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PubMed1982

The effects of high-dose fentanyl on cerebral circulation and metabolism in rats.

There is considerable controversy with respect to the effects of narcotics on the cerebral blood flow (CBF) and the cerebral metabolic rate for oxygen (CMRo2). The present study examined the effects of high doses of intravenous fentanyl (25-400 micrograms/kg) on the CBF and CMRo2 in rats. Cerebral cortical blood flow and metabolism were measured using the 133Xenon modification of the Kety-Schmidt technique. Fentanyl produced a dose-related decrease in both the CBF and the CMRo2. CBF and CMRo2 were maximally depressed by 50 and 35%, respectively, in rats given fentanyl 100 micrograms/kg compared with nitrous oxide-oxygen ventilated controls. The values for CBF and CMRo2 were 168 +/- 15 ml . 100 g-1 . min-1 and 10.3 +/- 0.7 ml . 100 g-1 . min-1, respectively in the nitrous oxide controls compared with 85 +/- 3 ml . 100 g-1 . min-1 and 7.1 +/- 0.1 ml . 100 g-1 . min-1 in animals receiving fentanyl 100 micrograms/kg. Higher doses of fentanyl did not further decrease either CBF or CMRo2 (108 +/- 12 ml . 100 g-1 . min-1 and 7.0 +/- 0.4 ml . 100 g-1 . min-1, respectively for fentanyl 400 micrograms/kg); however, seizures activity was noticed in about 25% of the rats receiving either 200 or 400 micrograms/kg fentanyl. The seizures seemed to be related to the narcotic in that they could be abolished by injections of naloxone. The seizure activity appeared to increase the CMRo2 relative to animals who received the same dose of fentanyl but did not have seizures. The CBF was not affected. The results confirm that narcotics in high enough doses may depress the CBF and CMRo2.

Animals↗
PubMed1983

Use of continuous infusion versus intermittent bolus administration of fentanyl or ketamine during outpatient anesthesia.

The intraoperative and postoperative effects of fentanyl and ketamine administered continuously by infusion were compared with those produced by conventional intermittent bolus administration in 100 patients. After a standardized induction with thiopental 4 mg/kg intravenously, patients received either fentanyl (50 micrograms boluses vs. 2 micrograms/ml infusion) or ketamine (25 mg boluses vs. 1 mg/ml infusion) as intravenous adjuvants to nitrous oxide, 70% in oxygen. With continuous infusion, the doses of fentanyl and ketamine required were decreased 45% and 43%, respectively. Similarly, the times to awakening were decreased significantly, 62% and 60%, in the fentanyl and ketamine infusion groups, respectively. Intraoperative side effects (e.g., hypoventilation, hypotension, rigidity) were less frequent in the fentanyl infusion (vs. bolus) group but did not differ in the ketamine groups. Trieger scores were consistent with a more rapid recovery in both infusion groups. Incidences of common postoperative side effects (e.g., nausea, vomiting, visual disturbances, dizziness) did not differ significantly between bolus and infusion groups. However, excessive sedation was noted in 48% and 52% of patients in the fentanyl and ketamine bolus groups, respectively, compared with 4% and 8%, respectively, in the infusion groups. Discharge times were decreased by 29% and 13% in the fentanyl and ketamine infusion groups, respectively. The author concludes that continuous infusion fentanyl (0.1 micrograms . kg-1 . min-1) or ketamine (50 micrograms . kg-1 . min-1) significantly decreases the drug dosage requirement, improves intraoperative conditions, and decreases recovery time compared with the traditional intermittent bolus technique.

Adult↗
PubMed1988

Pharmacokinetics of fentanyl in neonatal humans and lambs: effects of age.

To determine whether the clearance of fentanyl in neonates varies with age, the authors determined the pharmacokinetics of fentanyl in 14 humans ages 1-71 days and 15 lambs ages 3-37 days. In humans, fentanyl, 54.1 +/- 2.3 (mean +/- SD) micrograms/kg, was administered as a 2-min iv infusion; in lambs, fentanyl, 50 micrograms/kg, was administered as an iv bolus. Ventilation was controlled to maintain end-tidal or arterial PCO2 normal, and potent inhaled anesthetics were not administered; in humans, additional anesthesia was provided with iv morphine. Arterial or venous samples were obtained for 12 h, and plasma concentrations of fentanyl were determined by radioimmunoassay. Plasma concentration versus time data were fitted to two- and three-compartment pharmacokinetic models, and clearance, volume of distribution at steady-state (Vdss), and elimination half-life were determined. Clearance increased with age in both humans and lambs. Two humans who had intraabdominal surgery had no clearance of fentanyl: plasma concentrations of fentanyl remained constant for approximately 10 h after an initial distribution phase. In lambs, but not in humans, Vdss increased with age; elimination half-life did not change with age in either lambs or humans. The authors conclude that at least two factors--postnatal age and the type of surgery--affect fentanyl clearance during the neonatal period. The effect of other factors, such as inhaled anesthetics, remains to be determined.

Aging↗
PubMed1989

Induction of anesthesia with small doses of sufentanil or fentanyl: dose versus EEG response, speed of onset, and thiopental requirement.

The purpose of this study was to examine the dose versus EEG response relationship, the speed of onset, and the thiopental requirement for induction of anesthesia with small doses of sufentanil and fentanyl. The power spectrum of the electroencephalogram (EEG) was used to quantify the effect of the opioids. Eight male surgical patients, 52-80 yr old, were randomly divided into eight groups of ten to receive fentanyl, 5, 7, 10, or 13 micrograms/kg, or sufentanil, 0.5, 0.7, 1.0, or 1.3 micrograms/kg. The opioid was given iv over 1 min at a constant rate of infusion. Three to four minutes after the start of the opioid dose, thiopental was given iv in 25 mg increments every 30 s until the patient was unconscious. Power in the 1-3 Hz band reached maximum levels in less than 4 min after the start of opioid administration. At fentanyl doses of 7.0 micrograms/kg or less, or sufentanil doses of 1.0 micrograms/kg or less, the EEG effects did not increase in proportion to the dose of opioid. There was not a significant difference in the maximum power achieved in the 1-3 Hz band for sufentanil, 0.5, 0.7 and 1.0, and fentanyl, 5 and 7 micrograms/kg. Doses of fentanyl, 10 or 13 micrograms/kg, or sufentanil, 1.3 micrograms/kg were substantially more effective; the maximum power increased significantly between 7 and 10 micrograms/kg of fentanyl and 1.0 and 1.3 micrograms/kg of sufentanil (P less than 0.0001). The potency of sufentanil and fentanyl were compared by super-imposing, the dose versus response (power) curves. The potency ratio was 1:8 (sufentanil:fentanyl).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1989

Interaction of fentanyl and pentobarbital on peripheral and cerebral hemodynamics in newborn lambs.

The effects of 3.0 mg.kg-1 fentanyl on cerebral and peripheral hemodynamics alone and when combined with subanesthetic doses of pentobarbital (4.0 mg.kg-1), were studied in 11 unanesthetized, newborn lambs, in whom catheters had been previously inserted. After a control period, drugs were administered at 20-min intervals by intravenous bolus injection. Group 1 animals (n = 5) received fentanyl, pentobarbital, and naloxone (0.01 mg.kg-1), whereas Group 2 animals (n = 6) had the order of fentanyl and pentobarbital reversed. All animals responded to pain (withdrawal to tail clamping) and appeared conscious (eyes open, alert to sound) when either fentanyl or barbiturate was given alone. The combination of drugs, however, produced complete unresponsiveness. All of these effects were reversed by naloxone. Cardiac output did not change after either fentanyl or pentobarbital was administered individually but decreased significantly (29% in Group 1, 21% in Group 2) after administration of the combination of both. Mean arterial pressure and heart rate were unchanged. Cerebral blood flow, oxygen (O2) transport, and O2 consumption did not change after either administration of fentanyl or pentobarbital alone but decreased significantly after both (22%, 30%, 19%, respectively, in Group 1 and 35%, 40%, 38%, respectively, in Group 2). The decrease in cerebral O2 transport nearly paralleled the decrease in cerebral O2 consumption such that the ratio, the fractional O2 extraction, increased slightly. Fentanyl decreased kidney blood flow alone (24%) and in combination with pentobarbital (25%), although pentobarbital did so only when combined with fentanyl.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Pharmacokinetics of fentanyl administered by computer-controlled infusion pump.

Fentanyl was administered to 21 patients using a computer-controlled infusion pump (CCIP) based on a pharmacokinetic model. Eleven of the patients were dosed according to the pharmacokinetics described by McClain and Hug, and ten of the patients were dosed according to the pharmacokinetics described by Scott and Stanski. The authors measured the difference between the measured arterial fentanyl concentrations and the concentrations predicted by the CCIP for each pharmacokinetic parameter set. The median absolute performance error (MDAPE) in patients dosed according to McClain and Hug's parameters was 61%, and the MDAPE in patients dosed according to Scott and Stanski's parameters was 33%. The population pharmacokinetics in these 21 patients were analyzed using a pooled data technique. The pharmacokinetics of fentanyl in this population showed a smaller central compartment volume and a more rapid initial distribution half-life than previously estimated for fentanyl. The derived pharmacokinetic parameters described these patients well and also predicted the observed fentanyl concentrations from four previously published fentanyl studies with reasonable accuracy. Comparison of the parameters used by the authors with those of McClain and Hug demonstrated that dosing regimens designed from pharmacokinetic models can be fairly accurate at the times sampled in the original study but may not be accurate at time points not sampled in the original research. The authors concluded that although the pharmacokinetics of fentanyl administered by CCIP are the same as the pharmacokinetics of fentanyl administered by a bolus or constant rate infusion, a pharmacokinetic study using a CCIP may be particularly effective at characterizing the most rapid distribution pharmacokinetic parameters, and thus may provide parameters appropriate for subsequent use in a CCIP.

Adult↗
PubMed1991

A randomized double-blind comparison of epidural versus intravenous fentanyl infusion for analgesia after thoracotomy.

This study compared epidural and intravenous fentanyl infusions for pain relief for the first 20 h after thoracotomy, in order to examine whether an thoracic epidural fentanyl infusion offers clinical advantage over an intravenous infusion. Forty patients were assigned randomly to receive either fentanyl epidurally and saline intravenously or fentanyl intravenously and saline epidurally in a double-blind fashion. For each patient the fentanyl infusion was titrated to a rate required for pain relief (pain score less than 3, maximum 10). Patients reported similar median pain scores, but in the epidural group the required mean fentanyl infusion rate was less (0.95 +/- 0.23 vs. 1.67 +/- 0.46 micrograms.kg-1.h-1, P = 0.0001) and plasma fentanyl concentrations were less at 4 and 18 h (4 h: 0.81 +/- 0.27 vs. 1.38 +/- 0.36 ng.ml-1, P = 0.0001; 18 h: 0.94 +/- 0.32 vs. 1.54 +/- 0.65 ng.ml-1, P = 0.0007) than those in the intravenous group. Respiratory function was better preserved and the incidence of nausea and sedation was less in the epidural group than in the intravenous group. In conclusion there appears to be a clinical advantage to the epidural infusion over the intravenous infusion of fentanyl for analgesia after thoracotomy.

Analgesia, Epidural↗
PubMed1992

A randomized comparison of intravenous versus lumbar and thoracic epidural fentanyl for analgesia after thoracotomy.

Administration of large doses of fentanyl is a popular method to provide postoperative analgesia after thoracotomy. It is however unclear whether epidural lumbar (L) or epidural thoracic (T) administration of fentanyl confers any major advantage over intravenous (iv) infusion. Using a randomized prospective study design, we compared the potential benefits of L, T, and iv fentanyl administration after thoracotomy in 50 patients. Epidural catheters were not injected during surgery. Postoperatively a fentanyl infusion (5 micrograms/ml) was started at 1 microgram.kg-1.h-1 after a bolus of 1 microgram/kg and adjusted to maintain a score < or = 30/100 at rest using a visual analog scale (VAS) for pain. Data were prospectively collected before surgery, at fixed intervals during the 48 h of fentanyl infusions, and the day of discharge. There was no difference between the groups in overall quality of analgesia at rest and after coughing, quantity of fentanyl delivered (L = 1.15 +/- 0.38, T = 1.22 +/- 0.23, iv = 1.27 +/- 0.3 micrograms.kg-1.h-1), incidence of pruritus needing treatment (L = 2, T = 1, iv = 0 patients), need to decrease fentanyl infusion rate because of side effects (L = 2, T = 2, iv = 4 patients), importance of pulmonary infiltrates, or arterial blood gas values. One patient (L group) needed naloxone (0.04 mg iv). Intravenous patients were more frequently nauseated (P = .009) and needed boluses of fentanyl more often (L = 3 +/- 9, iv = 6 +/- 12, T = 4 +/- 8; P = .04).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1997

Effects of intracoronary fentanyl on left ventricular mechanoenergetics in the excised cross-circulated canine heart.

BACKGROUND: It is still unclear whether fentanyl directly alters left ventricular (LV) contractility and oxygen consumption. This is because of the difficulty in defining and evaluating contractility and energy use independently of ventricular loading conditions and heart rate in beating whole hearts. METHODS: This study was conducted to clarify the mechanoenergetic effects of intracoronary fentanyl in six excised cross-circulated canine hearts. The authors used the framework of the E(max) (a contractility index)-PVA (systolic pressure-volume area, a measure of total mechanical energy)-VO2 (myocardial oxygen consumption per beat) relationship practically independent of ventricular loading conditions. The authors measured LV pressure, volume, coronary flow, and arteriovenous oxygen content difference to calculate E(max), PVA, and VO2. They first obtained the VO2-PVA relationship for varied LV volumes at control E(max). The authors then obtained the VO2-PVA relationship at a constant LV volume, whereas coronary blood fentanyl concentration was increased in steps up to 240 ng/ml. Finally, they obtained the VO2-PVA relationship for varied LV volumes at the final dose of fentanyl. RESULTS: Fentanyl at any concentrations did not significantly change E(max), PVA, and VO2 from the control. The linear end-systolic pressure-volume relations and their slopes were virtually the same between the control and fentanyl volume loading in each heart. Further, either the slope (oxygen cost of PVA) or the VO2 intercept (unloaded VO2) of the linear VO2-PVA relationship remained unchanged by fentanyl. CONCLUSIONS: These results indicate that intracoronary fentanyl produces virtually no effects on LV mechanoenergetics for a wide range of its blood concentration.

Anesthetics, Intravenous↗
PubMed1997

Effects of intracoronary fentanyl on left ventricular mechanoenergetics in the excised cross-circulated canine heart (revised publication).

BACKGROUND: It is still unclear whether fentanyl directly alters left ventricular (LV) contractility and oxygen consumption. This is because of the difficulty in defining and evaluating contractility and energy use independently of ventricular loading conditions and heart rate in beating whole hearts. METHODS: This study was conducted to clarify the mechanoenergetic effects of intracoronary fentanyl in six excised cross-circulated canine hearts. The authors used the framework of the Emax (a contractility index)-PVA (systolic pressure-volume area, a measure of total mechanical energy)-VO2 (myocardial oxygen consumption per beat) relationship practically independent of ventricular loading conditions. The authors measured LV pressure, volume, coronary flow, and arteriovenous oxygen content difference to calculate Emax, PVA, and VO2. They first obtained the VO2-PVA relationship for varied LV volumes at control Emax. The authors then obtained the VO2-PVA relationship at a constant LV volume, whereas coronary blood fentanyl concentration was increased in steps up to 240 ng/ml. Finally, they obtained the VO2-PVA relationship for varied LV volumes at the final dose of fentanyl. RESULTS: Fentanyl at any concentrations did not significantly change Emax, PVA, and VO2 from the control. The linear end-systolic pressure-volume relations and their slopes were virtually the same between the control and fentanyl volume loading in each heart. Further, either the slope (oxygen cost of PVA) or the VO2 intercept (unloaded VO2) of the linear VO2-PVA relationship remained unchanged by fentanyl. CONCLUSIONS: These results indicate that intracoronary fentanyl produces virtually no effects on LV mechanoenergetics for a wide range of its blood concentration.

Anesthetics, Intravenous↗
PubMed1998

Mood during epidural patient-controlled analgesia with morphine or fentanyl.

BACKGROUND: Mood states during epidural opioids are not known. The authors studied the change in mood during the 48-h period of epidural morphine and epidural fentanyl in 47 patients after elective hip or knee joint arthroplasty. METHODS: An epidural catheter was inserted at the L2-L3 or L3-L4 interspace. Anesthesia was induced with thiopenthal and maintained with isoflurane and nitrous oxide. One hour before the conclusion of the operation, patients received an epidural bolus injection of 2 mg morphine (n = 23) or 100 microg fentanyl (n = 24), followed by the same opiate (125 microg/ml morphine or 25 microg/ml fentanyl) epidurally delivered by a patient-controlled analgesia (PCA) pump in the postoperative period for 48 h. Mood was assessed using the bipolar form of the Profile of Mood States before operation and 24 h, 48 h, and 72 h after operation. RESULTS: There was no significant difference in pain intensity between the groups during epidural PCA. Mood states became more positive over time in the patients who received morphine (P < 0.01 at 48 h) and negative in those who were given fentanyl (P < 0.01 at 24 and 48 h, respectively) compared with those before the operation, and they were more positive in the morphine than in the fentanyl group at 24 h, 48 h (P < 0.05), and 72 h (P < 0.01). Patients in the morphine group were more composed, agreeable, elated, confident, energetic, and clearheaded than were those in the fentanyl group (P < 0.05). There was no correlation between mood scores and pain scores in either group. There was an inverse correlation at 48 h between mood scores and plasma fentanyl concentrations (r = -0.58, P < 0.05). CONCLUSION: Mood states are significantly more positive during epidural morphine PCA than they are during epidural fentanyl PCA.

Adult↗
PubMed1999

Ritonavir's role in reducing fentanyl clearance and prolonging its half-life.

BACKGROUND: The human immunodeficiency virus protease inhibitor ritonavir is a potent inhibitor of the cytochrome P450 3A4 enzyme, and ritonavir's concomitant administration with the substrates of this enzyme may lead to dangerous drug interactions. METHODS: The authors investigated possible interactions between ritonavir and intravenously administered fentanyl in a double-blind, placebo-controlled, cross-over study in two phases. Twelve healthy volunteers received orally ritonavir or placebo for 3 days; the dose of ritonavir was 200 mg three times on the first day and 300 mg three times on the second. The last dose of ritonavir 300 mg or placebo was given on the morning of the third day. On the second day, 2 h after the afternoon pretreatment dose, fentanyl 5 microg/kg was injected intravenously in 2 min with naloxone to moderate its effects, and 15 timed venous blood samples were collected for 18 h. RESULTS: Ritonavir reduced the clearance of fentanyl by 67% from 15.6+/-8.2 to 5.2+/-2.0 ml x min(-1) x kg(-1) (P<0.01). The area under the fentanyl plasma concentration-time curve from 0 to 18 h was increased from 4.8+/-2.7 to 8.8+/-2.3 ng x ml(-1) x h(-1) by ritonavir (P<0.01). Ritonavir did not affect the initial concentrations and the steady-state volume of distribution of fentanyl. One subject discontinued participation before fentanyl administration because of severe side effects, and during the study 8 of the remaining 11 subjects reported nausea. CONCLUSIONS: Ritonavir can inhibit the metabolism of fentanyl significantly, so caution should be exercised if fentanyl is given to patients receiving ritonavir medication.

Adult↗
PubMed2003

Simultaneous assessment of drug interactions with low- and high-extraction opioids: application to parecoxib effects on the pharmacokinetics and pharmacodynamics of fentanyl and alfentanil.

BACKGROUND: Parecoxib is a parenteral cyclooxygenase-2 (COX-2) inhibitor intended for perioperative analgesia. It is an inactive prodrug hydrolyzed in vivo to the active inhibitor valdecoxib, a substrate for hepatic cytochrome P450 3A4 (CYP3A4); hence, a potential exists for metabolic interactions with other CYP3A substrates. This study determined the effects of parecoxib on the pharmacokinetics and pharmacodynamics of the CYP3A substrates fentanyl and alfentanil compared with the CYP3A inhibitor troleandomycin. Alfentanil is a low-extraction drug with a clearance that is highly susceptible to drug interactions; fentanyl is a high-extraction drug and, thus, is theoretically less vulnerable. We therefore also tested the hypothesis that the extraction ratio influences the consequence of altered hepatic metabolism of these opioids. METHODS: After Institutional Review Board-approved, written, informed consent was obtained, 12 22- to 40-yr-old healthy volunteers were enrolled in the study. The protocol was a randomized, double-blinded, balanced, placebo-controlled, three-session (placebo, parecoxib, or troleandomycin pretreatment) crossover. Subjects received both alfentanil (15 microg/kg) and fentanyl (5 microg/kg; 15-min intravenous infusion) 1 h after placebo, parecoxib (40 mg intravenously every 12 h), or troleandomycin (every 6 h). Study sessions were separated by 7 or more days. Opioid concentrations in venous blood were determined by liquid chromatography-mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. Opioid effects were determined by pupillometry, respiratory rate, and Visual Analog Scale scores. RESULTS: There were no significant differences between the placebo and parecoxib treatments in alfentanil or fentanyl plasma concentration, maximum observed plasma concentration, area under the plasma time-concentration time curve, clearance, elimination half-life, or volume of distribution. However, disposition of alfentanil, and to a lesser extent fentanyl, was significantly altered by troleandomycin. Clearances were reduced to 12% (0.64 +/- 0.25 ml. kg-1. min-1) and 61% (9.35 +/- 3.07) of control (5.53 +/- 2.16 and 15.3 +/- 5.0) for alfentanil and fentanyl (P < 0.001). Pupil diameter versus time curves were similar between placebo and parecoxib treatments but were significantly different after troleandomycin. CONCLUSIONS: Single-dose parecoxib does not alter fentanyl or alfentanil disposition or clinical effects and does not appear to cause significant CYP3A drug interactions. CYP3A inhibition decreases alfentanil clearance more than fentanyl clearance, confirming that the extraction ratio influences the consequence of altered hepatic drug metabolism. Modified cassette, or "cocktail," dosing is useful for assessing drug interactions in humans.

Adult↗
PubMed2003

Efficacy, safety, and pharmacokinetics of levobupivacaine with and without fentanyl after continuous epidural infusion in children: a multicenter trial.

BACKGROUND: Levobupivacaine, the levo-enantiomer of bupivacaine, is as potent as bupivacaine but less toxic. Therefore, the authors investigated the efficacy, safety, and pharmacokinetics of perioperative epidural levobupivacaine with and without fentanyl in children. METHODS: After Research Ethics Board approval and informed written consent, 120 healthy children aged 6 months to 12 yr who were scheduled to undergo urologic or abdominal surgery were randomized in a double-blinded and concealed manner to receive one of four epidural solutions as a continuous infusion for 24 h: 0.125% levobupivacaine; 0.0625% levobupivacaine; 1 mug/ml fentanyl; or the combination, 0.0625 levobupivacaine and 1 mug/ml fentanyl. After induction of anesthesia and tracheal intubation, a lumbar epidural catheter was sited, a loading dose was administered (0.75 ml/kg levobupivacaine, 0.175%), and the epidural infusion was commenced. The primary endpoint was the need for rescue analgesia (morphine) in the first 10 h after surgery. Pain, motor strength, and side effects were recorded for 24 h. Venous blood was collected from 18 children to determine the plasma concentrations of levobupivacaine and/or fentanyl before and 2, 4, 8, 16, 24, and 26 or 30 h after the start of the epidural infusion. RESULTS: Of the 114 children who were analyzed for intention to treat, a similar number of children in each group reached the 10-h mark. The time to the first dose of morphine in the first 10 h was less in the plain fentanyl group (P < 0.044). All other effects were similar among the four groups. The plasma concentration of levobupivacaine increased during the infusion period, reaching a maximum of 0.76 +/- 0.11 mug/ml in the 0.125% group and 0.48 +/- 0.12 mug/ml in the 0.0625% group by 24 h. The plasma concentration of fentanyl also increased steadily, reaching a maximum concentration of 0.37 +/- 0.11 ng/ml by 24 h. CONCLUSION: We conclude that 0.0625% levobupivacaine without fentanyl is an effective perioperative epidural solution in children when infused at a rate of 0.3 ml. kg-1. h-1. The plasma concentrations of 0.125% and 0.0625% levobupivacaine and fentanyl (1 mug/ml) at the end of a 24-h infusion are low.

Analgesics, Opioid↗
PubMed1995

Transdermal fentanyl therapy: system design, pharmacokinetics and efficacy.

The transdermal route of drug delivery has been used for the effective administration of therapeutic agents for more than a decade. The most important consideration in selecting a drug for transdermal delivery is the potential for improving therapeutic efficacy. The development of a transdermal fentanyl system provided an opportunity to add fentanyl to the armamentarium of strong opioids available for the treatment of cancer pain. The transdermal route of administration has advantages over both the oral and parenteral routes. In addition, patient and caregiver factors allow improved acceptance of and compliance to strong opioids and therefore improved analgesic outcome. Four transdermal fentanyl systems are available, providing delivery rates ranging from 25-100 micrograms/h; higher rates can be achieved by multiple system application. The system releases fentanyl continuously for 3 days when applied to the skin. Concentrations of fentanyl in the blood are measurable within a few hours of system application. Fentanyl serum concentrations increase gradually, generally levelling off after 12-24 h and remaining relatively constant for the remainder of the 3-day period. Steady state serum concentrations are reached by the second application. Clinical trials have established the efficacy and safety of transdermal fentanyl for the treatment of cancer pain. Transdermal fentanyl is not licensed for the treatment of acute pain, e.g. postoperative pain, and should not be prescribed for this purpose.

Administration, Cutaneous↗
PubMed1995

Transdermal fentanyl: clinical development in the United States.

The first clinical experience in the United States of the transdermal therapeutic system (TTS) for delivery of fentanyl in cancer pain was a small study of five patients. Pain relief was established with intravenous (i.v.) fentanyl. A transdermal system was selected to deliver the same hourly dose while the i.v. infusion was tapered over 6 h. The transdermal system was changed every 24 h for a total duration of 3-156 days. A larger multicentre outpatient trial was conducted in 39 patients for a median of 84 days (range 5-365). The TTS fentanyl dose was established from a conversion table based on the dose of oral immediate-release morphine required to control pain. The TTS fentanyl patches were changed every 72 h. Immediate-release morphine was used on an as required basis for incident pain. The initial study demonstrated that steady-state plasma levels were linearly related to the TTS fentanyl dose. The multicentre trial further demonstrated that patients could be converted from oral morphine to an equianalgesic dose of TTS fentanyl and that pain relief could be maintained for a lengthy period of time on an outpatient basis. The systems were used throughout a variety of concomitant complications of the cancer process. This experience demonstrated the safety and clinical effectiveness of TTS fentanyl in the treatment of chronic cancer pain. TTS fentanyl has been used widely in the USA since it was approved for marketing in 1990.

Administration, Cutaneous↗
PubMed1994

Prospective study on the occurrence of withdrawal in critically ill children who receive fentanyl by continuous infusion.

OBJECTIVE: To determine the occurrence of narcotic withdrawal in critically ill children who receive continuous infusions of fentanyl. DESIGN: Prospective case series. SETTING: A university hospital pediatric intensive care unit. PATIENTS: Twenty-three children, aged 1 wk to 22 months (mean 6 months), who required assisted mechanical ventilation and who received continuous infusions of fentanyl for > 24 hrs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Total fentanyl dose received, length of infusion, and peak infusion rate were recorded. Patients were evaluated for narcotic withdrawal by the Neonatal Abstinence Scoring System of Finnegan. Children with scores of > or = 8 were considered to have narcotic withdrawal. Withdrawal was observed in 13 (57%) of 23 infants. Total fentanyl dose (2.96 +/- 4.10 vs. 0.53 +/- 0.37 mg/kg, p < .005) and length of fentanyl infusion (13.1 +/- 11.3 vs. 3.8 +/- 1.5 days, p < .0001) were significantly greater in those infants with narcotic withdrawal than in those infants with no withdrawal, respectively. Peak fentanyl infusion rate (9.9 +/- 7.8 vs. 9.2 +/- 4.4 micrograms/kg/hr) did not differ significantly between the two groups. A total fentanyl dose of > 2.5 mg/kg or a duration of infusion of > 9 days was 100% predictive of withdrawal. CONCLUSIONS: Continuous infusions of fentanyl produce a high occurrence rate of narcotic withdrawal when administered to critically ill children. This effect is both dose- and duration-dependent.

Chi-Square Distribution↗
PubMed2004

Apoptogenic effect of fentanyl on freshly isolated peripheral blood lymphocytes.

BACKGROUND: Opioids may trigger the apoptotic death of widely ranging cell types, and apoptosis contributes to the immune deficiency of critically ill patients and subjects experiencing surgical trauma. There is evidence that an altered mitochondrial membrane potential constitutes an early and irreversible step in the death-signaling pathway of apoptosis. This study investigated whether fentanyl, a opioid widely used in the management of these patients, may induce apoptosis of T cells by altering their mitochondrial membrane potential. METHODS: Peripheral blood lymphocytes were cultured in the presence of 30 ng fentanyl for 60 (time 1), 90 (time 2), and 120 (time 3) minutes, respectively. The cells then were processed for assessment of mitochondrial membrane potential by means of flow cytometry and confocal scanning microscopy. Furthermore, production of reactive oxygen species, expression of the Fas-Fas L pro-apoptotic pathway, and apoptosis frequency were measured by means of flow cytometry. Control cells were incubated for the same times in the complete culture medium without the drug. RESULTS: Flow cytometry analysis showed a significantly increased rate (p < 0.05) of lymphocytes with disrupted mitochondrial membrane potential after incubation with fentanyl for 90 and 120 minutes, as compared with both control cells and lymphocytes cultured in the presence of fentanyl for 60 minutes. In addition, as early as 60 minutes after exposure to fentanyl, cells displayed a disrupted mitochondrial membrane potential when this was assayed by means of confocal laser scanning. These findings were associated with increased production of reactive oxygen species. The frequency of apoptotic lymphocytes was markedly increased (p < 0.05) after 120 minutes of incubation, as compared with untreated cells and cells exposed to fentanyl for only 60 and 90 minutes. Expression of Fas-FasL was not substantially affected by exposure to fentanyl. CONCLUSIONS: Fentanyl may induce a time-dependent apoptosis of lymphocytes by altering their mitochondrial redox metabolism.

Adult↗