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Transdermal fentanyl in children with cancer pain: feasibility, tolerability, and pharmacokinetic correlates.

OBJECTIVES: (1) To assess the feasibility and tolerability of the therapeutic transdermal fentanyl system (TTS-fentanyl) by using a clinical protocol developed for children with cancer pain. (2) To estimate the pediatric pharmacokinetic parameters of TTS-fentanyl. METHODS: The drug was administered in open-label fashion; and measures of analgesia, side effects, and skin changes were obtained for a minimum of 2 doses (6 treatment days). Blood specimens were analyzed for plasma fentanyl concentrations. The pharmacokinetics of TTS-fentanyl were estimated by using a mixed effect modeling approach. RESULTS: Treatment was well tolerated. Ten of the 11 patients who completed the 2 doses continued treatment with TTS-fentanyl. The duration of treatment ranged from 6 to 275 days. The time to reach peak plasma concentration ranged from 18 hours to >66 hours in patients receiving the 25 microg/h patch. Compared with published pharmacokinetic data from adults, the mean clearance and volume of distribution of transdermal fentanyl were the same, but the variability was less. CONCLUSIONS: Treatment of children with TTS-fentanyl is feasible and well tolerated and yields fentanyl pharmacokinetic parameter estimates similar to those for adults. A larger study is required to confirm these findings and further test the clinical protocol.

Administration, Cutaneous↗

Randomised double-blind active-placebo-controlled crossover trial of intravenous fentanyl in neuropathic pain.

BACKGROUND: The effectiveness of opioid analgesics in non-cancer neuropathic pain is unpredictable and can be disappointing. It is not clear whether opioids, when effective, relieve pain by decreasing pain intensity or pain unpleasantness or by their sedative effect. The aim of this prospective randomised double-blind placebo-controlled crossover trial was to assess relief of pain intensity and pain unpleasantness with intravenous infusions of fentanyl. METHODS: We compared the analgesic effect of intravenous dose titration of fentanyl with diazepam (active placebo) or saline (inert placebo) in 53 patients with different types of neuropathic pain. Patients were randomly assigned two consecutive infusions: fentanyl plus diazepam (27 patients) or fentanyl plus saline (26 patients). Study medication was infused at a constant rate for a maximum of 5 h. Pain, sedation, and side-effects were assessed from the start of infusion for 8 h. The primary outcome measure was maximum relief of pain intensity. FINDINGS: One patient in the fentanyl/diazepam group and two in the fentanyl/saline group were withdrawn. Maximum relief of pain intensity was better with fentanyl than with diazepam (66% [95% CI 53-80] vs 23% [12-35]) or with saline (50% [36-63] vs 12% [4-20]). The beneficial effect of fentanyl was independent of the type of neuropathic pain and the degree of sedation. Fentanyl therapy produced equal relief of pain intensity and pain unpleasantness, whereas diazepam and saline did not reduce either pain index. Patients reported significantly more side-effects while receiving fentanyl than during diazepam or saline infusion (p < 0.0001), but none of the side-effects was severe. INTERPRETATION: Fentanyl may relieve non-cancer neuropathic pain by its intrinsic analgesic effect. The clinical characteristics of neuropathic pain do not predict response to opioids.

Adult↗

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

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

Adult↗

Stability of midazolam and fentanyl in infusion solutions.

The administration of drugs by subcutaneous infusion is routinely practiced in palliative medicine for the management of patients who are no longer able to take oral medication. It is not uncommon for two or more drugs to be combined in subcutaneous infusion solutions. The combination of an opioid and a short-acting benzodiazepine is frequently required. Unfortunately, the stability of benzodiazepines and newer opioids, such as fentanyl, has not been determined. This study examined the stability of solutions containing either fentanyl alone or fentanyl and midazolam in combination. Eight different solutions were assessed for up to 7 days following preparation. The solutions were prepared in polypropylene syringes using 0.9% saline as a diluent. Duplicate syringes were stored at approximately 5 degrees C, 22 degrees C, and 38 degrees C. High performance liquid chromatography was the analytical technique used to measure fentanyl and midazolam. Initial concentrations ranges were 13.2-38.9 micrograms/mL for fentanyl and 282-959 micrograms/mL for midazolam. It was found that fentanyl (+/- midazolam) was very stable (> 95%) when stored at temperatures ranging from 5 degrees C to 38 degrees C for at least 1 week. Midazolam (+ fentanyl) was not as stable as fentanyl under the same storage conditions and underwent time-dependent decomposition of up to 12.1% (observed at 7 days when stored at 38 degrees C). When stored at 22 degrees C and 38 degrees C, more than 90% of initial midazolam concentrations were retained for 4 days following preparation and for 7 days when stored at 5 degrees C. The clinical implications of these results are that, on the basis of physicochemical stability, subcutaneous infusion solutions containing fentanyl and midazolam may be prepared at intervals of 4 days (or 7 days if stored under refrigerated conditions).

Analgesics, Opioid↗

Fentanyl intermittent bolus technique for anesthesia in infants and children undergoing cardiac surgery.

The use of fentanyl by an incremental intravenous (IV) bolus technique was evaluated in eight pediatric patients (ages 4 months to 5 years, ASA III-IV) undergoing corrective surgery for congenital heart defects. Anesthesia was induced with 5 to 10 micrograms/kg of fentanyl. Additional boluses of comparable size were given intermittently thereafter, in order that a total dose of 100 micrograms/kg was achieved just before instituting cardiopulmonary bypass (CPB). Heart rate, systolic blood pressure, various measures of anesthetic depth, and plasma fentanyl levels measured by radioimmunoassay were compared at various points during anesthesia, surgery, and recovery. Decreases in heart rate were observed at the time of sternal incision and at 30 minutes thereafter, when doses of fentanyl were near-maximal. No changes from baseline in systolic blood pressure or in anesthetic depth occurred at any of the intervals studied. The plasma concentration of fentanyl was 30 +/- 8 ng/mL just after completion of the fentanyl administration, immediately before CPB. With onset of CPB, the fentanyl level fell to 13 +/- 9 ng/mL, a statistically significant difference from the baseline value. No further change occurred over the additional 231 +/- 74 minutes in the operating room. The fentanyl concentration was 10 +/- 4 ng/mL upon entry into the recovery room. It is concluded that administration of fentanyl in small, intermittent IV boluses, with dosing completed before the onset of CPB, produces satisfactory plasma levels, anesthesia, and hemodynamic stability in children undergoing corrective surgery for congenital cardiac defects.

Anesthesia, Intravenous↗

Transdermal fentanyl in postoperative pain.

BACKGROUND AND OBJECTIVES: The aim of this study was to determine the safety and effectiveness of a transdermal fentanyl delivery system for the relief of pain following abdominal surgery. METHODS: In a nonblinded, noncrossover, placebo-controlled study, 40 ASA I and II patients of both sexes, 18-69 years of age, who were scheduled for abdominal surgery under general anesthesia, were randomly divided into two groups of 20 patients each. Patients in group I received a transdermal patch containing 0.16 mg/cm2 of fentanyl, which was applied to the skin over the subclavian area 60 minutes before the induction of anesthesia. For body weight less than 60 kg, a 30 cm2 patch was applied, and for weight greater than 60 kg, a 40 cm2 patch was used. A second group of 20 patients received placebo patches of identical size. Approximately 20 to 30 minutes before the expected end of surgery, 60 mg ketorolac was administered intramuscularly. Patients were observed for 36 hours after placement of the patch. If patients reported their pain at rest as 5 or greater at rest on a 0-10 visual analog scale, they were given 30-mg increments of ketorolac 5 to 7 hours apart. If this regimen did not relieve their pain, they received 1,300 mg acetaminophen between two ketorolac doses. If despite this, they still had pain 30 minutes afterward, intravenous morphine was given, and the patients were excluded from further study. The patch was removed in four patients in the fentanyl group and seven in the placebo group for various reasons, which included, inadequate pain relief requiring additional analgesia postoperatively and more than 1 microgram/kg of sufentanil given intraoperatively or immediately prior to the end of surgery. During the 36-hour observation period, 30 doses of 30 mg ketorolac and 14 doses of 1.3 g acetaminophen were given to 13 patients in the placebo group and 18 doses of ketorolac and 8 doses of acetaminophen were administered to 16 in the fentanyl group. RESULTS: The differences in postoperative analgesic requirements were significant. Plasma fentanyl concentrations at 12 and 24 hours after the application of the fentanyl patch were 0.98 +/- 0.14 ng/mL and 1.22 +/- 0.17 ng/mL, respectively. At 8, 16, 24, and 36 hours after application of the patch, the pain relief, assessed by a VAS at rest and with movement, was similar in the two groups. In the fentanyl and control groups, 12 and 5 patients, respectively, experienced nausea, and 2 and 3 patients, respectively, vomited. CONCLUSIONS: Similar postoperative analgesia was achieved with less parenteral analgesics in patients who received transdermal fentanyl preoperatively than in control patients. Fentanyl, 50-75 micrograms/h, administered in a transdermal delivery system, did not depress respiratory rate or hemoglobin oxygen saturation. Although the exact role of continuously administered opioids in managing acute postoperative pain has yet to be clearly defined, it is concluded that if properly used, this new transdermal device can be effective in providing a background of analgesia, which may assist in the management of acute postoperative pain as well as some chronic pain states.

Administration, Cutaneous↗

Neonatal monitoring after maternal fentanyl analgesia in labor.

OBJECTIVE: To characterize different methods of monitoring neonatal effects associated with maternal opioid analgesia. Special focus was on the static-charge-sensitive bed (SCSB), which could potentially serve as a non-invasive neonatal monitor. METHODS: 12 healthy, term newborns from normal pregnancies were included in this prospective, randomized, controlled study. Maternal labor analgesia was either intravenous fentanyl (n = 5) or paracervical bupivacaine blockade (n = 7). Neonatal recording from delivery to the age of 12 hours included continuous SCSB monitoring with ECG and oximeter for sleep states, respiration, oxygenation, heart rate, and body movements. In addition, umbilical blood pH, Apgar, Amiel-Tison's Neurologic and Adaptive Capacity Scoring (NACS), skin cyanosis scoring, blood pressure, rectal and skin temperatures, and skin blood flow measurements were performed. RESULTS: The study was interrupted, because one baby in the fentanyl group had a significant decrease in oxyhemoglobin saturation (SpO2) to 59%. This was considcred to be residual effect of fentanyl and was treated with naloxone. SpO2 was generally lower in the fentanyl group. Epochs with SpO2 < 90% were more frequent in the fentanyl group, especially during active sleep (mean +/- SD 11.9 +/- 10.7% vs. 2.0 +/- 1.7% of epochs, p = 0.034). Mean heart rate values were lower in the fentanyl group (121.1 +/- 6.4 vs. 132.6 +/- 6.8 beats per minute, p = 0.02), and this difference was seen during wake and all sleep states. Maximum heart rate values were lower in the fentanyl group, too. The opiate group had less quiet sleep than controls (9.6 +/- 2.8% vs. 18.3 +/- 8.3%, p = 0.05). NACS after birth was lower in the fentanyl group (median [range] 15 [13-26] vs. 22 [20-25], p = 0.004). CONCLUSIONS: Several differences were seen between the fentanyl and the control group babies. The SCSB method proved sensitive enough to find neonatal effects of maternal analgesia. Together with ECG and SpO2 monitoring, SCSB gives plentiful information on neonatal well-being in a non-invasive way. Results of this study emphasize the importance of neonatal monitoring after maternal opiate use in labor.

Adult↗

Ropivacaine 1 mg x ml(-1) does not decrease the need for epidural fentanyl after hip replacement surgery.

BACKGROUND: Ropivacaine is a new long-acting local anesthetic. Laboratory trials have demonstrated a synergistic analgesic effect between intrathecal opioids and local anesthetics. We tested the hypothesis that addition of ropivacaine 1 mg x ml(-1) to epidural fentanyl (10 microg x ml(-1)) postoperatively decreases the need for fentanyl, improves the quality of analgesia and decreases the side-effects of fentanyl. METHODS: Forty patients were enrolled in this double-blind, randomized study to receive either fentanyl 10 microg x ml(-1) (group F) alone or fentanyl combined with ropivacaine 1 mg x ml(-1) (group R) for 20 h as an epidural infusion at TH12-L1 or L1-L2 for analgesia after hip replacement surgery. The patients were free to use a patient-controlled epidural analgesia device, which was programmed to infuse 3 ml of the study medication hourly and to allow a 3-ml bolus when needed (maximal hourly dose of fentanyl was 150 microg). The consumption of medication, visual pain scores at rest and on movement, hemodynamic and respiratory parameters, motor and sensory block, nausea, pruritus and sedation were recorded. RESULTS: There were no significant differences between the groups in the total mean fentanyl consumption (1.10+/-0.18 mg in group F, 1.08+/-0.31 mg in group R, 95% CI: -0.14 to 0.19, P = 0.774). The pain scores were similar at rest (median scores < or = 1) and on movement (median scores < or = 3). The adverse effects were similar and of a minor nature, consisting mostly of pruritus and nausea. CONCLUSION: Addition of ropivacaine 1 mg x ml(-1) to epidural fentanyl 10 microg x ml(-1) did not significantly decrease the requirement for fentanyl administered for pain relief after hip replacement surgery.

Adult↗

Intravenous fentanyl kinetics.

Fentanyl is considered to be a short-acting narcotic analgesic but prolonged and recurrent ventilatory depression has been reported. We examined fentanyl kinetics and excretion in 7 healthy male subjects who were given a 3.2- or 6.4-micrograms/kg dose of 3H-fentanyl intravenously. Arterial blood and urine samples were analyzed for unchanged fentanyl and total radioactivity. Fentanyl concentrations fell rapidly and 98.6% of the dose was eliminated from plasma in 60 min but the terminal elimination phase of fentanyl from the body was slow (t1/2 beta = 219 min) due to the slow return of the unchanged drug from a peripheral compartment to the central compartment where elimination occurred primarily by biotransformation. Eighty-five percent of the dose was recovered in urine and feces in 72 hr; less than 8% was recovered as unchanged fentanyl. There were fluctuations in plasma fentanyl levels during the elimination phase in all cases. The long t1/2 beta and fluctuations in plasma levels may contribute to prolonged and recurrent ventilatory effects of fentanyl.

Adult↗

Uptake pharmacokinetics of the Fentanyl Oralet in children scheduled for central venous access removal: implications for the timing of initiating painful procedures.

BACKGROUND: The Fentanyl Oralet (Abbott Laboratories, Abbott Park, IL, USA) is an oral transmucosal drug delivery system. We previously examined pharmacokinetic parameters of children who had completed consumption of the Fentanyl Oralet. The present study was designed to clarify pharmacokinetic parameters during the consumption phase to determine if there is an optimal administration time before painful procedures. METHODS: Patients, aged 3-10 years, who were scheduled for elective removal of central venous access devices under general anaesthesia, received a Fentanyl Oralet (fentanyl 10-15 microg x kg(-1)). Plasma fentanyl concentrations were measured by radioimmunoassay. Data from blood samples obtained during and after consumption of the Fentanyl Oralet from 17 patients in the present study were combined with data from our previous study to better characterize both the consumption and postconsumption concentration versus time profiles. RESULTS: Estimated fentanyl bioavailability (mean +/- SD) was low (36.1 +/- 0.4%), as were peak plasma concentrations (1.03 +/- 0.31 ng.ml-1), suggesting that many children swallowed a large fraction of the dose. This led to a relatively late and variable peak concentration time of 53 +/- 40 min. In addition, because of the apparently large degree of gastrointestinal absorption, concentration versus time curves were wide and flat. CONCLUSIONS: The wide and flat concentration versus time profile may allow flexibility in the timing of a painful procedure following Fentanyl Oralet administration. However, the variability of the time to peak concentration makes it difficult to suggest a minimum interval between Fentanyl Oralet consumption and the start of a painful procedure.

Administration, Buccal↗

Analgesic effects of interpleural bupivacaine with fentanyl for post-thoracotomy pain.

OBJECTIVE: The analgesic effect of bupivacaine/fentanyl with epinephrine given interpleurally after thoracotomy was investigated in a randomized placebo and intravenous controlled study. DESIGN: Prospective clinical study. SETTING: University teaching hospital. PARTICIPANTS: Sixty American Society of Anesthesiologists physical status II and III patients scheduled for posterolateral thoracotomy with general anesthesia. INTERVENTIONS: Patients were randomly divided into 4 groups to receive either 0.5% bupivacaine/1.5 microg/kg of fentanyl with 5 microg/mL of epinephrine (n = 15, group IPBF), 0.5 % bupivacaine with 5 microg/mL of epinephrine (n = 15, group IPB), or saline (n = 15, group IPS) in a total volume of 15 to 20 mL in 60 seconds by an interpleural catheter placed at the end of surgery by direct vision. The same volume of bupivacaine 0.25% and 1.5 microg/kg of fentanyl with 5 microg/mL of epinephrine to group IPBF, bupivacaine 0.25% with 5 microg/mL of epinephrine to group IPB or saline to group IPS was injected through the interpleural catheter every 6 hours for 48 hours postoperatively. Intravenous fentanyl (n = 15, group IVF) and interpleural saline groups received 1.5 microg/kg of fentanyl intravenously at the first complaint of pain. All patients also received patient-controlled analgesia (PCA) with fentanyl for 48 hours postoperatively. Metamizol sodium was used as a rescue analgesic. MEASUREMENTS AND MAIN RESULTS: Adequacy of pain relief was evaluated with the "Prince Henry Pain Scale" and visual analog pain scale. Fentanyl consumption via PCA and complications were evaluated for 48 hours. Visual analog scale scores were significantly higher in the interpleural saline group at 4 and 12 hours (6.6 +/- 1.2 and 5.0 +/- 2.1, respectively) postoperatively. Significantly more patients in the IPBF group had lower pain scores during coughing and deep breathing. Fentanyl consumption via PCA device was significantly higher in the intravenous fentanyl group (1,069 +/- 96.9 microg) than the interpleural groups (577.3 +/- 72.2 microg, 651.1 +/- 61.9 microg, and 601.0 +/- 22.6 microg in IPBF, IPB, and IPS groups, respectively). CONCLUSION: It is concluded that total fentanyl consumption via PCA decreased in all interpleural groups, but pain during coughing and deep breathing was significantly reduced in only the interpleural bupivacaine/fentanyl with epinephrine group.

Adult↗

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

OBJECTIVE: 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. DESIGN: Prospective cohort study. SETTING: Tertiary care, academic children's hospital. PARTICIPANTS: Fifteen neonates and infants undergoing cardiac surgery with hypothermic cardiopulmonary bypass (CPB). INTERVENTIONS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.

Analgesics, Opioid↗

Postoperative pain management with a patient-controlled transdermal delivery system for fentanyl.

PURPOSE: The efficacy and safety of fentanyl hydrochloride patient-controlled trans-dermal system (PCTS) for management of acute postoperative pain are discussed. SUMMARY: Fentanyl hydrochloride PCTS is a self-contained, needle-free, credit-card-sized fentanyl-delivery system that is worn on the patient's arm or chest. The system uses iontophoretic technology to actively deliver preprogrammed doses of fentanyl into the systemic circulation when activated by the patient on demand. PCTS is as safe and effective as i.v. morphine patient-controlled analgesia and superior to placebo for managing acute postoperative pain. Fentanyl absorption from PCTS is clinically insignificant when the device is not activated. This contrasts with the transdermal fentanyl patch, which delivers fentanyl continuously for 72 hours via passive absorption and is indicated only for use in the management of chronic pain. CONCLUSION: Fentanyl hydrochloride PCTS is a self-contained iontophoretic fentanyl-delivery system that provides patients control over pain management and consistent management of pain without analgesic peaks and troughs.

Administration, Cutaneous↗

Extradural pain relief in labour: bupivacaine sparing by extradural fentanyl is dose dependent.

The minimum local analgesic concentration (MLAC) of bupivacaine in labour is defined as the effective concentration in 50% of subjects (EC50). We have used the technique of double-blinded sequential allocation to quantify the bupivacaine sparing effect of the addition of four different doses of extradural fentanyl in 223 labouring women. There were five groups: (1) plain bupivacaine (control); (2) bupivacaine with fentanyl 1 microgram ml-1; (3) bupivacaine with fentanyl 2 micrograms ml-1; (4) bupivacaine with fentanyl 3 micrograms ml-1; and (5) bupivacaine with fentanyl 4 micrograms ml-1. The MLAC of bupivacaine were 0.069% w/v, 0.057% w/v, 0.048% w/v, 0.031% w/v and 0.015% w/v, respectively. We observed a reduction in MLAC of 18%, 31% (P = 0.03%), 55% (P < 0.0001) and 72% (P < 0.0001) with fentanyl 1, 2, 3 and 4 micrograms ml-1, respectively, demonstrating a significant negative linear trend (P < 0.0001) with increasing fentanyl dose. The incidence of pruritus was increased significantly with fentanyl 4 micrograms ml-1 (P = 0.0015). Because of this, fentanyl 3 micrograms ml-1 may be the optimal dose when the aim is bupivacaine sparing extradural analgesia during labour.

Adolescent↗

Sevoflurane requirements for tracheal intubation with and without fentanyl.

We studied 80 healthy ASA 1 patients (aged 20-52 yr) to determine if fentanyl affects sevoflurane requirements for achieving 50% probability of no movement in response to laryngoscopy and tracheal intubation (MAC-TI). Patients were allocated randomly to one of four fentanyl dose groups (0, 1, 2 and 4 micrograms kg-1). Patients in each group received sevoflurane at a pre-selected end-tidal concentration according to an 'up-down' technique. After steady state sevoflurane concentration had been maintained for at least 10 min, fentanyl was administered i.v. Tracheal intubation was performed 4 min after administration of fentanyl, and patients were assessed as moving or not moving. Heart rate (HR) and mean arterial pressure (MAP) were recorded before induction of anaesthesia, just before administration of fentanyl, just before laryngoscopy for intubation, and after intubation. The MAC-TI of sevoflurane was 3.55% (95% confidence intervals 3.32-3.78%), and this was reduced markedly to 2.07%, 1.45% and 1.37% by addition of fentanyl 1, 2 and 4 micrograms kg-1, with no significant difference in the reduction between 2 and 4 micrograms kg-1, showing a ceiling effect. Fentanyl attenuated haemodynamic responses (HR and MAP) to tracheal intubation in a dose-dependent manner, even with decreasing concomitant sevoflurane concentration. Fentanyl 4 micrograms kg-1 suppressed the changes in HR and MAP more effectively than fentanyl 1 or 2 micrograms kg-1 at sevoflurane concentrations close to MAC-TI.

Adult↗

The effects of i.v. fentanyl administration on the minimum alveolar concentration of isoflurane in horses.

BACKGROUND: Fentanyl decreases the minimum alveolar concentration (MAC) of inhaled anaesthetics and has been used clinically to reduce the requirements of other anaesthetic drugs in humans and small animals. We hypothesized that i.v. fentanyl would decrease the MAC of isoflurane in horses in a dose-dependent manner. METHODS: Following determination of baseline MAC of isoflurane, fentanyl was administered i.v. to target plasma concentrations of 1, 8 and 16 ng ml(-1). Each horse was randomly assigned two of three target concentrations administered in ascending order. Loading and infusion doses for each horse were determined from previously derived individual pharmacokinetic values. Isoflurane MAC determination began 45 min after fentanyl administration at each target fentanyl concentration. Venous blood was collected at fixed intervals during the infusion for measurement of plasma fentanyl concentrations. RESULTS: Mean actual fentanyl plasma concentrations were 0 (baseline), and 0.72 (SD 0.26), 8.43 (3.22), and 13.31 (6.66) ng ml(-1) for the target concentrations of 1, 8 and 16 ng ml(-1), respectively. The corresponding isoflurane MAC values were a baseline of 1.57 (0.23), and 1.51 (0.24), 1.41 (0.23) and 1.37 (0.09)%, respectively. The fentanyl concentrations of 0.72 and 8.43 ng ml(-1) did not significantly alter the MAC of isoflurane, but an 18 (7)% ISO-MAC reduction was observed at the 13.31 ng ml(-1) concentration. CONCLUSIONS: These results cautiously encourage further study of fentanyl as an opioid anaesthetic adjunct to inhalant anaesthesia in horses.

Adjuvants, Anesthesia↗

Duragesic transdermal patch: postmortem tissue distribution of fentanyl in 25 cases.

Fentanyl is a potent, short-acting narcotic analgesic widely used as a surgical anesthetic and for the control of pain when administered in the form of a transdermal patch. The success of the patch can be attributed to fentanyl's low molecular weight and its highly lipophilic nature, which enables it to be readily absorbed through the skin and subsequently distributed throughout the body. Over the past three years, the Los Angeles County Coroner's Toxicology Laboratory has encountered 25 cases involving Duragesic patches (fentanyl), and their postmortem tissue distributions are presented here. The analysis of fentanyl from postmortem specimens (3-mL or g sample size) consisted of an n-butyl chloride basic extraction followed by identification and quantitation on a gas chromatograph-mass spectrometer using the selected ion monitoring (SIM) mode. The fentanyl ions monitored were m/z 245, 146, and 189 and the internal standard, fentanyl-d5 ions, were m/z 250, 151, and 194 (quantitation ion underlined). The linear range of the assay was 1.67 microg/L to 500 microg/L with the limit of quantitation and detection of 1.67 microg/L. The postmortem tissue distribution ranges of fentanyl in the 25 fatalities were as follows: heart blood, 1.8-139 microg/L (23 cases); femoral blood, 3.1-43 microg/L (13 cases); vitreous, +<2.0-20 microg/L (4 cases); liver, 5.8-613 microg/kg (22 cases); bile, 3.5-262 microg/L (15 cases); urine, 2.9-895 microg/L (19 cases); gastric, 0-1200 microg total (17 cases); spleen, 7.8-79 microg/kg (3 cases); kidney, 11 microg/kg (1 case); and lung, 31 microg/kg (1 case). The age of the decedents in this study ranged from 19 to 84, with an average age of 46. The modes of death included 15 accidental, 5 natural, 3 suicidal, and 2 undetermined. The main objectives of this paper are to show the prevalence of fentanyl patches in our community and to aid the forensic toxicologist with the interpretation of postmortem fentanyl levels in casework.

Administration, Cutaneous↗

Epinephrine decreases postoperative requirements for continuous thoracic epidural fentanyl infusions.

Epidural thoracic fentanyl infusions provide effective preoperative analgesia after thoracotomy; however, side effects can limit the effectiveness of this technique. This study evaluates epinephrine as an adjunct to continuous thoracic epidural fentanyl infusions after thoracotomy. Thirty-eight patients were studied in a prospective, randomized, double-blind trial comparing fentanyl alone to fentanyl with epinephrine 1:300,000. Epidural infusion rates were titrated to equivalent pain relief using a visual analog scale. With the addition of epinephrine, there was a significant reduction in fentanyl requirements (0.82 +/- 0.07 vs 1.19 +/- 0.11 micrograms.kg-1.h-1, P = 0.005, repeated-measures analysis of variance) and in plasma fentanyl concentrations (steady state: 0.91 +/- 0.13 vs 1.65 +/- 0.23 ng/mL, P = 0.007, repeated-measures analysis of variance). There were no differences in pain scores, side effects, spirometry, patient satisfaction scores, or hemodynamic variables. This study demonstrates that adding epinephrine 1:300,000 to continuous thoracic epidural infusions decreases fentanyl requirements titrated for effective analgesia. The reduction in fentanyl requirements was associated with reduced fentanyl plasma concentrations.

Analgesia, Epidural↗