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PubMed1989

Pharmacologic effects and detection methods of methylated analogs of fentanyl in horses.

Pharmacologic effects of alpha-methylfentanyl and 3-methylfentanyl, analogs of fentanyl, were investigated in mares. The ability of an 125I-labeled fentanyl radioimmunoassay (125I-RIA) to detect these methylated fentanyl analogs in individual and pooled urine samples from horses was evaluated. Also, the ability of 7 fentanyl antibodies to react with fentanyl and fentanyl derivatives (sufentanil, alfentanil, and carfentanil) was investigated. Mares were studied in a locomotor test to determine the amount of stimulation methylated fentanyl analogs might induce. Two mares each were given alpha-methylfentanyl at 1, 2, 4, 8, or 13 micrograms/kg of body weight, IV, or 3-methylfentanyl at 0.4, 0.7, or 1 microgram/kg IV. The cross-reactivity of sufentanil, alfentanil, carfentanil, alpha-methylfentanyl, and 3-methylfentanyl with 7 fentanyl antibodies was studied, using the 125I-RIA. All fentanyl analogs, with the exception of alfentanil, cross-reacted well with a C1 antibody raised to fentanyl. Less satisfactory cross-reactivity was determined with 6 other antibodies raised to fentanyl derivatives. When the C1 antibody was combined with an iodinated analog to fentanyl, good detectability of alpha-methylfentanyl and 3-methylfentanyl, in terms of fentanyl equivalents, was obtained from urine samples of dosed mares. The ability of the 125I-RIA to detect methylated fentanyl analogs in forensic urine samples pooled in groups of up to 20 samples was evaluated. When these methylated analogs were administered to mares in doses that induced measurable locomotor stimulation, the analog's presence was readily detected in individual or pooled samples.

Alfentanil↗

PubMed1988

Tolerance and cross-tolerance to the discriminative stimulus properties of fentanyl and morphine.

The investigation tested the hypothesis that tolerance would develop to the discriminative stimulus properties of fentanyl upon discontinuation of discrimination training and injection of fentanyl in doses larger than the training dose. Rats were trained to discriminate an injection of fentanyl, 0.04 mg/kg, from saline using a two-lever choice procedure with food as a reinforcer. Given acutely, morphine substituted for fentanyl and was 100-times less potent. Subsequently, training was stopped, and fentanyl, 0.08 mg/kg, was injected every 12 hr for 1 week. This procedure did not produce tolerance nor did tolerance occur when fentanyl, 0.16 mg/kg every 24 hr, was continued for an additional week. In contrast, a dose of morphine (8.0 mg/kg) that was equated for efficacy to the 0.08-mg/kg dose of fentanyl produced both tolerance to the morphine stimulus and cross-tolerance to the fentanyl stimulus after 3 to 4 days of administration. In an additional experiment, the time course for detection of fentanyl was found to be significantly shorter than the time course for the detection of morphine. These results suggest that the present, as well as a previous, report of failure to find tolerance to the stimulus properties of fentanyl is perhaps attributable to fentanyl's brief duration of action. To test this hypothesis, 16 rats were trained to discriminate fentanyl, 0.04 mg/kg, and dose-effect data were obtained for the generalization of fentanyl and the substitution of morphine for this discriminative stimulus. Subsequently, training was stopped and fentanyl was injected for 4 days in a design that called for injection of 0.12 mg/kg every 6 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1998

Prehospital fentanyl analgesia in air-transported pediatric trauma patients.

OBJECTIVE: To review the 5.5-year safety record of a protocol guiding fentanyl administration to pediatric trauma patients undergoing aeromedical transport. METHODS: Retrospective review of an urban aeromedical program's trauma scene responses from October 1991 to March 1997 identified the study population as all pediatric patients (age <15 years) receiving fentanyl for analgesia during air transport. Patients receiving fentanyl concurrently with other agents, eg, paralytics, were not studied. The air transport team consisted of a flight nurse and flight paramedic who provided protocol-driven patient care with off-line medical control. Study patients' flight records were reviewed to determine vital signs (systolic blood pressure [SBP], heart rate [HR], and oxygen saturation [SAT]) before and after fentanyl administration. Postfentanyl vital signs were reviewed for evidence of hemodynamic or ventilatory compromise. Pre- and postfentanyl vital signs were compared with the paired t test (P < 0.05). Flight records were also analyzed for narrative information, eg, naloxone administration and assisted ventilation, indicative of fentanyl side effects. RESULTS: Fentanyl (0.33-5.0 microg/kg) was administered 211 times to 131 patients who had a median age of 6.2 years (0.1-14 years), median Glasgow coma score (GCS) of 9 (3-15), and a mean pediatric trauma score of 8.3+/-2.4. Seventy-nine (60.3%) patients were intubated; these patients received 139 (65.9 %) of the 211 total fentanyl doses. No adverse effects from fentanyl were noted in flight record narratives. The median interval between fentanyl administration and postfentanyl vital sign assessment was 9.5 minutes (1-35 minutes). Median postfentanyl changes in SBP and HR were -4.7 and -2.9%, respectively. No patient became hypotensive after fentanyl administration. In nonintubated patients, mean postfentanyl SAT (99.2+/-1.3%) was not significantly different (P = 0.70) from prefentanyl SAT (99.1+/-1.3%), and no patient was noted to have clinically significant SAT decrement after fentanyl. CONCLUSION: Retrospective review of more than five years of prehospital fentanyl administration revealed no untoward events. Although prospective definitive demonstration of fentanyl's field use is pending, it is reasonable to continue discretionary fentanyl administration to injured pediatric children in pain.

Adolescent↗

PubMed2001

A safe and effective method for converting cancer patients from intravenous to transdermal fentanyl.

BACKGROUND: Therapeutic fentanyl blood levels are reached approximately 12-16 hours after the initial application of transdermal fentanyl patches. For this reason, fentanyl patches should not be used to treat acute exacerbations of cancer pain. Acute cancer-related pain can be treated with fentanyl administered by continuous intravenous infusion (CII) in combination with patient-controlled analgesia (PCA). Patients then can be switched from intravenous (IV) to transdermal fentanyl once stable pain relief has been achieved. The objective of the current case series was to evaluate and describe the safety and effectiveness of a method for converting hospitalized patients with cancer-related pain from IV to transdermal fentanyl. METHODS: The authors prospectively evaluated 15 consecutive cancer patients during the conversion from IV to transdermal fentanyl. In all patients, a transdermal patch delivering fentanyl at a rate equivalent to that of the final continuous IV infusion was applied. The CII rate was decreased by 50% 6 hours after application of the fentanyl patch and then discontinued after another 6 hours. Demand boluses of IV fentanyl equivalent in dosage to 50-100% of the final CII rate remained available via PCA during the 24 hours after patch application. Pain intensity (on a scale of 0-10), sedation (on a scale of 0-3), and hourly PCA administration (microg/hr) were assessed and recorded immediately prior to application of the fentanyl patch and 6, 12, 18, and 24 hours thereafter. RESULTS: Pain intensity, sedation, and hourly PCA administration appeared to remain stable throughout the transition from IV to transdermal fentanyl. CONCLUSIONS: The results of the current study demonstrate that the conversion from IV to transdermal fentanyl can be accomplished safely and effectively using a 1:1 (IV:transdermal) conversion ratio and a two-step taper of the CII over 12 hours.

Administration, Cutaneous↗

PubMed1988

Fentanyl uptake by the scimed membrane oxygenator.

With the initiation of cardiopulmonary bypass (CPB), using a membrane oxygenator, the drop in circulating fentanyl concentration is greater than can be attributed to dilution alone. This study examined the Scimed brand (2A-800) membrane oxygenator as a site of fentanyl binding. Initial experiments used an assembled CPB circuit. Subsequent dissection and analysis of the oxygenator revealed that the silicone-based membrane sheets were the primary site of fentanyl binding. The silicone-containing waterproof wrapper was also responsible for 1% to 2% of fentanyl binding. Binding of fentanyl to the Scimed membrane oxygenator occurs at a rapid rate and continues until the membrane has taken up 130 ng/cm2 of membrane surface area. The interaction is complete by 15 to 30 minutes if suprasaturated concentrations are used. Samples of membrane material with a surface area of 1 cm2 were also studied. Isolated membrane squares in a nonmoving prime solution required two hours for saturation at the same fentanyl concentrations as the intact membrane with circulating prime. Introduction of motion to the priming solution accelerated the rate of fentanyl binding by the isolated membrane squares to a rate similar to the intact membrane. Motion also provided results similar to those previously reported using different analysis techniques. Therefore, this method of studying fentanyl-membrane interactions using samples of membrane and tritiated fentanyl is a valid model for the intact membrane oxygenator in the assembled bypass circuit. In addition to solution movement, fentanyl concentration of the priming solution was also found to affect the rate of fentanyl uptake. When fentanyl concentrations were used which were insufficient to achieve saturation of the membrane (10 ng/mL and 20 ng/mL), the rate of uptake was slowed. Binding of all available fentanyl under these conditions occurred within three hours. There is potential modification of this interaction by several clinically relevant factors, including temperature, pH, protein content of prime solution, and other drugs. These areas require further study before the saturation data are applied to clinical practice.

Absorption↗

PubMed2000

The role of 5-HT(1A)-receptors in fentanyl-induced bulbospinal inhibition of a spinal withdrawal reflex in the rabbit.

The sural to gastrocnemius withdrawal reflex is inhibited after injection of the OP(3) (micro)-receptor-selective opioid fentanyl into the fourth ventricle of decerebrated rabbits. This effect is abolished by complete section of the spinal cord but not by the selective alpha(2)-adrenoceptor antagonist RX 821002 (Clarke RW, Parry-Baggott C, Houghton AK, Ogilvie J. The involvement of bulbo-spinal pathways in fentanyl-induced inhibition of spinal withdrawal reflexes in the decerebrated rabbit. Pain 1998;78:197-207). We have now investigated the role of 5-HT(1A) receptors in mediating the descending inhibition activated by intraventricular fentanyl. In the control state, intraventricular fentanyl (3-30 microgram/kg) inhibited gastrocnemius reflex responses to a median of 34% of pre-drug levels. After intrathecal administration of the selective 5-HT(1A) receptor antagonist WAY-100635 (100 microgram), fentanyl reduced reflex responses to 83% of pre-fentanyl values, significantly less inhibition than in the control state. In a separate group of experiments, intravenous fentanyl (0.3-30 microgram/kg) depressed the sural-gastrocnemius reflex to 17% of pre-drug controls. This inhibition was not affected by intrathecal WAY-100635 (100 microgram), but combined administration of the 5-HT(1A) antagonist with RX 821002 (100 microgram) significantly reduced the effectiveness of i.v. fentanyl. After the highest dose reflexes were 37% of pre-fentanyl levels. These data show that the bulbospinal inhibition activated by fentanyl is mediated, at least in part, by activation of spinal 5-HT(1A) receptors. That blockade of these receptors failed to influence the inhibition induced by i.v. fentanyl might be taken to mean that the brain-stem action of fentanyl does not contribute significantly to the systemic actions of this opioid. A more probable explanation is that, in the preparation used in the present study, the bulbospinal and direct spinal actions of fentanyl occlude each other to produce an overall inhibition that is less than the sum of the two effects.

Adrenergic alpha-Antagonists↗

PubMed1998

A clinical evaluation of transdermal therapeutic system fentanyl for the treatment of cancer pain.

Fentanyl has been incorporated into a transdermal therapeutic system (TTS) containing a rate-limiting membrane that provides constant release of the opioid. TTS fentanyl provides continuous opioid delivery for up to 72 hr without the need for special equipment. After Institutional Review Board approval, 53 patients with cancer pain requiring 45 mg or more of oral morphine daily were admitted into an open-label, prospective, multicenter evaluation of TTS fentanyl for the relief of pain. After a 1-week stabilization on oral morphine, patients were transferred from morphine to an appropriate dose of TTS-fentanyl (25, 50, 75, or 100 micrograms/hr) administered as a transdermal patch every 3 days. TTS fentanyl was titrated to pain relief, and patients were followed up for as long as 3 months. Pain relief and the side effects of the medications were assessed daily. Twenty-six men and 27 women with a mean (+/- SD) age of 61 (+/- 12) years entered the study; 23 patients completed the full 84-day study. The mean duration of TTS fentanyl use was 58 +/- 32 days. The mean (+/- SEM) daily morphine dose during the last 2 days of stabilization was 189 (+/- 20) mg, and the mean initial fentanyl patch dose was 58 (+/- 6) micrograms/hr. The mean daily morphine dose taken "as needed" for breakthrough pain at study completion was 35 mg. The mean final fentanyl dosage at study completion was 169 (+/- 29) micrograms/hr. Pain relief was rated as good or excellent by 82% of patients during the treatment period. When asked to compare pain relief during the first month of TTS-fentanyl use to that provided by their last analgesic before study entry, 63% preferred TTS fentanyl. Side effects considered related to the fentanyl patch were nausea (13%), vomiting (8%), skin rash (8%), and drowsiness (4%). Thirty percent of patients reported adverse experiences related to the fentanyl patch, and 17% had to be discontinued from the study. We conclude that TTS fentanyl administered every 3 days for the treatment of cancer pain is effective, safe, and well tolerated by most patients.

Administration, Cutaneous↗

PubMed1989

Absorption characteristics of transdermally administered fentanyl.

Fentanyl was administered intravenously and transdermally to eight surgical patients to determine the systemic bioavailability and rate of absorption of the transdermally administered drug. Serum fentanyl concentrations reached a plateau approximately 14 h after placement of the transdermal fentanyl delivery system. This plateau was maintained until removal of the system at 24 h. The decline in serum fentanyl concentrations after removal of the transdermal system had a terminal half-life of 17.0 +/- 2.3 h (mean +/- SD), considerably longer than the terminal elimination half-life seen after intravenous administration of fentanyl in the same patients (6.1 +/- 2.0 h). The rate of fentanyl absorption, predicted to be 100 micrograms/h from in vitro data, appeared to be relatively constant during a period starting 4-8 h after placement of the transdermal system until removal of the system at 24 h. The rate of absorption during this period was 91.7 +/- 25.7 micrograms/h. After removal of the transdermal fentanyl delivery system, absorption continued at a declining rate. This indicates that the long terminal half-life of serum fentanyl concentrations after transdermal system removal is due to continued slow absorption of fentanyl, probably from a cutaneous depot of drug at the site of prior transdermal system placement. At the time of removal of the transdermal fentanyl system, 1.07 +/- 0.43 mg of drug remained in this depot. Systemic fentanyl bioavailability was found to be 0.92 +/- 0.33, with no evidence of significant cutaneous metabolism or degradation by the skin's bacterial flora. The transdermal administration of fentanyl produces relatively constant serum fentanyl concentrations for significant periods of time in the postsurgical patient requiring analgesic therapy.

Administration, Cutaneous↗

PubMed1994

Anesthetic and hemodynamic interactions of dexmedetomidine and fentanyl in dogs.

BACKGROUND: Anesthetic doses of dexmedetomidine (DMED), a highly selective alpha 2 agonist, are not well tolerated hemodynamically. The combination of an opioid with DMED might reduce the dosage requirements for each drug and thereby allow the same anesthetic depth to be achieved with lesser degrees of their individual side effects. METHODS: Dogs were anesthetized with enflurane. One group (n = 5) received intravenous doses of DMED from 0.1 to 10 micrograms/kg. Two other groups of five dogs each received fentanyl 15 micrograms/kg plus 0.05 microgram.kg-1.min-1 or fentanyl 45 micrograms/kg plus 0.2 micrograms.kg-1.min-1. Thereafter, they received DMED doses of 0.03-3 micrograms/kg. After the effects of the last DMED dose were measured, atipamezole 0.3 mg/kg was infused intravenously and all measurements were repeated. Then, naloxone (1 mg/kg) was injected intravenously and a final set of measurements obtained. Anesthetic effects were assessed by determining enflurane minimum alveolar concentration (MAC). Hemodynamics and plasma fentanyl concentrations were measured at each determination of MAC. RESULTS: DMED and fentanyl individually produced dose-related reductions of enflurane MAC. During the lower rate infusion of fentanyl (plasma fentanyl concentration 1.0 +/- 0.3 ng/ml), DMED reduced enflurane MAC more than could be attributed to a simple additive interaction. During the higher rate infusion of fentanyl (plasma fentanyl concentration 4.4 +/- 0.7 ng/ml), DMED reduced enflurane MAC to greater degrees than were achievable by fentanyl alone. DMED caused a dose-dependent increase in arterial pressure concomitantly with a decrease in cardiac output, and these changes were not modified by fentanyl. The bradycardia following DMED was augmented by fentanyl. CONCLUSIONS: There was a positive interaction, additive or synergistic, between DMED and fentanyl with respect to their enflurane-sparing effects. The interaction allowed the same depth of anesthesia to be achieved by lower doses of all three drugs, potentially limiting the intensity of their individual side effects. However, the presence of fentanyl increased the degree of bradycardia induced by DMED.

Adrenergic alpha-Antagonists↗

PubMed1997

Comparison of remifentanil and fentanyl in patients undergoing craniotomy for supratentorial space-occupying lesions.

BACKGROUND: Remifentanil hydrochloride is an ultra-short-acting, esterase-metabolized mu-opioid receptor agonist. This study compared the use of remifentanil or fentanyl during elective supratentorial craniotomy for space-occupying lesions. METHODS: Sixty-three adults gave written informed consent for this prospective, randomized, double-blind, multiple-center trial. Anesthesia was induced with thiopental, pancuronium, nitrous oxide/oxygen, and fentanyl (n = 32; 2 micrograms.kg.-1. min-1) or remifentanil (n = 31; 1 mu.kg-1.min-1). After tracheal intubation, infusion rates were reduced to 0.03 microgram.kg-1.min-1 (fentanyl) or 0.2 microgram.kg-1.min-1 (remifentanil) and then adjusted to maintain anesthesia and stable hemodynamics. Isoflurane was given only after specified infusion rate increases had occurred. At the time of the first burr hole, intracranial pressure was measured in a subset of patients. At bone flap replacement either saline (fentanyl group) or remifentanil (approximately 0.2 microgram.kg-1.min-1) were infused until dressing completion. Hemodynamics and time to recovery were monitored for 60 min. Analgesic requirements and nausea and vomiting were observed for 24 h. Neurological examinations were performed before operation and on postoperative days 1 and 7. RESULTS: Induction hemodynamics were similar. Systolic blood pressure was greater in the patients receiving fentanyl after tracheal intubation (fentanyl = 127 +/- 18 mmHg; remifentanil = 113 +/- 18 mmHg; P = 0.004). Intracranial pressure (fentanyl = 14 +/- 13 mmHg; remifentanil = 13 +/- 10 mmHg) and cerebral perfusion pressure (fentanyl = 76 +/- 19 mmHg; remifentanil = 78 +/- 14 mmHg) were similar. Isoflurane use was greater in the patients who received fentanyl. Median time to tracheal extubation was similar (fentanyl = 4 min: range = -1 to 40 min; remifentanil = 5 min: range = 1 to 15 min). Seven patients receiving fentanyl and none receiving remifentanil required naloxone. Postoperative systolic blood pressure was greater (fentanyl = 134 +/- 16 mmHg; remifentanil = 147 +/- 15 mmHg; P = 0.001) and analgesics were required earlier in patients receiving remifentanil. Incidences of nausea and vomiting were similar. CONCLUSIONS: Remifentanil appears to be a reasonable alternative to fentanyl during elective supratentorial craniotomy.

Adult↗

PubMed1997

Reduction by fentanyl of the Cp50 values of propofol and hemodynamic responses to various noxious stimuli.

BACKGROUND: Propofol and fentanyl infusion rates should be varied according to the patient's responsiveness to stimulation to maintain satisfactory anesthetic and operative conditions. However, somatic and autonomic responses to various noxious stimuli have not been investigated systematically for intravenous propofol and fentanyl anesthesia. METHODS: Propofol and fentanyl were administered via computer-assisted continuous infusion to provide stable concentrations and to allow equilibration between plasma-blood and effect-site concentrations. The propofol concentrations needed to suppress eye opening to verbal command and motor responses after 50-Hz electric tetanic stimulation, laryngoscopy, tracheal intubation, and skin incision in 50% or 95% of patients (Cp50 and Cp95) were determined at fentanyl concentrations of 0.0, 1.0, 2.0, 3.0, and 4.0 ng/ml in 133 patients undergoing lower abdominal surgery. The ability of propofol with fentanyl to suppress hemodynamic reactions in response to various noxious stimuli also was evaluated by measuring arterial blood pressure and heart rate before and after stimulation. RESULTS: The various Cp50 values for propofol alone (no fentanyl) for the various stimuli increased in the following order: Cp50loss of consciousness, 4.4 microg/ml (range, 3.8-5.0); Cp50tetanus, 9.3 microg/ml (range, 8.3-10.4); Cp50laryngoscopy, 9.8 microg/ml (range, 8.9-10.8); Cp50skin incision, 10.0 microg/ml (range, 8.1-12.2); and Cp50intubation, 17.4 microg/ml (range, 15.1-20.1; 95% confidence interval). The reduction of Cp50loss of consciousness, with fentanyl was minimal; 11% at 1 ng/ml of fentanyl and 17% at 3 ng/ml of fentanyl. A plasma fentanyl concentration of 1 ng/ml (3 ng/ml) resulted in a 31-34% (50-55%) reduction of the propofol Cp50s for tetanus, laryngoscopy, intubation, and skin incision. Propofol alone depresses prestimulation blood pressure but had no influence on the magnitude blood pressure or heart rate increase to stimulation. Propofol used with fentanyl attenuated the systolic blood pressure increases to various noxious stimuli in a dose-dependent fashion. CONCLUSIONS: The authors successfully defined the propofol concentration required for various stimuli. Tracheal intubation was the strongest stimulus. The absence of somatic reactions for propofol does not guarantee hemodynamic stability without fentanyl. Propofol with fentanyl was able to suppress motor and hemodynamic reactions to various noxious stimuli.

Adult↗

PubMed1998

Bupivacaine 0.01% and/or epinephrine 0.5 microg/ml improve epidural fentanyl analgesia after cesarean section.

BACKGROUND: The authors studied the addition of bupivacaine and epinephrine, separately and together, to epidural fentanyl to determine whether this improved postcesarean analgesia and reduced the incidence of side effects. METHODS: After elective cesarean section, 100 parturient patients who received fentanyl (3 microg/ml) epidurally for 48 h were allocated randomly in a double-blinded manner to four groups to receive, in addition to the study solution, 0.01% bupivacaine, 0.5 microg/ml epinephrine, both, or neither. A neurologic assessment of breast-fed neonates was made at 2 and 48 h of life. Plasma fentanyl concentrations were determined in a subset of patients at intervals after treatment. RESULTS: Patients receiving fentanyl alone made more attempts at patient-controlled analgesia (P < 0.01), required a greater total dose of fentanyl (P < 0.01), reported more pain (P < 0.003) and less satisfaction (P < 0.003), and had more nausea and urinary retention (P < 0.05) than all other groups. Patients who received bupivacaine with or without epinephrine had better overall satisfaction scores than those who did not receive bupivacaine (P < 0.001), and they required less fentanyl (P < 0.02) than patients who received fentanyl with only epinephrine. Motor blockade or orthostatic hypotension did not develop in any patient, and all patients could ambulate without difficulty. Neurobehavioral scores, which were similar among all neonates, were within the normal range. Plasma concentrations of fentanyl increased after epinephrine-containing solutions were discontinued. CONCLUSIONS: During the conditions of this study, the addition of epinephrine and bupivacaine to a 3-microg/ml epidural fentanyl solution for postcesarean section pain relief provided superior analgesia compared with fentanyl alone or fentanyl with epinephrine. Whether increasing the concentration of fentanyl alone might improve the efficacy of fentanyl remains unclear.

Adult↗

PubMed1992

Use of patient-controlled analgesia to compare the efficacy of epidural to intravenous fentanyl administration.

Fentanyl, unlike morphine, is highly lipophilic and rapidly diffuses out of the epidural space. Respiratory depression is, therefore, unlikely when fentanyl is given epidurally. However, much of fentanyl's analgesic effect is mediated by systemic rather than spinal receptor binding. To test this hypothesis, we performed a prospective, double-blind, cross-over study comparing epidural and intravenous (IV) administration of fentanyl in 16 patients for the first 12 h after lower abdominal or lower extremity surgery. To allow direct comparison of these two routes of administration, patient-controlled analgesia was used so patients could self-titrate their analgesia. Patients were randomized to receive fentanyl initially by an epidural (group A, n = 8) or IV (group B, n = 8) catheter for 6 h, after which they were crossed-over to the alternate route by means of a hidden three-way stopcock. The degree of analgesia was subjectively evaluated by a visual analogue scale, and by an observer rating patient's comfort and sedation. Cumulative dosage of fentanyl was recorded, and plasma fentanyl concentrations were measured. The onset of analgesia and increase in plasma fentanyl concentrations were more rapid with intravenous fentanyl. However, after 60 min, analgesia (visual analogue scale 2-4 cm) or plasma fentanyl concentrations (0.3-0.7 ng/mL) did not differ between the two routes of administration. There were also no significant differences in the cumulative dosage of fentanyl within each group (epidural vs IV) or between the groups. Thus, the analgesic effects of epidural fentanyl appear largely mediated by systemic absorption. Intravenous fentanyl achieves a similar degree of analgesia and a more rapid onset of effect without the need for epidural catheterization.

Aged↗

PubMed2001

Enteral methadone to expedite fentanyl discontinuation and prevent opioid abstinence syndrome in the PICU.

STUDY OBJECTIVE: To determine if enterally administered methadone can facilitate fentanyl discontinuation and prevent withdrawal in children at high risk for opioid abstinence syndrome. DESIGN: Retrospective analysis. SETTING: Pediatric intensive care unit (PICU) in a tertiary care children's hospital. PATIENTS: Twenty-two children (aged 6.1 +/- 5.4 yrs) who received continuous fentanyl infusion for 9 days or longer. INTERVENTION: Guidelines for initiating enteral methadone, rapidly tapering and discontinuing fentanyl infusions, and tapering methadone were implemented in the PICU. Development of opioid abstinence syndrome was evaluated during fentanyl and methadone dosage reductions and for 72 hours thereafter. MEASUREMENTS AND MAIN RESULTS: Children received fentanyl by continuous infusion for 17.8 +/- 8.4 days. Peak fentanyl infusion rate was 5.9 +/- 3.8 microg/kg/hour, and the median cumulative dose was 1302 microg/kg (range 354-7535 microg/kg). Methadone 0.50 +/- 0.22 mg/kg/day was begun 1.6 +/- 1.9 days before tapering fentanyl. The fentanyl infusion rate on starting the taper was 5.0 +/- 3.6 microg/kg/hour. Fentanyl was tapered and discontinued in a median of 2.6 days (range 0-11.9 days). Twenty-one patients had no opioid abstinence syndrome during or after fentanyl taper. One patient experienced significant opioid withdrawal after fentanyl discontinuation, which resolved after reinstitution of fentanyl and increasing the dosage of methadone to 0.3 mg/kg every 6 hours. Overall, methadone was tapered and discontinued in 18.2 +/- 11.9 days without precipitating opioid abstinence syndrome. CONCLUSION: Enteral administration of methadone may expedite fentanyl discontinuation and reduce the risk of withdrawal in critically ill children at high risk for opioid abstinence syndrome.

Adolescent↗

PubMed2001

Effects of diazepam and flumazenil on minimum alveolar concentrations for dogs anesthetized with isoflurane or a combination of isoflurane and fentanyl.

OBJECTIVE: To determine the effect of a constant-rate infusion of fentanyl on minimum alveolar concentration (MAC) of isoflurane and to determine the interaction between fentanyl and a benzodiazepine agonist (diazepam) and antagonist (flumazenil) in isoflurane-anesthetized dogs. ANIMALS: 8 mixed-breed adult dogs. PROCEDURE: Dogs were anesthetized with isoflurane 3 times during a 6-week period. After a 30-minute equilibration period, each MAC determination was performed in triplicate, using standard techniques. Fentanyl was administered as a bolus (10 microg/kg of body weight, IV) that was followed by a constant infusion (0.3 microg/kg per min, IV) throughout the remainder of the experiment. After determining isoflurane-fentanyl MAC in triplicate, each dog received saline (0.9% NaCl) solution, diazepam, or flumazenil. After 30 minutes, MAC was determined again. RESULTS: Fentanyl significantly decreased isoflurane MAC (corrected to a barometric pressure of 760 mm Hg) from 1.80+/-0.21 to 0.85+/-0.14%, a reduction of 53%. Isoflurane-fentanyl-diazepam MAC (0.48+/-0.29%) was significantly less than isoflurane-fentanyl-saline MAC (0.79+/-0.21%). Percentage reduction in isoflurane MAC was significantly greater for fentanyl-diazepam (74%), compared with fentanyl-saline (54%) or fentanyl-flumazenil (61%). Mean fentanyl concentrations for the entire experiment were increased over time and were higher in the diazepam group than the saline or flumazenil groups. CONCLUSIONS AND CLINICAL RELEVANCE: Fentanyl markedly decreased isoflurane MAC in dogs. Diazepam, but not flumazenil, further decreased isoflurane-fentanyl MAC. Our results indicate that diazepam enhances, whereas flumazenil does not affect, opioid-induced CNS depression and, possibly, analgesia in dogs.

Adjuvants, Anesthesia↗

PubMed1999

[Prolonged antinociceptive effect of poly (DL-lactic acid)-fentanyl composites after their intrathecal injection in rats].

We synthesized poly (DL-lactic acid)-fentanyl composites and compared the duration of analgesia after the administration of a single intrathecal dose of these agents in rats. The drug was injected with an intrathecal catheter into the intrathecal space. Fentanyl composites or plain fentanyl in doses of 2.5 or 25 micrograms were administered, respectively. Animals were then tested for analgesia using the tail-flick test. The release rate of fentanyl from fentanyl composites in vitro was also evaluated. The antinociceptive effect of fentanyl composites (25 micrograms) was significantly longer than that of plain fentanyl. Administration of poly (DL-lactic acid) alone did not induce the antinociceptive effect. Four of 7 animals given plain fentanyl (25 micrograms) exhibited temporary respiratory depression, but none of the animals given fentanyl composites showed this response. In vitro experiments demonstrated a slow release of fentanyl from the fentanyl composites. We conclude that the antinociceptive effect of fentanyl can be prolonged when administered as a poly (DL-lactic acid)-fentanyl composite in the intrathecal space with decreased systemic side effects compared with the plain formulation.

Analgesics, Opioid↗

PubMed1998

[Characterization of dose profile of remifentanil with computer simulation: comparative study with fentanyl and alfentanyl].

OBJECTIVES: To estimate the optimum dosing regimen and delivery system for remifentanil, a new opioid, using computer simulations based on information from pharmacokinetic and pharmacodynamic models available for fentanyl, alfentanil and remifentanil, as well as from clinical trials of fentanyl and alfentanil. PATIENTS AND METHODS: We estimated the site concentration ranges likely to be needed to blunt response to anesthetic or surgical stimuli and to recover from spontaneous ventilation. Dosing guidelines for remifentanil, fentanyl and alfentanil were estimated for three methods of administration (bolus, bolus + variable continuous infusion or constant continuous infusion). To that end, the time course of opioid concentration was simulated for hypothetical balanced anesthesia lasting 60 min. We then studied the number of boluses, the number of infusion rate steps, time taken to reach the terapeutic threshold, and time from turning off the infusion until reaching a concentration compatible with spontaneous ventilation. RESULTS: The estimated "effect site" concentration ranges for remifentanil were 6 to 10 ng.ml-1 during intubation; 4 to 6 ng.ml-1 during cutaneous incision; 4 to 7 ng.ml-1 for maintenance; and less than 2.5 ng.ml-1 for recovery of spontaneous ventilation. Simulated bolus administration indicated that 21 boluses of remifentanil, 4 boluses of fentanyl and 7 boluses of alfentanil were needed during one hour. The therapeutic threshold was reached within the first minute with remifentanil, within 2 minutes with fentanyl and within 1 min with alfentanil. Time until recovery of spontaneous ventilation was 7 min with remifentanil, 22 min with fentanyl and 14 min with alfentanil. In the simulation of bolus plus variable infusion, the initial bolus of remifentanil was 100 micrograms, the infusion rate for induction and maintenance was 25 micrograms.min-1 and the maintenance rate was 15 micrograms.min-1. The initial bolus of fentanyl was 300 micrograms, the infusion rate for induction and maintenance was 5 micrograms.min-1. The initial bolus of alfentanil was 2,000 micrograms, the infusion rate for induction was 200 micrograms.min-1 and the maintenance rates were 75 and 25 micrograms.min-1. The therapeutic threshold was reached in 1 min with remifentanil, in 2 min with fentanyl and within 1 min with alfentanil. Spontaneous ventilation was recovered 4 min after turning off the infusion of remifentanil, 4 min afterwards with fentanyl and 6 min afterwards with alfentanil. The simulated constant infusion rate for remifentanil of 15 micrograms.min1 (8 micrograms.min-1 for fentanyl and 75 micrograms.min-1 for alfentanil) allowed the therapeutic threshold to be reached in 10 min with remifentanil, in 22 min with fentanyl and in 17 min with alfentanil. Recovery of spontaneous ventilation occurred 5 min after closure of the infusion pump with remifentanil (24 min with fentanyl and 17 min with alfentanil). CONCLUSIONS: Information from pharmacokinetic and pharmacodynamic models allows us to establish the effect site concentration ranges for remifentanil and determine the ideal administration technique for this drug. The simulation also allows us to compare the properties of remifentanil to those of other common opioids such as fentanyl and alfentanil. The results are fairly consistent with clinical evidence, demonstrating the power of pharmacokinetic and pharmacodynamic models for rationally establishing opioid dosing guidelines.

Adult↗

PubMed1986

Agonist and antagonist effects of prototype opiate drugs in fentanyl dose-dose discrimination.

The experiments characterized the effects of fentanyl, morphine, naloxone, cyclazocine, nalorphine, ketocyclazocine and N-allylnormetazocine in rats that were trained to discriminate 0.04 mg/kg from 0.02 mg/kg fentanyl (dose-dose discrimination). The data are compared to results obtained previously in rats discriminating 0.04 mg/kg fentanyl from saline (drug-saline discrimination). In the dose-dose discrimination fentanyl and morphine produced responding appropriate to 0.04 mg/kg fentanyl at doses which were 3.0- and 1.6-fold higher, respectively, than in drug-saline discrimination. Naloxone antagonized the stimulus effects of 0.04 mg/kg fentanyl at 9.8-fold lower doses than in drug-saline discrimination. The dose-effect curves of fentanyl and naloxone in rats discriminating 0.04 mg/kg from 0.02 mg/kg fentanyl, were steeper than in rats discriminating 0.04 mg/kg fentanyl from saline. While cyclazocine, nalorphine and N-allylnormetazocine acted as mixed and partial agonists/antagonists in drug-saline discrimination, those compounds acted as pure and complete antagonists of 0.04 mg/kg fentanyl in dose-dose discrimination. The rank order of compounds in antagonizing the stimulus effects of 0.04 mg/kg fentanyl in dose-dose discrimination was naloxone greater than N-allylnormetazocine greater than cyclazocine greater than nalorphine. It is suggested that a greater magnitude of opiate activity is required for producing generalization with the same 0.04 mg/kg dose of fentanyl in dose-dose as compared with drug-saline discrimination. Dose-dose discrimination may afford a more accurate method of the discriminative stimulus properties of drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗