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PubMed1994

Comparative physiological pharmacokinetics of fentanyl and alfentanil in rats and humans based on parametric single-tissue models.

The objectives of this investigation were to characterize the disposition of fentanyl and alfentanil in 14 tissues in the rat, and to create physiological pharmacokinetic models for these opioids that would be scalable to man. We first created a parametric submodel for the disposition of either drug in each tissue and then assembled these submodels into whole-body models. The disposition of fentanyl and alfentanil in the heart and brain and of fentanyl in the lungs could be described by perfusion-limited 1-compartment models. The disposition of both opioids in all other examined tissues was characterized by 2- or 3-compartment models. From these models, the extraction ratios of the opioids in the various tissues could be calculated, confirming the generally lower extraction of alfentanil as compared to fentanyl. Assembly of the single-tissue models resulted in a wholebody model for fentanyl that accurately described its disposition in the rat. A similar assembly of the tissue models for alfentanil revealed non-first-order elimination kinetics that were not apparent in the blood concentration data. Michaelis-Menten parameters for the hepatic metabolism of alfentanil were determined by iterative optimization of the entire model. The parametric models were finally scaled to describe the disposition of fentanyl and alfentanil in humans.

Alfentanil↗
PubMed1990

Anticonvulsant therapy increases fentanyl requirements during anaesthesia for craniotomy.

This study was designed to determine whether patients receiving chronic anticonvulsant therapy demonstrate an altered requirement for fentanyl during anaesthesia. Sixty-one patients undergoing craniotomy were studied; 20 controls (MED = 0) who had never received anticonvulsants and 41 epileptics in whom therapeutic plasma concentrations of either one (MED = 1), two (MED = 2), or three (MED = 3) different anticonvulsants were documented. During anaesthesia with 60-70 per cent N2O in O2 and 0.2 per cent isoflurane, a maintenance dose (MD) of fentanyl was administered using a continuous variable-rate IV fentanyl infusion, supplemented by intermittent 50 micrograms IV boluses. In order to define the minimal dosage of fentanyl required, the MD was titrated according to increases or decreases in the heart rate and/or mean arterial pressure exceeding 15 per cent of baseline ward values. A progressively higher fentanyl MD was required in the epileptic patients (MED = 1-4.3 +/- 0.5 microgram.kg-1.hr-1; MED = 2-5.4 +/- 0.6; MED = 3-7.6 +/- 0.6) compared with the control MD (MED = 0-2.6 +/- 0.5) (P less than 0.001). These findings indicate that there appears to be a dose-effect relationship between the number of anticonvulsants received and the maintenance dose of fentanyl required during balanced anaesthesia.

Adolescent↗
PubMed1976

The cardiovascular effects of diazepam and of diazepam and pancuronium during fentanyl and oxygen anaesthesia.

The cardiovascular effects of diazepam 0.5 and 1.0 mg/kg and diazepam with pancuronium 0.1 mg/kg after fentanyl 0.5 mg/kg were determined in thirteen dogs premedicated with atropine. Fentanyl produced significant reductions in heart rate, cardiac ouptut and arterial blood pressure. Administration of 0.5 mg/kg of diazepam after fentanyl did not significantly alter stroke volume, arterial blood pressure or peripheral vascular resistance but did increase heart rate and cardiac output. Additional diazepam did not further change the heart rate, but did reduce stroke volume, cardiac output, arterial blood pressure and peripheral vascular resistance. Administration of pancuronium after fentanyl and diazepam produced marked elevations in heart rate, cardiac output and arterial blood pressure. There was no difference in mean heart rate and cardiac output when values prior to fentanyl and those obtained three minutes following pancuronium were compared. These data demonstrate that large doses of fentanyl decrease heart rate, cardiac these changes can be partially reversed with diazepam 0.5 mg/kg and completely antagonized with pancuronium 0.1 mg/kg.

Anesthesia, Inhalation↗
PubMed1990

Analgesia and serum concentrations of extradural, subdural and intraperitoneal fentanyl in a rat model.

The effects of epidural, subdural and intraperitoneal fentanyl were determined on the tail flick response of the rat using the response latency as a measure of analgesia. Dose-time-response curves were generated for incremental doses of fentanyl administered at constant injection volumes. Serum concentrations at varying doses were determined using a radioimmunoassay technique. It was found that serum concentrations for extradural, subdural and intraperitoneal fentanyl were similar at the low doses, but differed significantly at higher doses suggesting that pharmacokinetic differences may be concentration dependent. Extradural administration of naloxone (0.004 mg) was able to antagonize extradural fentanyl (8.0 micrograms), a dose eight-fold greater than the lowest maximally effective dose. The relationship between serum fentanyl concentrations and administered doses suggest that the analgesic properties of extradural and subdural fentanyl are in part dependent on centrally mediated actions.

Analgesia↗
PubMed1982

Effect of enflurane and fentanyl on the clinical characteristics of long-term succinylcholine infusion.

The characteristics of the neuromuscular block produced by prolonged succinylcholine infusion were compared in 40 patients anaesthetized with either nitrous oxide with enflurane (1-2 per cent inspired) or nitrous oxide and fentanyl. Neuromuscular transmission was monitored using train-of-four stimulation and the infusion rate was adjusted to keep the first twitch at 10-15 per cent of its control value. Initially, all patients, exhibited a depolarizing-type block all twitches of the train-of-four being roughly the same size, and the infusion rates were similar in the enflurane (54 microgram X kg-1/min) and the fentanyl (58 microgram X kg-1/min) groups. Tachyphylaxis developed later in both groups and correlated well with the onset of phase II block (dual block). This occurred sooner and at a lower cumulative dose in the enflurane group. Fourth to first twitch ratios decreased to 50, 25 and 0 per cent in 31, 46 and 59 minutes in the enflurane group, at cumulative succinylcholine doses of 2.2, 3.2 and 4.2 mg X kg-1 respectively. Corresponding figures for the fentanyl group were 52, 73 and 86 minutes, with dose of 3.4, 5.0 and 5.9 mg X kg-1. Infusion rates increased markedly after establishment of dual block, but were similar with enflurane (0.99 mg X kg-1/min) and fentanyl (1.12 mg X kg-1/min). Ten minutes after stopping the infusion fourth to first twitch ratios failed to reach 50 per cent in most patients given enflurane who had received more than 6 mg X kg-1 succinylcholine over more than 90 minutes. Corresponding figures for fentanyl patients were 13 mg x kg-1 and 150 minutes. The block in all 15 patients (9 enflurane, 6 fentanyl) who did not recover spontaneously was successfully antagonized with atropine and neostigmine.

Adult↗
PubMed1992

Concentration of fentanyl in colostrum after an analgesic dose.

The purpose of this study was to measure the concentration of fentanyl in human colostrum after intravenous administration of an analgesic dose. Thirteen healthy women were given fentanyl 2 micrograms.kg-1 for analgesic supplementation during either Caesarean section or postpartum tubal ligation. Serum and colostrum were collected for 45 min, two, four, six, eight, and ten hours following administration of the drug. Radioimmunoassay showed that colostrum fentanyl concentrations were greatest at 45 min, the initial sampling time, reaching 0.40 +/- 0.059 ng.ml-1, but were virtually undetectable ten hours later. Fentanyl concentrations were always higher in colostrum than in serum. This concluded that with these small concentrations and fentanyl's low oral bioavailability, intravenous fentanyl analgesia may be used safely in breast-feeding women.

Adult↗
PubMed1986

Haemodynamic and plasma vasopressin responses during high-dose fentanyl or sufentanil anaesthesia.

This study compared the haemodynamic and arginine vasopressin responses of patients to fentanyl or sufentanil anaesthesia for coronary artery bypass surgery. Fourteen normotensive patients with normal left ventricular function were studied. Patients were induced with fentanyl (N = 7) 37.5 micrograms X kg-1 or sufentanil (N = 7) 7.5 micrograms X kg-1 by intravenous infusion over three minutes. Clinically important chest wall rigidity, bradycardia and recall of intraoperative events did not occur. All of the fentanyl patients became hypertensive after induction and five required vasodilator therapy since they did not respond to boluses of fentanyl (12.5 micrograms X kg-1). Two of these five patients had S-T depression greater than 1 mm. Five patients in the sufentanil group became hypertensive after induction. Four of these patients responded to additional sufentanil (3.75 micrograms X kg-1) while one required vasodilator therapy for concomitant S-T depression. Sufentanil attenuated the increase of arginine vasopressin during cardiopulmonary bypass. Levels of arginine vasopressin in the fentanyl group were significantly higher than those of the sufentanil group during bypass. Levels of AVP after bypass were higher in the sufentanil group. The incidence of hypertension was similar in both groups. The hypertension was more easily treated with sufentanil but concomitant vasodilators (nitroglycerine) were required in both patient groups. Neither fentanyl in doses up to 128 +/- 8.7 micrograms X kg-1 nor sufentanil in doses up to 23 +/- 1.4 micrograms X kg-1 can be used as sole agents for anaesthesia in adult coronary artery bypass patients with good ventricular function when induction times are three minutes and bolus top-up doses are used.

Adult↗
PubMed1995

Intrathecal fentanyl prolongs sensory bupivacaine spinal block.

The purpose of investigation was to study the effect of intrathecal fentanyl on the onset and duration of hyperbaric bupivacaine-induced spinal block in adult male patients. Forty-three patients undergoing lower extremity or genitourinary surgery were enrolled to receive either 13.5 mg hyperbaric bupivacaine 0.75% + 0.5 ml CSF it, (Group I) or 13.5 mg hyperbaric bupivacaine 0.75% + 25 micrograms fentanyl it, (Group II) according to a randomized assessor-blind protocol. The onset and duration of sensory block were assessed by pinching the skin with forceps in the midclavicular line bilaterally every two minutes for first twenty minutes and then every five to ten minutes. Similarly, the onset and duration of motor block were assessed and graded at the same time intervals using the criteria described by Bromage. The time required for two sensory segment regression and sensory regression to L1 dermatome was 74 +/- 18 and 110 +/- 33 min vs 93 +/- 22 and 141 +/- 37 min in Groups I and II, respectively (P < 0.05). Intrathecal fentanyl did not enhance the onset of sensory or motor block, or prolong the duration of bupivacaine-induced motor spinal block. Fewer patients demanded pain relief in the fentanyl-treated group than in the control group in the early postoperative period (19% vs 59%; P < 0.05). Episodes of hypotension were more frequent in the fentanyl-treated group than in the control group (43% vs 14%; P < 0.05). We conclude that fentanyl, 25 micrograms it, prolonged the duration of bupivacaine-induced sensory block (sensory regression to L1 dermatone) by 28% and reduced the analgesic requirement in the early postoperative period following bupivacaine spinal block.

Adjuvants, Anesthesia↗
PubMed1999

Intraarticular fentanyl compared with morphine for pain relief following arthroscopic knee surgery.

PURPOSE: To compare the analgesia produced by comparable doses of intra-articular (IA) morphine and fentanyl. METHODS: Sixty-nine healthy patients undergoing arthroscopic surgery received a standardized general anesthetic of 4 mg x kg(-1) thiopental and 2 microg x kg(-1) fentanyl followed by 2 mg x kg(-1) succinylcholine prior to tracheal intubation and controlled ventilation. Maintenance of anesthesia was achieved with N2O/O2 and isoflurane. At the conclusion of surgery intra-articular injection was: Group I (n=23) 50 microg fentanyl in 20 ml saline; Group II (n=24) 3 mg morphine in 20 ml saline; Group III (n=22) 20 ml saline. Pain scores at rest using a visual analogue scale were recorded by a separate blinded observer at one, two, four, and eight hours postoperatively. RESULTS: Pain scores at one, two, four, and eight hours were 36, 26.3, 20.9, and 12.8 vs 35.8, 33.8, 28.8, and 21.9 vs 70.5, 57.7, 58.4, and 53.6 for the IA-fentanyl, IA-morphine, and control groups respectively. Pain scores were greater at all times for Group III. Pain scores for Groups I and II were similar at one hour, but thereafter were less (P < 0.001) for the IA-fentanyl group. CONCLUSION: Better postoperative analgesia was achieved with 50 microg intraarticular fentanyl than with 3 mg intraarticular morphine.

Adolescent↗
PubMed1996

Epidural fentanyl improves the onset and spread of epidural mepivacaine analgesia.

PURPOSE: To determine the extent of enhanced blockade by the combined use of epidural fentanyl and mepivacaine. We compared the onset of hypoalgesia, analgesia and the threshold of pressure pain. METHODS: Thirty patients were randomly divided into three groups. The fentanyl group received 10 ml saline containing 0.1 mg fentanyl, mepivacaine group received 10 ml mepivacaine 1% and a mixed group received 10 ml mepivacaine 1% with 0.1 mg fentanyl. All solutions, without epinephrine, were injected through an epidural catheter at T5-6 to T6-7. The change in sensation, loss of pin-prick and pain threshold sensation, measured by pressure algometer, were assessed at 2.5-min intervals for 15 min at the T4 dermatome. Spread of analgesia was determined at 15 min. RESULTS: Loss of pinprick was more rapid in the mixed, 11.0 +/- 2.7 (SD) min, than in the mepivacaine group, 15.0 +/- 2.9 min, (P < 0.05), although there was no difference in change of sensation. Pressure pain threshold increased with time in the mepivacaine (P < 0.05) and mixed (P < 0.05) groups. It was higher in the mixed than in the fentanyl and mepivacaine groups at 5, 7.5 and 10 min (P < 0.05). The lower level of analgesia was lower in the mixed than in the mepivacaine groups (P < 0.05). Blood pressure was unchanged in the three groups, but heart rate decreased at 7.5, 10, 12.5, and 15 min in the mepivacaine and mixed groups (P < 0.05). CONCLUSIONS: The addition of fentanyl to mepivacaine accelerates the onset of analgesia and enhances the analgesic effect of epidural block.

Adult↗
PubMed1997

Transdermal fentanyl system plus im ketorolac for the treatment of postoperative pain.

PURPOSE: To assess the safety and efficacy of transdermal fentanyl plus im ketorolac vs im ketorolac alone in the treatment of postoperative pain. METHODS: Ninety-two patients scheduled for surgery involving moderate to severe postoperative pain were randomized to one of two groups. Group A (n = 46) received an active fentanyl patch and group P (n = 46) received a placebo patch. Patches remained in place for 24 hr. Each patient received intraoperative ketorolac, 60 mg im. Patients were monitored for 36 hr postoperatively and the groups were analyzed for ketorolac usage, pain scores, vital signs, serum fentanyl concentrations, and adverse events. Intramuscular ketorolac was available on demand. RESULTS: Group A had lower pain scores at 8.12, 16 and 24 hr after patch placement (P < 0.05). Group A had lower heart rates, lower respiratory rates and fewer dropouts due to inadequate pain relief (4.3% vs 21.7% P < 0.05). Group A patients also used less ketorolac than group P patients (P < 0.05). The incidence of pruritus was higher in group A patients (19% vs 2%, P < 0.05), while the incidence of nausea and vomiting was not different between the two groups. Transdermal fentanyl was adequate "stand-alone" analgesia in only 23.8% of group A patients while 93.7% of the remaining group A patients receiving a combination of transdermal fentanyl and ketorolac had adequate pain relief. CONCLUSION: The transdermal fentanyl delivery system plus ketorolac im was more effective in controlling post-operative pain than ketorolac im alone. The two treatment modalities were comparable in safety with no difference in serious adverse events.

Administration, Cutaneous↗
PubMed1995

Phosphatidylinositol responses are involved in the vascular effects of thiamylal and fentanyl.

Although thiobarbiturates potentiate, and fentanyl attenuates peripheral vasoconstriction, the intracellular mechanism involved in this phenomenon is not clear. Because smooth muscle contraction induced by alpha 1-adrenoceptor agonists is mediated by the phosphatidylinositol (PI) response, this study was carried out to clarify if thiamylal and fentanyl affect the norepinephrine-induced PI response in rat aortic slices. Rat aortic slices were incubated in Krebs-Henseleit solution containing 5 mM LiCl, [3H]myo-inositol, and varying concentrations of thiamylal or fentanyl. The Pl response was stimulated by 0.9 microM (ED50) norepinephrine (NE). The [3H]inositol monophosphate (IP1) was separated from [3H]myo-inositol by column chromatography and counted with a liquid scintillation counter. The basal IP1 accumulation was not affected by thiamylal and fentanyl. Norepinephrine-induced IP1 accumulation was potentiated by thiamylal at concentrations of 10 microM and 100 microM. Norepinephrine-induced IP1 accumulation was attenuated by 1 microM and 10 microM fentanyl. The results suggest that thiamylal stimulates the NE-induced PI response, which potentiates the vasoconstriction, and fentanyl attenuates NE-induced PI response, which would attenuate the vasoconstriction.

Anesthetics, Intravenous↗
PubMed1987

Plasma concentrations of fentanyl in infants, children and adults.

To evaluate whether there are age-related differences in the plasma concentration-vs-time course of fentanyl, the authors administered fentanyl to seven infants (3-10 months), seven children (1-9 years) and seven adults (18-41 years). Anaesthesia was induced with thiopentone, nitrous oxide, and pancuronium; following tracheal intubation, fentanyl (approximately 30 micrograms X kg-1 for infants and children, 20 micrograms X kg-1 for adults) was administered as a 2-min IV infusion. Anaesthesia was maintained with nitrous oxide, pancuronium, and morphine sulphate as clinically indicated. Plasma samples were obtained for 4 h and fentanyl concentrations determined by radioimmunoassay. Plasma concentrations per microgram X kg-1 fentanyl administered were lowest in infants 4-10 and 60-240 min after the start of the 2-min infusion; values for children were lower than those for adults 4, 180 and 210 min after the start of the 2-min infusion. These findings are consistent with the authors' clinical observation that infants tolerate larger doses of fentanyl than do adults.

Adolescent↗
PubMed2002

Fentanyl is more effective than remifentanil at preventing increases in cerebral blood flow velocity during intubation in children.

PURPOSE: Controlling the cerebral and systemic hemodynamic responses to laryngoscopy and tracheal intubation may play a role in determining clinical outcome in pediatric neurosurgical patients. This study compared the effects of remifentanil and fentanyl on cerebral blood flow velocity (CBFV) and hemodynamic profile during laryngoscopy and tracheal intubation in children under sevoflurane anesthesia. METHODS: Sixty healthy children aged two to six years undergoing dental surgery under general anesthesia were enrolled. Each child was randomly assigned to receive a remifentanil or fentanyl infusion, at a rate of 0.75, 1.0, or 1.5 microg x kg(-1) x min(-1) after induction of anesthesia with 2% sevoflurane. Middle cerebral artery blood flow velocity was measured by transcranial Doppler (TCD) sonography. Once a baseline set of hemodynamic variables and TCD measurements were recorded, the opioid infusion was started. Measurements were taken at two-minute intervals, starting four minutes prior to laryngoscopy until four minutes following naso-tracheal intubation. RESULTS: Remifentanil caused a more significant decrease in mean arterial pressure and CBFV prior to tracheal intubation than did fentanyl (P < 0.001). During laryngoscopy and for two minutes following tracheal intubation, CBFV increased in all remifentanil groups (P < 0.05), whereas it remained stable in all fentanyl groups. CONCLUSION: This study suggests that fentanyl was more effective than remifentanil at preventing increases in CBFV during and immediately following laryngoscopy and tracheal intubation in children undergoing sevoflurane anesthesia. Fentanyl also seemed to provide a more stable hemodynamic profile prior to laryngoscopy and tracheal intubation when compared to remifentanil.

Blood Flow Velocity↗
PubMed2006

Protective effect of prior administration of magnesium on delayed hyperalgesia induced by fentanyl in rats.

PURPOSE: Magnesium exerts a physiological block of the ion channel on the N-methyl-D-aspartate receptor, and may therefore prevent the induction of central sensitization. The purpose of this study was to assess whether systemic magnesium can prevent long-lasting hyperalgesia induced by sc fentanyl administration in uninjured rats. METHODS: Long-lasting hyperalgesia was induced in male Sprague Dawley rats with sc fentanyl (four injections, 60 microg x kg(-1) per injection at 15-min intervals). Magnesium sulphate (100 mg x kg(-1)) was injected ip 30 min prior to the first sc fentanyl injection. Sensitivity to nociceptive stimuli (paw-pressure test) was assessed for several days after injections. RESULTS: Subcutaneous fentanyl led to delayed hyperalgesia associated with a decrease in the nociceptive threshold lasting two days (35% decrease for the maximum effect). Intraperitoneal magnesium sulphate partially but significantly (P < 0.05) prevented the delayed decrease in the nociceptive threshold following sc administration of fentanyl. CONCLUSIONS: This study shows that magnesium may prevent the delayed and prolonged hyperalgesia following fentanyl administration in rats.

Analgesics↗
PubMed2001

Intrathecal fentanyl does not modify the duration of spinal procaine block.

PURPOSE: To document the clinical characteristics of spinal procaine with or without the addition of fentanyl in light of the failure rate observed previously with procaine 10%. METHODS: In a randomized, prospective, double-blind study, 52 patients received spinal anesthesia with 100 mg procaine and either saline 0.9% (0.4 ml) (CONTROL group) or 20 microg fentanyl (0.4 ml) (FENTANYL group). Sensory anesthesia to needle prick was evaluated each minute for ten minutes, every three minutes for 33 minutes and every five minutes until regression to T10. Motor block was assessed with the Bromage scale. Patients were questioned by telephone for pain suggesting transient radicular irritation (TRI) 48 hr later. RESULTS: Mean time to reach highest sensory level, maximum number of segments blocked and mean time for regression of the sensory level to T10 showed no difference. Time to recuperate to full flexion of knees and feet (Bromage 4) showed no difference. Nine patients had nausea (five in CONTROL group and four in FENTANYL group) and nine had pruritus (three in CONTROL group and six in FENTANYL group). No patient reported pain suggesting TRI. CONCLUSION: Spinal procaine is appropriate for short-duration surgery. Fentanyl does not change the characteristics of the block or the incidence of side effects associated with spinal procaine.

Adolescent↗
PubMed2004

Value of fentanyl in flexible sigmoidoscopy.

Studies have recorded significant patient discomfort during flexible sigmoidoscopy when it is performed without sedation/analgesia. This study observed whether a single dose of 50 mcg intravenous fentanyl reduces pain, improving compliance, acceptability, and completion rates. In a prospective study, 109 consecutive patients were offered the option of 50 mcg intravenous fentanyl or no analgesia. Patient's pre-procedure expectations, objective pain scores, and willingness to undergo a subsequent procedure using the same technique were recorded. Endoscopist recorded the success, complications, and objective pain scores for each patient. Of the 46 patients (42%) choosing fentanyl, 9 (20%) experienced moderate/severe pain as against 26 (41%) of the 63 patients (58%) opting for no analgesia (p < 0.05). Further, 52% receiving fentanyl had a significantly better experience compared to their pre-procedure expectations as against 33% who received no analgesia (p < 0.05). No patient receiving fentanyl expressed unwillingness to undergo the procedure again using the same technique, whereas 16 (25%) of those receiving no analgesia indicated they would not (p < 0.01). Endoscopists recorded moderate/severe pain in 13 patients (12%), whereas 35 patients (32%) recorded moderate/severe pain (p < 0.001). Analgesia for endoscopy should involve patient choice. However, a single dose of 50 mcg fentanyl reduced patient discomfort and improved satisfaction. It appeared safe and likely to improve patient compliance and acceptability for flexible sigmoidoscopy.

Analgesics, Opioid↗
PubMed2006

Effects of morphine, fentanyl and tramadol on human immune response.

Morphine has been reported to suppress human immune response. We aimed to observe the effects of morphine, fentanyl and tramadol on NF-kappa B and IL-2 from both laboratory and clinical perspective. Jurkat cells were incubated with ten times clinically relevant concentrations of morphine, fentanyl and tramadol before being stimulated with PMA. NF-kappa B binding activity and IL-2 levels were measured. In the clinical study, 150 consenting patients were randomized into 3 groups according to the analgesics used in them, namely, group morphine (M), group fentanyl (F) and group tramadol (T). IL-2 was measured preoperatively and 1, 3 and 24 h after operation. Consequently, NF-kappa B activation was suppressed by morphine and fentanyl but not by tramadol. IL-2 was significantly decreased by morphine and fentanyl but not by tramadol in vitro. In the PCA patients, IL-2 was decreased in group M and increased in group F postoperatively. Whereas in group T, IL-2 was unchanged 1 h after operation but was significantly elevated 3 and 24 h after operation. Our results showed that the inhibition of morphine on IL-2 was most probably related to its suppression on NF-kappa B. Fentanyl had different effects on human immune response in vitro and in vivo. Tramadol may have immune enhancing effect.

Analgesia, Patient-Controlled↗