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PubMed1977

Urine catecholamine excretion after large doses of fentanyl, fentanyl and diazepam and fentanyl, diazepam and pancuronium.

The effects of fentanyl (0.5 mg/kg iv), fentanyl with diazepam (1 mg/kg iv) and fentanyl, diazepam and pancuronium (0.1 mg/kg iv) on heart rate (HR), mean arterial blood pressure (BP), cardiac output (QT), urine flow rate and urine epinephrine and norepinephrine excretion were determined in nine dogs. Fentanyl did not significantly change QT or BP but did reduce HR and urine flow rate (P less than 0.05). Urine epinephrine and norepinephrine excretion rates were signicantly increased by fentanyl (P less than 0.05). Diazepam caused no significant further changes in QT, BP or HR 30 minutes after administration, but urine epinephrine and norepinephrine excretion rates were reduced to control (pre-fentanyl) levels. Addition of pancuronium after fentanyl and diazepam increased urine flow rate to pre-fentanyl levels and elevated QT, BP and HR above controls but produced no significant change in urine epinephrine or norepinephrine excretion. These data suggest that fentanyl increases catecholamine blood levels and imply that the latter may be one mechanism by which cardiovascular dynamics are maintained stable during fentanyl anaesthesia. Our findings also demonstrate that cardiovascular stimulation after pancuronium is not associated with increased urinary catecholamine excretion.

Animals↗

PubMed2001

Epidural fentanyl markedly improves thoracic epidural analgesia in a low-dose infusion of bupivacaine, adrenaline and fentanyl. A randomized, double-blind crossover study with and without fentanyl.

BACKGROUND: The objectives of the present study were to evaluate the effects on postoperative pain intensity, pain relief, and side effects when removing fentanyl from an optimally titrated epidural infusion consisting of bupivacaine, fentanyl and adrenaline. METHODS: A prospective, randomized, double-blind, crossover study was carried out in 20 patients after major upper abdominal surgery requiring a large longitudinal incision. Patients with only mild pain when coughing during thoracic epidural infusion of about 10 ml per hour of bupivacaine 1 mg x ml(-1), fentanyl 2 microg x ml(-1), and adrenaline 2 microg x ml(-1) were included. On the 1st and 2nd postoperative days, each patient was given a double-blind epidural infusion, at the same rate, with or without fentanyl. The effects were observed for 6 h or until pain when coughing became unacceptable in spite of rescue analgesia. Rescue analgesia consisted of up to two patient-controlled epidural bolus injections (4 ml) per hour and intravenous morphine if necessary. RESULTS: Main outcome measures, i.e. pain intensity when coughing and at rest, increased (P<0.001) when fentanyl (19.2+/-5.2 microg x h(-1)) was omitted from the epidural infusion: after 6 h pain intensity when coughing had increased to unacceptable levels in spite of increased consumption of rescue bupivacaine and adrenaline (P<0.001). Within 15-20 min after restarting the triple epidural mixture with fentanyl, pain intensity was again reduced to mild pain when coughing. CONCLUSIONS: A low dose of epidural fentanyl (20 microg x h(-1)) markedly improved the pain-relieving effect of bupivacaine and adrenaline infused epidurally at a thoracic level after major upper abdominal surgery. This dose of fentanyl is much too small to relieve severe dynamic pain when given systemically. Therefore, this study indirectly supports the view that a low-dose thoracic epidural infusion of fentanyl has a spinal analgesic site of action.

Analgesics, Opioid↗

PubMedDate not supplied

Fentanyl receptor assay. I. Development of a radioreceptor assay for analysis of fentanyl and fentanyl analogs in urine.

Radioreceptor binding assays may be useful methods for determining the plasma and urine concentration of drugs. We have evaluated the possibility of employing CNS receptors in an assay to measure fentanyl and fentanyl-like drugs. This in vitro assay is based on the competition of these drugs with [3H]fentanyl for opioid receptors in membrane preparations of rat forebrain. The binding is stereospecific, reversible, and saturable. Scatchard plots of saturation suggest the presence of high and low affinity binding sites. Naloxonazine, which selectively binds to mu 1-opioid site, competed with [3H]fentanyl for its high affinity binding site. Morphine and hydromorphone competed with [3H]fentanyl for the opioid receptor, but other morphine-like compounds were relatively weak displacers of [3H]fentanyl. Many other commonly abused drugs did not displace [3H]fentanyl from the opiod receptors. Urine samples from animals injected with fentanyl were evaluated by other analytical techniques, including radioimmunoassay (RIA) and gas chromatography/mass spectrometry (GC/MS), and results were compared to those from the radioreceptor assay. Urinary analysis of fentanyl showed a good correlation between all three methods.

Animals↗

PubMed2001

Stress response in infants undergoing cardiac surgery: a randomized study of fentanyl bolus, fentanyl infusion, and fentanyl-midazolam infusion.

UNLABELLED: There have been significant changes in the management of neonates and infants undergoing cardiac surgery in the past decade. We have evaluated in this prospective, randomized, double-blinded study the effect of large-dose fentanyl anesthesia, with or without midazolam, on stress responses and outcome. Forty-five patients < 6 mo of age received bolus fentanyl (Group 1), fentanyl by continuous infusion (Group 2), or fentanyl-midazolam infusion (Group 3). Epinephrine, norepinephrine, cortisol, adrenocortical hormone, glucose, and lactate were measured after the induction (T1), after sternotomy (T2), 15 min after initiating cardiopulmonary bypass (T3), at the end of surgery (T4), and after 24 h in the intensive care unit (T5). Plasma fentanyl concentrations were obtained at all time points except at T5. Within each group epinephrine, norepinephrine, cortisol, glucose and lactate levels were significantly larger at T4 (P values < 0.01), but there were no differences among groups. Within groups, fentanyl levels were significantly larger in Groups 2 and 3 (P < 0.001) at T4, and among groups, the fentanyl level was larger only at T2 in Group 1 compared with Groups 2 and 3 (P < 0.006). There were no deaths or postoperative complications, and no significant differences in duration of mechanical ventilation or intensive care unit or hospital stay. Fentanyl dosing strategies, with or without midazolam, do not prevent a hormonal or metabolic stress response in infants undergoing cardiac surgery. IMPLICATIONS: We demonstrated a significant endocrine stress response in infants with well compensated congenital cardiac disease undergoing cardiac surgery, but without adverse postoperative outcome. The use of large-dose fentanyl, with or without midazolam, with the intention of providing "stress free" anesthesia, does not appear to be an important determinant of early postoperative outcome.

Anesthetics, Intravenous↗

PubMed1994

[TIVA with etomidate-fentanyl versus midazolam-fentanyl. The perioperative stress of coronary surgery overcomes the inhibition of cortisol synthesis caused by etomidate-fentanyl anesthesia].

Etomidate is a hypnotic with only minor effects on haemodynamics. Although its rapid elimination kinetics would suggest its use in total intravenous anaesthesia (TIVA) and sedation, its administration in higher doses or for a prolonged period has been discouraged due to its inhibitory effects on corticosteroid synthesis. Newer evidence that the suppression of cortisol synthesis might not be total requires a re-evaluation of this drug as a component of a TIVA technique. The effects of high-dose etomidate with fentanyl on spontaneous and stimulated corticosteroid levels as a measure of the magnitude and duration of adrenocortical suppression, as well as on plasma concentrations of adrenocorticotropic hormone (ACTH) beta-endorphin, and catecholamines during cardiac surgery were investigated in a prospective, randomised study and compared to those following the administration of midazolam-fentanyl. PATIENTS AND METHODS. Nineteen patients undergoing myocardial revascularisation were assigned to two groups: group 1: etomidate-fentanyl (n = 9) and group 2: midazolam-fentanyl (n = 10). Anaesthesia was induced with fentanyl 0.5 mg and either etomidate 0.3 mg/kg or midazolam 0.2 mg/kg. Relaxation was achieved with pancuronium 0.1 mg/kg. Anaesthesia was maintained during extracorporeal circulation (ECC) with an infusion of etomidate (0.36 mg.kg-1.h-1) or midazolam (0.16 mg.kg-1.h-1) and fentanyl 10 micrograms.kg-1.h-1. Blood samples were drawn before induction, before ECC, and 1, 6, and 20 h after surgery. Cortisol secretion was stimulated with 0.25 mg ACTH1-24 IV at 6 and 20 h postoperatively. RESULTS. The total drug doses were etomidate 87 +/- 3 mg and midazolam 46 +/- 2 mg. Plasma cortisol concentrations decreased in the etomidate group from 20 (10-31) to 10 (6-31) micrograms.dl-1 (median and range) before ECC, but had returned to baseline at 1 h and were significantly increased at 6 h [29 (15-47) micrograms.dl-1] and 20 h [46 (29-62) micrograms.dl-1]. There was no difference between the groups except at 20 h, when cortisol levels were higher in the etomidate group. The stimulated cortisol increase was markedly impaired in this group at both measuring points. ACTH and beta-endorphin were markedly increased in the etomidate group and ACTH concentrations were eight times greater than the corresponding values in the midazolam group after surgery (ACTH 141 vs. 18 pmol.l-1). Plasma catecholamine concentrations increased significantly in both groups. Noradrenaline concentrations were greater in the etomidate group at 6 h after surgery. Two patients in the midazolam group and none in the etomidate group required circulatory support with exogenous catecholamines. DISCUSSION. It is concluded that the stress of cardiac surgery can overcome the block in cortisol synthesis caused by the administration of high-dose etomidate by substantially increasing ACTH secretion. The administration of high-dose etomidate was not associated with cardiovascular instability. The use of etomidate as a component of TIVA can therefore not be ruled out on the grounds of insufficient cortisol secretion.

Adrenocorticotropic Hormone↗

PubMed2003

Intracranial pressure and cerebral hemodynamic in patients with cerebral tumors: a randomized prospective study of patients subjected to craniotomy in propofol-fentanyl, isoflurane-fentanyl, or sevoflurane-fentanyl anesthesia.

BACKGROUND: A critical point during craniotomy is opening of dura, where a high intracranial pressure (ICP) results in swelling of cerebral tissue. Controlled studies concerning ICP, degree of dural tension, and degree of cerebral swelling are therefore warranted. METHODS: In an open-label study, 117 patients with supratentorial cerebral tumors were randomized to propofol-fentanyl (group 1), isoflurane-fentanyl (group 2), or sevoflurane-fentanyl anesthesia (group 3). Normo- to moderate hypocapnia was applied, with a target level of arterial carbon dioxid tension of 30-40 mmHg. Mean arterial blood pressure was stabilized with intravenous ephedrine (2.5-5 mg) if necessary. Subdural ICP, mean arterial blood pressure, cerebral perfusion pressure (CPP), arteriovenous oxygen difference (AVDo2), internal jugular vein oxygen saturation were monitored before and after a 10-min period of hyperventilation, and the carbon dioxide reactivity was calculated. Furthermore, the tension of dura before and during hyperventilation and the degree of cerebral swelling during hyperventilation and after opening of the dura were estimated by the neurosurgeon. RESULTS: No differences were found between groups with regard to demographics, neuroradiologic examination, positioning of the head, and time to ICP measurement. Before and during hyperventilation, ICP was significantly lower and mean arterial blood pressure and CPP significantly higher in group 1 compared with groups 2 and 3 (P < 0.05). The tension of dura before and during hyperventilation was significantly lower in group 1 compared with group2 (P < 0.05), but not significantly different from group 3. In group 1, cerebral swelling after opening of dura was significantly lower compared with groups 2 and 3 (P < 0.05). Furthermore, AVDo was significantly higher and jugular vein oxygen saturation and carbon dioxide reactivity were significantly lower in group 1 compared with groups 2 and 3 (P < 0.05). No significant differences with regard to ICP, CPP, AVDo, carbon dioxide reactivity, and jugular vein oxygen saturation were found between patients anesthetized with isoflurane and sevoflurane. CONCLUSIONS: The study indicates that before as well as during hyperventilation, subdural ICP and AVDo2 are lower and CPP higher in propofol-anesthetized patients compared with patients anesthetized with isoflurane or sevoflurane. These findings were associated with less tendency for cerebral swelling after opening of dura in the propofol group. The carbon dioxide reactivity in patients anesthetized with isoflurane and sevoflurane was significantly higher than in the propofol group. The differences in subdural ICP between the groups are presumed to be caused by differences in the degree of vasoconstriction elicited by the anesthetic agents, but autoregulatory mechanisms caused by differences in CPP cannot be excluded.

Adolescent↗

PubMed1998

Fentanyl in hair. Chemical factors involved in accumulation and retention of fentanyl in hair after external exposure or in vivo deposition.

The levels of fentanyl extractable from mouse hair after chronic systemic administration and the suitability of externally loaded hair samples for establishing control and comparison samples were determined. Additionally, the effects of chemical modification of specific polar functionalities within the hair protein matrix on the deposition and recovery of fentanyl in hair subjected to external loading were determined. BALB/c mice entering a second phase of synchronized hair growth were treated ip with fentanyl (0.02, 0.05, or 0.10 mg/kg) on Monday, Wednesday, and Friday for 3 weeks. At that time, fentanyl concentrations in hair, as determined by GC/MS, were 0.025-0.050 ng/mg of hair. Hair samples exposed to fentanyl in phosphate buffer (ionized drug) showed no significant accumulation of drug into the hair, as determined by loss of fentanyl from the loading solution or by extraction of the hair. Hair samples exposed to nonionized fentanyl in methanolic solution (10, 50, and 100 ng/ml) showed significant accumulation of drug in the hair and significant removal of drug from the incubation solution. Fentanyl removal from solution plateaued after 24 hr, suggesting equilibration between fentanyl in solution and fentanyl in the hair. A mass balance between drug lost from the incubation solution and drug recovered from hair samples suggests that 94% of accumulated fentanyl is tightly bound to the hair matrix or resides in water-inaccessible compartments within the hair. These results suggest that fentanyl accumulation after in vivo administration differs, in the nature of storage, from fentanyl accumulation from external solutions and that external spiking of hair may not provide suitable control samples. Chemical modification of hair protein functionalities (reaction with diazomethane to esterify carboxylic acid groups or with acetic anhydride and pyridine to acetylate amine and hydroxyl functionalities) led to reproducible protein structure modification, as demonstrated by Fourier transform-IR and by pH titration. Hair from BALB/c mice was used. The accumulation of fentanyl was examined in hair samples exposed to fentanyl in methanol or methylene chloride solutions (10 ng/ml, 24 hr). Fentanyl was recovered from hair by 24-hr extraction in phosphate buffer, pH 6. Esterification of hair resulted in significantly less uptake of nonionized fentanyl from a methanolic solution and significantly lower recovery of drug from hair, relative to untreated hair, suggesting that carboxylic acid functionalities are necessary for the incorporation of drug. Acetylation of hair resulted in increased removal of fentanyl from methylene chloride solutions and increased recovery of fentanyl. This is consistent with the creation or expansion of a less polar compartment. Fentanyl uptake from a methanolic solution was also greater in acetylated hair. These results demonstrate that solution-accessible ionizable functionalities of hair play a significant role in the accumulation and retention of nonionized fentanyl from organic solutions.

Animals↗

PubMed2005

Characterisation of the pharmacokinetics of the fentanyl HCl patient-controlled transdermal system (PCTS): effect of current magnitude and multiple-day dosing and comparison with IV fentanyl administration.

INTRODUCTION: The fentanyl HCl patient-controlled transdermal system (PCTS) is a self-contained, preprogrammed, noninvasive analgesic delivery system for acute pain management. We carried out three studies with the following objectives: study I to evaluate the relationship between fentanyl absorption and the magnitude of current applied to the system; study II to determine dose-proportionality for the fentanyl HCl PCTS (25 and 40 microg); and study III to describe the effects of single- and multiple-day administration on the pharmacokinetics of fentanyl delivered by the PCTS. METHODS: All studies were open-label, crossover studies with washout periods between treatments. In study I, randomised participants (n = 36) received three of a potential five fentanyl HCl PCTS prototypes, each of which used a different current magnitude, and each of which was evaluated for 24 hours. In study II, participants (n = 40) received fentanyl (25 microg) from the PCTS for 23.33 hours, followed by fentanyl (40 microg) from the PCTS for 23.33 hours. Intravenous (IV) fentanyl (80 microg/h) was administered intermittently over 24 hours as a reference treatment in Studies I and II. In study III, participants (n = 28) received fentanyl (40 microg) from the PCTS for 20 hours, followed by fentanyl (40 microg) from the PCTS for 68 hours. Pharmacokinetic parameters, including maximum serum fentanyl concentration (Cmax), time to Cmax (tmax), area under the serum concentration-time curve (AUC) and terminal half-life (t(1/2)), were determined for each treatment. RESULTS: The amount of fentanyl absorbed from the PCTS was linearly dependent on the magnitude of current applied to the system, with a current of 170 microA resulting in the absorption of 39.5 microg of fentanyl at hour 23. Mixed-effect ANOVA indicated no significant difference (p > 0.1) in the dose-normalised pharmacokinetics of the fentanyl HCl PCTS 25 and 40 microg. No significant difference existed between the corrected AUC(0-5) of the fentanyl HCl PCTS during the single- and multiple-day treatment periods (0.40 and 0.54 microg x h/L, respectively; p = 0.133). The system was well tolerated, with headache and mild application site erythema being the most common treatment-related adverse events. CONCLUSIONS: A linear relationship exists between the amount of current applied to the fentanyl HCl PCTS and the amount of fentanyl absorbed. There is dose-proportionality in the pharmacokinetics of the fentanyl HCl PCTS 25 and 40 microg. Multiple-day administration does not affect the pharmacokinetics of the fentanyl HCl PCTS 40 microg. The system was well tolerated, even after repeated application.

Administration, Cutaneous↗

PubMed2000

Fentanyl self-administration in juvenile rats that were tolerant and dependent to fentanyl as infants.

Human neonates and infants can become tolerant and dependent during continuous fentanyl or morphine administration. The long-term consequences in these individuals as juveniles and adults are unknown. This study compared fentanyl self-administration behavior in juvenile rats that were opioid naive or were exposed chronically to fentanyl as infants. Postnatal day 14 infant rats remained naive or were implanted with saline- or fentanyl-filled Alzet minipumps. After 72 h, fentanyl's antinociceptive potency was 3.0-fold lower in the fentanyl-infused rats. Naloxone precipitated withdrawal occurred only in the fentanyl-infused animals. Other similarly treated infant rats were allowed to mature into P42 juvenile rats before enrolling them in an oral fentanyl self-administration study. Rats from each group consumed significantly more fentanyl than quinine. However, those rats, tolerant and dependent to fentanyl as infants, did not self-administer more fentanyl than their opiate-naive littermates. The issue of whether fentanyl was consumed for its reinforcing properties was demonstrated when noncontingent administration of opiate antagonists significantly reduced fentanyl intake in another group of juvenile rats. These data indicate that fentanyl is consumed for its reinforcing properties, but that infant fentanyl tolerance and dependence did not predispose them to self-administer more fentanyl than opiate-naive animals.

Animals↗

PubMed1989

Fentanyl and morphine discrimination in rats continuously infused with fentanyl.

Rats were trained to detect the stimulus properties of fentanyl, 0.04mg/kg. Tested acutely, fentanyl generalized to, and morphine substituted for, the fentanyl training stimulus, although morphine was approximately 100-fold less potent than fentanyl in producing this stimulus. Subsequently, these rats were implanted with pumps (0.25ml volume) that delivered osmotically 1µl/h of solution containing either 3µg/µl (n = 16) or 6µg µl (n = 16) of fentanyl. When tested shortly after pump implantation, saline administration resulted in fentanyl-lever selection, indicating that the pumps were releasing fentanyl. Fentanyl-lever selection peaked at approximately 8 h after implantation; by 24 to 72 h after implantation, saline injection produced mainly saline-lever selection. On days 4 and 5 of chronic infusion of fentanyl, the fentanyl and morphine dose-effect curves were redetermined in both groups: both curves had shifted upwards, and the degree of shift occurred as a function of the dose of fentanyl infused continuously. After 6 days of infusion, the pumps were removed, and the detection of the fentanyl training stimulus was tested at 4, 12 and 24h after pump removal. At 12 h after removal, the percentage of subjects selecting the fentanyl lever following 0.04 mg/kg of fentanyl decreased to 53%, and this recovered to 87% by 24 h following pump removal. These results demonstrate tolerance to the stimulus properties of opioids with a few hours from the time of insertion of the pumps; the tolerance was not complete as shown by the results obtained during dose-effect testing with the pumps in place; finally tolerance was observed for a brief period when the pumps infusing fentanyl were removed (withdrawal tolerance). No evidence was obtained for asymmetric tolerance between fentanyl and morphine.

Journal Article↗

PubMed2002

Patient-controlled epidural fentanyl following spinal fentanyl at Caesarean section.

Spinal fentanyl can improve analgesia during Caesarean section. However, there is evidence that, following its relatively short-lived analgesic effect, there is a more prolonged spinal opioid tolerance effect. The effectiveness of postoperative epidural fentanyl analgesia may therefore be reduced following the use of spinal fentanyl at operation. This randomised, double-blind study was designed to assess whether patient-controlled epidural fentanyl could produce effective analgesia following 25 microg of spinal fentanyl at operation. Patients undergoing elective Caesarean section received spinal bupivacaine combined with either fentanyl 25 microg (fentanyl group; n = 18) or normal saline (saline group; n = 18). Patient-controlled epidural fentanyl was used for postoperative analgesia. The fentanyl group used a mean of 23.4 (SD 14.5) microg x h(-1) of fentanyl, compared with 27.0 (10.8) microg x h(-1) for the saline group (p =0.41). Using a 0-100 mm visual analogue score for pain, the maximum pain score recorded at rest for the fentanyl group was median 24 [IQR 15-35] mm, compared with 15 [13-45] mm for the saline group (p = 0.41). The maximum pain score recorded on coughing for the fentanyl group was 29 [24-46] mm, compared with 27 [19-47] mm for the saline group (p = 0.44). Nine of the fentanyl group rated postoperative analgesia as excellent and nine as good, compared with 10 of the saline group who rated it as excellent and eight as good (p = 0.74). Epidural fentanyl can produce effective analgesia following the use of 25 microg spinal fentanyl at Caesarean section.

Adult↗

PubMed1986

Fentanyl-oxygen versus fentanyl-N2O/oxygen anaesthesia in children undergoing cardiac surgery.

Fentanyl-oxygen (fentanyl-O2) anaesthesia was compared to fentanyl-nitrous oxide/oxygen (fentanyl-N2O/O2) anaesthesia in 14 children undergoing cardiac surgery. Children were randomly assigned to one of the two techniques studied, with seven patients in each group. The mean age (mean +/- SE) was 3.9 +/- 0.75 years (0.5-8.25 years) and mean weight 14.7 +/- 2 kg (3.5-29.5 kg). Patients were premedicated with IM atropine 0.02 mg . kg-1 and morphine 0.2 mg . kg-1 1 hour preoperatively. They received a fentanyl bolus of 30 micrograms . kg-1 with a concomitant continuous infusion of 0.3 micrograms . kg-1 . min-1. Pancuronium 0.1 mg . kg-1 was administered immediately following the fentanyl bolus. Fifty per cent nitrous oxide was given with oxygen in one group and 100 per cent oxygen was administered to the other group. Fentanyl plasma concentrations were similar in the two groups at the various stages of surgery. There were no significant differences between the two treatment groups in systolic and diastolic blood pressure or in heart rate in response to induction, intubation, and incision. There was a significantly greater increase in systolic blood pressure after sternotomy in the fentanyl-O2 group. In addition, in six of seven patients receiving fentanyl-O2 there were events of sudden increase in blood pressure during various stages of surgery before the bypass, necessitating an additional fentanyl bolus or the addition of droperidol in four cases. Similar phenomena were not documented in the fentanyl-N2O/O2 group. Our studies suggest that fentanyl-O2 anaesthesia in the schedule described, in children undergoing elective cardiac surgery for Tetralogy of Fallot, A-V canal, and transposition of the great arteries, is not sufficient to prevent elevation in systolic blood pressure despite fentanyl plasma concentrations in excess of 20 ng X ml-1. The addition of nitrous oxide prevents this phenomenon.

Anesthesia, General↗

PubMed2001

Postoperative epidural analgesia in children after major orthopaedic surgery. A randomised study of the effect on PONV of two anaesthetic techniques: low and high dose i.v. fentanyl and epidural infusions with and without fentanyl.

BACKGROUND: The study was performed in order to improve postoperative pain management in children after major orthopaedic surgery. Two different anaesthetic techniques (sevoflurane-low fentanyl and propofol-higher fentanyl) and two different epidural mixtures (bupivacaine 1.5 mg ml(-1) and adrenaline 2 microg ml(-1) compared with bupivacaine 1 mg ml(-1), adrenaline 2 microg ml(-1) and fentanyl 2 microg ml(-1)) were investigated with regard to postoperative analgesia and side effects, primarily postoperative nausea and vomiting (PONV). METHODS: Forty-two children were randomised into one of three groups: sevoflurane anaesthesia and epidural solution with fentanyl (SBAF); sevoflurane anaesthesia and epidural solution without fentanyl (SBA); propofol anaesthesia and epidural solution without fentanyl (PBA). RESULTS: Including fentanyl in the epidural mixture resulted in excellent postoperative analgesia without any need of i.v. opioids. However, 7 out of 16 children were nauseated and needed antiemetic drugs. On average, a 55-75% higher dose of bupivacaine was necessary to assure adequate analgesia when an epidural mixture without fentanyl was used. In addition, significantly more children needed i.v. opioids. Under these conditions there was no significant difference in pain scoring between the groups. There was significantly less nausea and less use of antiemetic drugs in children having epidurals without fentanyl in the sevoflurane groups. The same tendency, although not significant, was observed in the whole material. Sevoflurane anaesthesia resulted in less PONV than propofol anaesthesia, probably due to the higher amount of intravenous fentanyl used with the latter. This difference was not significant due to the small number of children included. Incidence of pruritus related significantly to epidural fentanyl. CONCLUSION: A satisfactory postoperative analgesia can be achieved with both epidural mixtures used in the study. Epidural fentanyl results in better analgesia, but significantly more PONV and greater use of antiemetic drugs. Omitting epidural fentanyl results in less PONV, but significantly less profound analgesia and a need for additional treatment with i.v. opioids, in addition to a 55-75% higher epidural bupivacaine infusion. Both epidural treatments result in high and similar patient satisfaction and no serious complications. The study could not show any significant difference between the effect of sevoflurane and propofol anaesthesia on PONV.

Adjuvants, Anesthesia↗

PubMed2005

Determination of fentanyl in human plasma and fentanyl and norfentanyl in human urine using LC-MS/MS.

Fentanyl, a potent analgesic drug, has traditionally been used intravenously in surgical or diagnostic operations. Formulations with fentanyl in oral transmucosal delivery system and in transdermal depot-patch have also been developed against breakthrough pain in cancer patients. In this report, LC-MS/MS methods to determine fentanyl in human plasma as well as fentanyl and its main metabolite, norfentanyl, in human urine are presented together with validation data. The validation ranges were 0.020-10.0 and 0.100-50.0 ng/ml for fentanyl in plasma and urine, respectively, and 0.102-153 ng/ml for norfentanyl in urine. Liquid-liquid extraction of the compounds fentanyl, norfentanyl and the deuterated internal standards, fentanyl-d5 and norfentanyl-d5 from the matrixes was applied and separation was performed on a reversed phase YMC Pro C18-column followed by MS/MS detection with electrospray in positive mode. The inter-assay precision (CV%) was better than 4.8% for fentanyl in plasma and 6.2% and 4.7% for fentanyl and norfentanyl, respectively, in urine. The ruggedness of the methods, selectivity, recovery, effect of dilution and long-term stability of the analytes in plasma and urine were investigated. Effect of haemolysis and stability of fentanyl in blood samples were also studied. The methods have been applied for the determination of fentanyl in plasma samples and fentanyl/norfentanyl in urine samples taken for pharmacokinetic evaluation after a single intra-venous (i.v.) dose of 75 microg fentanyl.

Chromatography, Liquid↗

PubMed1997

Small-dose hypobaric lidocaine-fentanyl spinal anesthesia for short duration outpatient laparoscopy. II. Optimal fentanyl dose.

We performed a double-blind, controlled trial to determine the optimal dose of intrathecal fentanyl in small-dose hypobaric lidocaine spinal anesthesia for outpatient laparoscopy. Sixty-four gynecological patients were randomized into three groups, receiving 0, 10, or 25 micrograms fentanyl added to 20 mg lidocaine and sterile water (total 3 mL). Administration was with 27-gauge Whitacre needles and patients sat upright until the block was > T-8. One patient in the 0-microgram fentanyl group required general anesthesia 40 min after the start of surgery, leaving 21 patients per group. Three patients in each of the 0-microgram and 10-microgram fentanyl groups had mild discomfort with trocar insertion, or return of some sensation and felt discomfort or sutures toward the end of surgery. Shoulder-tip pain was less frequent in the 25-microgram than 0-microgram fentanyl group, 28% vs 67% (P < 0.0166). Intraoperative supplementation with alfentanil (+/- propofol) was needed less often in the 25-microgram than 0-microgram fentanyl group, 43% vs 76% (P = 0.028). Recovery of sensation took longer in the 25-microgram than in the 0-microgram and 10-microgram fentanyl groups, 101 +/- 21 vs 84 +/- 20 and 87 +/- 18 min (P < 0.05), although motor recovery and discharge times were the same. Postoperative analgesia was needed earlier in the 0-microgram than in the 25-microgram fentanyl group, median 54 (13-120) vs 87 (65-132) min (P < 0.05). Pruritus was the only side effect that occurred more often in the 10-microgram and 25-microgram groups than in the 0-microgram fentanyl group, 62% and 67% vs 14% (P < 0.0166). One patient required an epidural blood patch for postdural puncture headache. Based on these results, we concluded that 25 micrograms intrathecal fentanyl is required when 20 mg lidocaine is used for hypobaric spinal anesthesia (SA) to ensure reliable, durable anesthesia, reduce shoulder-tip pain, and minimize the need for intraoperative supplementation. This dose provides longer postoperative analgesia and does not increase side effects apart from pruritus. SA with small-dose hypobaric lidocaine-fentanyl was found to be a satisfactory technique for outpatient laparoscopy, although postdural puncture headache can occur in some patients.

Adult↗

PubMed1976

The magnitude and duration of respiratory depression produced by fentanyl and fentanyl plus droperidol in man.

In 10 healthy male volunteers breathing 100% oxygen, we determined the effect of four intravenous dose levels of fentanyl (0.0015, 0.003, 0.006 and 0.009 mg/kg) and two of fentanyl plus droperidol (i.e., Innovar, 0.003 and 0.006 mg/kg of fentanyl with 2.5 mg of droperidol for each 0.05 mg of fentanyl) on PECO2 and the slope of the ventilatory response to imposed increases in PECO2. All doses of fentanyl and fentanyl plus droperidol depressed the slope and shifted the curve to the right. Depression was dose related and was maximum 5 minutes after administration. The slope returned to control by 2 hours postinjection even at the highest narcotic dose. However, the rightward shift of the CO2 response curve require 4 hours to return to control. Droperidol added to fentanyl did not increase or prolong the respiratory depression seen with fentanyl alone at equivalent dose levels. Nausea and emesis occurred more frequently with fentanyl alone and orthostatic hypotension occurred more frequently with droperidol plus fentanyl. Dysphoria was a prominent consequence of fentanyl plus droperidol administration.

Adult↗

PubMed1992

Patient-controlled lumbar epidural fentanyl compared with patient-controlled intravenous fentanyl for post-thoracotomy pain.

Thirty-four patients undergoing thoracotomy were entered into a randomized, double-blind, placebo-controlled study to compare the effects of patient-controlled, lumbar epidural (PCA-E) fentanyl with patient-controlled intravenous (PCA-i.v.) fentanyl with respect to drug requirements, analgesic efficacy and respiratory function. Prior to chest closure patients received fentanyl 2 micrograms.kg-1 by the epidural or i.v. route. In the recovery room further doses of epidural or i.v. fentanyl, 50 micrograms, were administered by the patients who controlled two PCA pumps. Background fentanyl infusion rates were increased by 10 micrograms.hr-1 each time the patient administered a drug bolus and were decreased by 10 micrograms.hr-1 whenever visual analogue scale (VAS) pain scores were less than 2 on a maximum 10 scale. Twenty-nine patients completed the study. Patients in the PCA-E group (n = 14) required less total fentanyl than those in the PCA-i.v. (n = 15) group (1857 +/- 693 micrograms vs 2573 +/- 890 micrograms respectively, P less than 0.05). Fentanyl infusion rates were lower in the PCA-E group at most measurement times. There were no differences between groups in respiratory rates, PaCO2, VAS pain scores or changes in pulmonary function as measured by FVC and FEV1. It is concluded that satisfactory patient-controlled analgesia can be achieved with both epidural and i.v. fentanyl after thoracotomy but that fentanyl requirements are less when given via the epidural route. This supports a direct spinal cord site of action for lumbar epidural fentanyl.

Analgesia, Epidural↗

PubMed2006

Validated GC-MS analysis for the determination of residual fentanyl in applied Durogesic reservoir and Durogesic D-Trans matrix transdermal fentanyl patches.

The method development and validation characteristics are described of a simple gas chromatographic-mass spectrometric (GC-MS) analytical procedure to determine residual fentanyl in used Durogesic reservoir patches and Durogesic D-Trans matrix technology based systems to estimate the actual rate of transdermal fentanyl delivered in individual patients. The sample preparation protocol constituting a saline based extraction of sets of new patches of each nominal dose available, resulted in fentanyl extraction recoveries to increase steadily as a function of increasing extraction time. For the reservoir type transdermal therapeutic system (TTS), fentanyl extraction efficiencies at equilibrium (16 h) ranged from approximately 60% (100-microg/h TTS) to 95% (25-microg/h TTS), whereas for the matrix type system considerable lower recoveries were demonstrated for the highest nominal dose rates (35%-52%), while reaching 90% for the 25-microg/h system. For the latter type of fentanyl TTS, an optimized methanol based extraction protocol yielded virtually quantitative fentanyl recoveries for each matrix patch nominal dose level at substantially shorter extraction periods (15 min). The GC-MS analytical method using selected ion monitoring (SIM) and deuterated fentanyl as internal standard was shown to be adequately selective with regard to the presence of other compounds in the Durogesic patches. It was further demonstrated that the developed analytical protocols provided highly reproducible and accurate estimates of the initial fentanyl content of each patch type at all available nominal doses, with coefficients of variation and relative errors generally below 10%. These advantageous assay validation characteristics can be further transposed to the application of residual fentanyl level estimates in used patches, provided that with each batch of samples also a set of new TTSs with equal dose is assayed to perfectly mimic extraction phenomena. Finally, the presented GC-MS analytical protocol was successfully applied for the determination of residual fentanyl in a subset of 57 reservoir type patches obtained from four palliative patients.

Administration, Cutaneous↗