A Review of the Use of Fentanyl Analgesia in the Management of Acute Pain in Adults  (1999)

(Peng) Staff Anaesthetist, Department of Anaesthesia, The Toronto Hospital and Mount Sinai Hospital; Assistant Professor, University of Toronto.(Sandler) Anaesthetist-in-Chief, The Toronto Hospital and Mount Sinai Hospital; Professor, University of Toronto.FENTANYL was one of a series of opioids synthesized by Janssen Pharmaceutica in the 1950s and 1960s in an effort to produce opioid analgesics with enhanced analgesic activity and potency and fewer adverse effects compared with morphine or meperidine. [1,2]It was first used clinically as a component of neuroleptanalgesia in combination with the butyrophenone, droperidol. [3]Between 1975 and 1981, fentanyl was adopted widely as a potent intraoperative analgesic agent with relatively few adverse effects. In small-to-moderate bolus doses (3 to 5 [micro sign]g/kg), it combined with different intravenous supplements to produce “balanced” anesthesia, [4]whereas large doses (as much as 100 [micro sign]g/kg) were used to induce and to maintain anesthesia in critically ill patients and those undergoing cardiopulmonary bypass procedures. [5]Fentanyl's popularity as an intraoperative agent relates directly to the cardiovascular stability it provides, even in critically ill patients. [6,7]But its analgesic efficacy relative to the intensity of side effects prompted much interest in its use as an analgesic agent after operation or in the intensive care unit. Investigators began by exploring alternatives to the traditional intramuscular or intravenous routes for postoperative administration to optimize the potential clinical benefits of fentanyl's physiochemical properties. This article reviews the literature related to the use of fentanyl as an analgesic in the postoperative period and in patients in the intensive care unit, and it evaluates the pharmacokinetics, pharmacodynamics, efficacy, and limitations of existing and experimental routes of administration.Fentanyl, N-(1-phenethyl-4-piperidyl) propionanilide, is structurally related to meperidine. Commercially, fentanyl is formulated as a citrate, available in a water-soluble, white crystalline powder that requires no preservatives. It has a molecular weight of 528.29 and a melting point of 148.5 to 150[degree sign]C. Each milliliter of aqueous solution contains a base of 0.05 mg fentanyl (0.0785 mg of the citrate).The negative logarithm of the acid ionization constant of fentanyl (pKa) is 8.43. At physiologic pH, 8.5% of the compound is un-ionized in plasma and 84% is bound to erythrocytes, [small alpha, Greek]1-acidglycoprotein, and plasma albumin. [8]The octanol-water partition coefficient at physiologic pH is 816 for fentanyl compared with 1.4 for morphine. Therefore, fentanyl is highly lipophilic, whereas morphine is hydrophilic. Multiplying this partition coefficient by the plasma-free fraction (Table 1) yields a relative potential to enter the central nervous system that is approximately 133 times larger than that of morphine. [9]Optimization of the molecular configuration of fentanyl increased its potency. Fentanyl is 100 to 300 times more potent than morphine per dose, depending on the animal species. [10-12]This greater dose potency permits a low therapeutic blood concentration of approximately 0.6 to 3 ng/ml for analgesia. This, in turn, necessitates a sensitive method of assay.Radioimmunoassay and gas liquid chromatography are the two most common methods used. The current radioimmunoassay method can measure plasma fentanyl concentrations as low as 0.06 ng/ml and was first reported in 1977. [13]The standard curves are linear for a concentration range of 0.06-20 ng/ml, and the coefficient of variation of the assay ranges from 1-12%. [14-21]However, radioimmunoassay analysis can overestimate plasma fentanyl concentrations (fentanyl CP) by as much as 29 to 100%, [22]limiting reliability, and thereby contributing to the observed differences in the pharmacokinetic data reported for fentanyl. [22]Assay by gas liquid chromatography using either flame-ionization, nitrogen phosphorus, or mass spectrometric detection is sensitive and reproducible. With nitrogen phosphorus, [23]the mean coefficient of variation for concentrations ranging from 0.25-10 ng/ml is 4.65%; with mass spectrometric detection, the mean coefficient of variation is 6.9% for a range of 0.2-68 ng/ml. [24]When compared directly with the radioimmunoassay method, the gas liquid chromatography-nitrogen phosphorus method results in comparable values in the spiked control and patient samples. [25]At the detection limit of 0.25 ng/ml, gas liquid chromatography has a coefficient of variation of 14.7%, comparable to 14.2% for radioimmunoassay. At higher concentrations, the coefficient of variation decreases to approximately 5%. This increased variability at the detection limit significantly affects pharmacokinetic analysis, because the terminal half-life for low-to-moderate doses of fentanyl (5-15 [micro sign]g/kg) is estimated using serum levels in the region of this limit. Accordingly, limitations of the assay, whether radioimmunoassay or gas liquid chromatography, must be considered in that fentanyl has and a of and it an agent to and routes of administration than the traditional it has intravenous or and an intravenous fentanyl from plasma to highly and than of the dose plasma in than 5 by from the is as fentanyl to as and fentanyl in 5 after a bolus dose, and in at approximately from and is than because as in this is because of its and in because of the of fentanyl. with fentanyl and the fentanyl the This results in a of to (Table fentanyl's of after a dose results from than large or fentanyl as a of its and is in fentanyl from its of in the is in the to and activity of fentanyl is is to be than of fentanyl is by the of fentanyl is and and that of blood the The of fentanyl to a large of fentanyl and most side the intensity of fentanyl's with the concentration at the of and the plasma the or is the opioid in the and is for fentanyl to the to the The plasma concentration and the on the is constant the of the concentration and the serum the for the of the (Table to measure opioid one of a to fentanyl a fentanyl the was of fentanyl to of administration different of With a in plasma concentration after an intravenous the be with a in concentration with a the be data different must be compared with Fentanyl and fentanyl its analgesic and side effects estimated plasma fentanyl from concentrations in of patients. from to patients intravenous fentanyl for postoperative a mean analgesic ranging from ng/ml. of fentanyl to a reported in one produce at a mean concentration of 0.6 ng/ml and greater at a ng/ml, in analgesic range of ng/ml. With the mean analgesic concentration the patient the bolus dose has reported as ng/ml, ng/ml, ng/ml. mean values range from ng/ml, whereas values for patients range from ng/ml with a fentanyl analgesic no that the mean fentanyl to ng/ml and to ng/ml with at of 3 or to of to 3 are with a or ng/ml in different postoperative patient by a bolus dose of fentanyl. of the with are patients are at at a with or observed variability in the analgesic for fentanyl in large is by differences in and in of patients and different a range for fentanyl and to the of and of central nervous system the doses or the of fentanyl and the intensity of and side effects. The of by The of the of postoperative and thereby the analgesic With a a higher analgesic in patients undergoing than of analgesic are with in of blood at results with analgesic the patient the fentanyl in patients after operation at ranging from ng/ml. control at is this the analgesic with or that a higher be is to either of Fentanyl and the fentanyl a With intravenous bolus a 3 or ng/ml a in the of plasma concentrations concentrations of as a of the values with bolus using or a of the for clinically in patients undergoing a ng/ml or this clinically as a for with or of fentanyl has by the to using the an of central this be in patients after operation because it on patient and is significantly by and that are to patients. of is to the of or the of be by and used to the of of 100 for in and for 5 a of per operation in patients undergoing In the postoperative a or ng/ml was with of at a in and and the of blood levels of This of is a the and concentrations greater than ng/ml are with clinically the of is by the of of and a greater than ng/ml as a for The therapeutic for fentanyl is the range the analgesic concentration and that with in the analgesic side and fentanyl to be highly In in the of and has a to the fentanyl The concentration in patients 0.6 ng/ml. At plasma concentrations at intensity decreases by with in intensity 1.4 fentanyl decreases the of the concentration in by and At a 3 ng/ml, fentanyl and decreases this by and the therapeutic in with that for patients after is a fentanyl and and In and the range of fentanyl clinically is ng/ml. of with central and and pharmacokinetic differences can this and be considered the therapeutic range is of Fentanyl can be for postoperative using a dose with a or a with or Fentanyl intravenous of fentanyl used to postoperative after and intravenous bolus of fentanyl or [micro sign]g/kg) is the of the is or [micro and be or as by in analgesic or side effects. the is bolus doses of fentanyl are to the the is a analgesic either bolus or doses of or morphine (Table is used to the therapeutic of at of [micro can postoperative (Table At the of with it decreases even with higher fentanyl directly to the at with concentrations ranging from side effects can The of and after fentanyl from in of and in The values or the of because use postoperative that of is common after fentanyl most are reported clinically with (Table of and morphine it the of The methods of detection and of or of and blood intravenous fentanyl at at doses of or [micro in postoperative analgesic can be by the fentanyl or as a or by administration of bolus doses of opioid or to a with intravenous of fentanyl be combined with to with fewer adverse effects. bolus doses range from [micro be ranging from [micro or be and to clinical the larger the the the bolus period range from no to the most common (Table directly the use of intravenous fentanyl with and fentanyl of the data in a dose for than for variability in dose, and The of the dose that higher than or The of postoperative for for with the fentanyl has in patients at increased with of the with this a for fentanyl for and that from ng/ml. side effects can data the of adverse effects with this are and are estimated to in approximately of patients. two the of a range of the of the of and of clinically with the use of a fentanyl with fentanyl postoperative with a dose The of side effects with the two is to because of the data for Fentanyl is used for most because of the in its of The opioids most are morphine and meperidine. a few compared the efficacy and of fentanyl with those of used fentanyl as a control in clinical it with analgesic with opioids used for dose doses range from [micro with from to the to the from to that patients can the of a dose a of fentanyl's to of 5 or is from [micro and mean from [micro (Table than those for the (Table fentanyl's of patients one to and more than two bolus bolus doses of [micro fentanyl be for can be with fentanyl with efficacy comparable to that of morphine and meperidine. two using bolus doses [micro and a has directly compared the of a on the efficacy of intravenous fentanyl by in that fentanyl with dose as with a of opioids to to a to the use of an opioid is with an increased for it be to using with on the dose and for the relatively analgesic fentanyl be and with fentanyl In an of patients undergoing bolus dose of [micro with a of in a mean fentanyl 1.4 ng/ml after to ng/ml at at at and were at and fentanyl the with intravenous fentanyl in patients undergoing or a using the bolus dose and Fentanyl the first in the intravenous from ng/ml, in mean for this period of to at a few reported the of side effects with fentanyl and in of patients and in are no of clinically with fentanyl by with fentanyl comparable to that of intravenous of fentanyl's of most patients one to bolus The of a no to the of and the of with dose is with of fentanyl has This is and of fentanyl the The to the of the is the of the of has a of in a in fentanyl's it to the the of the be by or a of the system the of in by a more than the fentanyl is available in and of fentanyl at of approximately and 100 [micro for of The is to the by a to is a that the at fentanyl is from the to the The is a with a as much as mg to a concentration for the of the fentanyl the the has a of the is that it of the of the to as a The of has It the of fentanyl to be and to a fentanyl of fentanyl the system and after of the is At the of a period with a fentanyl at the of 100 [micro mg fentanyl of the dose from the in the concentrations, to and half-life after of the fentanyl are two of fentanyl after a of the with of the from the because of the large concentration the and the and a with of from the of the of the an of after the is a the concentration is to the of the fentanyl The concentration values for the doses of and 100 [micro are approximately and ng/ml, the analgesic range for fentanyl. is large variability in fentanyl of of the fentanyl ranges from ng/ml. for the estimated from the fentanyl fentanyl of system ranges from [micro a fentanyl is in for fentanyl to after the is fentanyl because of from the fentanyl The terminal ranges from is is by the of fentanyl and the fentanyl administration from the using fentanyl are to to patients or of because the fentanyl is a system that requires a to a In the is to the of postoperative with the postoperative after is with the a dose, whereas to after the the the of fentanyl from the is to that from a intravenous opioids are used to analgesic as of the of an analgesic are operation at at The of a The fentanyl system a of fentanyl to the the of dose This in to the intensity of postoperative opioids are to and in the to postoperative With fentanyl significantly postoperative than opioid of the of fentanyl significantly the dose The of and with ranges from In most it is values are comparable to those with intravenous and the control with opioid and bolus in of patients has in a few at a of in of it is to of the fentanyl and than after the is the and of reported by fentanyl of the and of the fentanyl system Janssen to postoperative a of in in the literature on the use of fentanyl a of clinically (Table in the of or of its use in the fentanyl system be to of The and has that the fentanyl system be used to to dose the period of and a of the fentanyl system to of the to of the of the methods of and are is one method to The system of a a current and an an of are the for administration has used to to for for clinically doses of morphine. administration of fentanyl has in (3 was for at and of on two times to detection of fentanyl in the for the and were and times to [micro and and the mean times to concentrations were and was ng/ml with the and was approximately that with the The mean terminal half-life was for the and the 100 and The results a and the fentanyl Fentanyl the and in was observed at the of the fentanyl use for postoperative can be used to clinically doses of fentanyl. has for fentanyl administration by this method and of using fentanyl. The terminal half-life estimated from the method is than that from of that be using the and analgesic efficacy of this experimental is its clinical of opioids to to an is a this has used to In current clinical fentanyl and to analgesia. fentanyl fentanyl in a a on a The of fentanyl is in and and it is to it to be a fentanyl has as a in it has in and in With fentanyl can be directly the or in and the Fentanyl the in the the of of fentanyl to is in and for much of the variability with of in doses ranging from [micro In a administration of fentanyl with were the fentanyl dose [micro sign]g/kg) or The was in the and in The fentanyl two times greater with than with administration (3 0.6 and was with was compared with with Fentanyl to than ng/ml of to The of this in concentration and the of terminal half-life values after intravenous and administration that a fentanyl in the a few the use of in postoperative a [micro sign]g/kg) was times at on the first postoperative in patients undergoing or morphine was available to patients in and control as The dose per [micro or were with the two at approximately the dose in the in patients undergoing that a dose of [micro and more than a dose of [micro with an and of to those with a intravenous bolus of mg The to of with is approximately of by and doses ranging from with a dose of [micro to with a dose of [micro of is as by reported of or dose of results in an and of comparable to those of a intravenous bolus of morphine in patients to postoperative The of adverse effects with by morphine to be comparable to that with morphine and reported in and of using morphine and and with morphine of to with and morphine are and fentanyl to of and comparable to that with an intravenous bolus of morphine. a in morphine the use of the of adverse With data on the use of in the postoperative its as a postoperative analgesic is of the in a is approximately and the is highly with blood of 100 the of fentanyl the that are to be and a low molecular weight produce serum concentrations to those with intravenous fentanyl pharmacokinetic The two to to a dose for fentanyl compared the effects of and intravenous fentanyl in the after was with a with [micro fentanyl. dose of [micro was after and 5 patients were of or The dose was to the control of doses of [micro in at in the postoperative The mean dose of [micro from that in the intravenous [micro from the mean times to and analgesic with fentanyl of and are than the times with intravenous administration and In the with administration from the with The was the with fentanyl the and effects in of and an of and than of administration of fentanyl for postoperative to be on two it that of fentanyl can produce to that by intravenous use of a low dose administration of as a of the and of the of morphine the system has can produce postoperative as a fentanyl's of a system has are of an aqueous by a that as a to of a a a on the of fentanyl are of 300 [micro fentanyl from the a ng/ml at and a ng/ml at With of 100 [micro fentanyl at a concentration to the detection limit of ng/ml. a and intravenous administration of of [micro of a of and fentanyl to in a ng/ml at blood was in this this be of at and concentrations of the was that the after the At and after fentanyl were 0.25 ng/ml and ng/ml, a doses of [micro were at The to the concentration after administration from and the fentanyl the analgesic therapeutic that ng/ml (Table The of is is with the of most the system dose of 300 [micro fentanyl an significantly after procedures. significantly the to the first dose of morphine relative to control in in a dose of 3 fentanyl solution of different concentrations and [micro in the dose [micro in a analgesic 5 of differences in results can be for by differences in administration and reported the dose for fentanyl in patients after of is in 5 this analgesic The has the potential to the as by the of a therapeutic concentration after of a dose of [micro clinically or of has reported in the few patients is in and relative to of fentanyl an of of is after administration of fentanyl at a dose [micro the of with this is for clinical The method significantly the of it the of analgesia. is to the and efficacy of fentanyl administration for postoperative and administration of fentanyl are routes for intraoperative anesthesia and postoperative analgesia. The of relatively is the of routes of after administration of fentanyl the the the from the the opioid or in the the to in the or and that molecular molecular and the of as by the partition with the coefficient in a The coefficient that results in and and the coefficient of a can be by the of the is the the a must the and and in the component of the and the region The is more for to the for the a is in the opioids of its partition fentanyl has and as the as the The of is by dose the of administration use of bolus of fentanyl as the bolus dose administration of a bolus of [micro [micro sign]g/kg) results in a fentanyl than ng/ml in the first is much than the range for of an bolus of [micro the concentration is ng/ml, that it is the range of the of from the blood the blood concentration at of doses in fentanyl or after of therapeutic doses of and intravenous fentanyl for postoperative fentanyl at and doses (Table administration dose compared with are no data on the of fentanyl in with or bolus administration to a of fentanyl significantly the fentanyl relative to intravenous the be by a in from or by a [small alpha, activity of in the to The concentration at the of the with 3 for morphine for meperidine. of the of fentanyl with in the a of the dose to the can from the the the is the of fentanyl. At an of mg is and fentanyl range from ng/ml. this range much than plasma analgesic concentrations intravenous fentanyl is used for that analgesic is in at the than clinical fentanyl administration and that fentanyl is than morphine to produce clinically has is reported to be with fewer adverse effects of administration are the as those used bolus dose bolus dose combined with and with a or and patients with from fentanyl is combined with and to postoperative control for and and from combined are in this The of fentanyl used for bolus administration from to [micro [micro and to 5 [micro and to the to using a concentration of [micro and the of the of by a bolus dose of fentanyl is administration by for postoperative range from [micro or intravenous bolus opioid be used to or maintain the is has used after with a in of [micro with a of and of [micro most in dose in the first after be with differences in intraoperative opioid the of postoperative after different or of fentanyl or and the limitations to the of with bolus is at with and is in to the at and with or by administration of fentanyl. compared the efficacy of intravenous and fentanyl in a series of in different postoperative patient the two is the in are for analgesic dose and and side effects. are the and of and the of or using a or using a or using a and fentanyl in are with the two of administration a bolus or that the at a to the for decreases the and dose for by compared with In no differences in the analgesic dose with for or (Table the fentanyl with the side for the two clinical to postoperative by the than intravenous of reviews of the side effects of and opioids on morphine. the most common side is with an of It an after bolus and to be related to and can be with that from that from morphine intensity or The is and are is of and with fentanyl is approximately is comparable to 3 of fentanyl with opioid or or opioid is opioids can produce The of this is to be to the of opioids with opioid in the the the of the thereby in reported of ranges from is than in most on the of after fentanyl are by the common postoperative of or an (Table is the most adverse of the use of to its with the use of opioids or or the of fentanyl were to of to in the the pharmacokinetic of fentanyl bolus administration at the that concentrations in the region are as much as of concentration in the can with either bolus doses or of fentanyl. The is after an bolus dose of [micro of reported after a of fentanyl ranging from [micro the clinically to be relatively with fentanyl. those 29 with a of approximately patients that the and of side the of clinically is approximately of in two of the one of fentanyl a or at an of [micro in in of patients. In the is to the clinical of the because the blood gas and administration of to patient in the of in blood of of clinical administration of fentanyl can to postoperative analgesia. administration a of or is more common in the postoperative and at with routes of the analgesic with and with intravenous the analgesic efficacy, dose and side effects of and intravenous fentanyl are no to using than intravenous fentanyl for postoperative fentanyl is combined with for anesthesia and in patients. a of of the use of fentanyl for postoperative of administration bolus or an bolus of fentanyl an has as the of the first of The bolus for postoperative is [micro a dose [micro is (Table of is is ranging from in most fentanyl has as an the bolus and for fentanyl with no clinically adverse effects can be with bolus doses of [micro and a of an of [micro in patients of 5 [micro approximately [micro in a in and the for opioid in patients. postoperative can be with bolus doses of [micro (Table this dose to [micro at the effects of or on the of in patients after and postoperative compared with morphine analgesic efficacy can be with an at [micro the effects of and with greater than or intravenous fentanyl at of and [micro the and more than fentanyl by that with or potential to the use of the is the for an the for or effects and necessitates clinical in and effects are relatively with and a few of or with relatively large bolus doses a [micro bolus and 5 [micro for of has reported at a of 5 [micro in has reported with the use of fentanyl (Table even at doses as as 100 [micro directly the the dose of fentanyl [micro has with for this in administration results in than the dose is than the the of of fentanyl administration of it to a of with fentanyl the more and at and with at a dose than either the or intravenous to a the of an the for or the popularity of this for use after is used widely as an analgesic agent in the postoperative or critically ill of its and it is routes of routes are use the most intravenous with its more is effects are with of and and are and patients fentanyl for postoperative to and effects. experimental and for postoperative for the for and for to the of bolus fentanyl in of fentanyl in intravenous fentanyl in patients