory (Figure Copy/Memory). In addition, women treated with estrogen demonstrated improved performance on a test of semantic memory (Boston Naming Test) compared with subjects who received a placebo. Estrogen appeared to have a suppressive effect on the insulin-like growth factor (IGF) system such that plasma concentration of IGF binding protein-3 was significantly reduced and plasma levels of estradiol and IGF-I were negatively correlated during estrogen treatment. Administration of a higher dose of estrogen may enhance attention and memory for postmenopausal women with AD. Although these findings provide further clinical evidence to support a cognitive benefit of estrogen for women with AD, studies evaluating the effect of estradiol administration, in particular, using larger sample sizes and for longer treatment durations are warranted before the therapeutic potential of estrogen replacement for women with AD can be firmly established.

Combat Trauma Lessons Learned from Military Operations of 2001 - 2013

DTIC Science & Technology

2015-03-09

and fentanyl citrate lozenges as described in the TCCC “triple-option analgesia” plan. - Documentation of care by using TCCC Casualty Cards and TCCC...o Meloxicam/acetaminophen o Oral transmucosal fentanyl citrate o Ketamine  Modified tactical combat casualty care (TCCC) measures to optimize

Therapeutically equivalent pharmacokinetic profile across three application sites for AG200-15, a novel low-estrogen dose contraceptive patch.

PubMed

Stanczyk, Frank Z; Archer, David F; Rubin, Arkady; Foegh, Marie

2013-06-01

AG200-15 Agile Patch (AP) is a novel 7-day contraceptive patch providing ethinyl estradiol (EE) exposure comparable to low-dose combination oral contraceptives. This study determined whether application of the AP to three different anatomical sites (lower abdomen, buttock and upper torso) influences the pharmacokinetic profile of EE and levonorgestrel (LNG). In this open-label, three-period, crossover study, 24 subjects were randomized to one of six treatment sequences; each included application of patch to abdomen, buttock and upper torso, with the AP worn on one site for 7 days. After a 7-day washout, a new patch was applied to the next anatomical site. Multiple blood samples were collected up to 240 h after patch application. For plasma EE levels, median time to maximum drug concentration (Tmax, 24-48 h) and mean maximum concentration (Cmax, 47.9-61.5 pg/mL) were similar among application sites. Compared with lower abdomen, EE exposure was higher (16%-30%) at buttock and upper torso (15%-22%). For plasma LNG levels, median Tmax (72-120 h) and mean Cmax (1436-1589 pg/mL) were similar across application sites. Compared with lower abdomen, LNG exposure was higher at buttock (1%-7%) and upper torso (16%-17%). No serious adverse events (AEs) or AE-related discontinuations occurred. The most common treatment-emergent AEs were nausea, application site pruritus and headache, with frequencies comparable across anatomical sites. Absorption from the abdomen was slightly lower versus other sites; however, exposure to EE and LNG for all sites was therapeutically equivalent. The AP was well tolerated at all three anatomical sites. Copyright © 2013 Elsevier Inc. All rights reserved.