A review of the use of fentanyl analgesia in the management of acute pain in adults.

Abstract

(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 r