(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 interpreting studies that profile fentanyl pharmacokinetics.Fentanyl has both high lipid solubility and a pattern of rapid and extensive redistribution, making it an ideal agent to evaluate drug delivery systems and routes of administration other than the traditional parenteral routes. Consequently, it has been administered via intramuscular, intravenous (bolus injection, infusion, patient-controlled analgesia [PCA]), neuraxial (epidural, intrathecal), transdermal, transmucosal (oral or intranasal), and inhalational routes.After an intravenous bolus, fentanyl distributes rapidly from plasma to highly vascular tissues (heart, lung, and brain). More than 80% of the injected dose leaves plasma in less than 5 min, [26]and 98.6% leaves by 1 h. [27]Elimination from the vascular tissue also is rapid as fentanyl redistributes to other sites, such as muscle and fat. [28]In rats, fentanyl CPpeaks in muscle 5 min after a bolus dose, and in fat at approximately 30 min (Figure 1). Removal from muscle and fat is slower than uptake, because both tissues act as storage sites; in muscle this is because of its mass, and in fat because of the high lipid solubility of fentanyl. [29]After initial equilibration with adipose tissue, fentanyl C (P) decreases, and then fat slowly releases the fentanyl back into the plasma. This slow release results in a lengthy elimination half-time of 3.1 to 7.9 h (Table 1). Thus, fentanyl's short duration of action after a single dose results from redistribution rather than elimination. After large or multiple smaller doses, fentanyl accumulates as a result of its long half-time, and redistribution is less effective in removing fentanyl from its site of action in the brain. [9,30]Fentanyl is metabolized almost exclusively in the liver to norfentanyl, hydroxy-proprionyl-fentanyl, and hydroxyproprionyl-norfentanyl. [31]The pharmacologic activity of fentanyl metabolites is unknown but is believed to be minimal. [31]Less than 10% of fentanyl is excreted unchanged by the kidney. [27]The total body clearance of fentanyl is high, between 8 and 21 ml [middle dot] kg-1[middle dot] min-1, and approaches that of liver blood flow, reflecting the high hepatic extraction ratio. The high lipid solubility of fentanyl contributes to a large volume of distribution (3.2-5.6 l/kg).Several studies correlate fentanyl CPwith analgesia (the desired effect) and respiratory depression (the most dangerous side effect). However, the intensity of fentanyl's effect correlates with the drug concentration at the site of action (effect site) and not necessarily the plasma concentration. For opioids, the effect site or biophase is the opioid receptor in the brain and spinal cord. Additional time is needed for fentanyl to cross the blood-brain barrier to reach the effect site. The temporal lag between plasma concentration and the effect on the biophase is called hysteresis. A first-order rate constant (keo) characterizes the temporal aspects of equilibration between the effect-compartment concentration and the serum concentration. Thus, the half-time for equilibration t1/2keo(0.693/keo) quantifies the magnitude of the hysteresis (Table 1). Using electroencephalography to measure opioid effect, one group of investigators found a 3- to 5-min lag between increasing fentanyl CPand electroencephalography slowing during a 5-min fentanyl infusion. [32]After the infusion was discontinued, resolution of electroencephalography changes lagged behind decreasing fentanyl CPby 10 to 20 min (Figure 2).Different modes of administration have different degrees of hysteresis. With a rapid change in plasma concentration (e.g., after an intravenous bolus), the temporal lag will be greatest; with a slow change in concentration (e.g., with a steady continuous infusion), the lag will be smallest. Consequently, pharmacodynamic data obtained via different modes must be compared with caution.Plasma Fentanyl Concentration and Analgesia. Most studies correlating fentanyl CPwith its analgesic and side effects have estimated plasma fentanyl from gradually changing concentrations in selected groups of patients. Data from studies limited primarily to patients receiving intravenous fentanyl for postoperative analgesia indicate a mean analgesic C (P) ranging from 0.6-3 ng/ml. [14,15,17,18,33-38]Infusion of fentanyl to achieve a steady state CPis reported in one study [14]to produce “slight but significant analgesia” at a mean concentration of 0.6 ng/ml and “significantly greater analgesia” at a CPof 1.7 ng/ml, and, in another, [35]an analgesic range of 1-3 ng/ml. With PCA, the mean minimum effective analgesic concentration (MEC-fentanyl CPimmediately before the patient administers the next bolus dose [37]) has been reported as 1.35 ng/ml, [15]1.54 ng/ml, [36]and 0.63 ng/ml. [37]Thus, mean MEC values range from 0.6-1.54 ng/ml, whereas values for individual patients range from 0.2-8.0 ng/ml with a log-normal distribution. [15]Studies correlating fentanyl CPwith analgesic effect via visual analog pain scale ([VAS] 0 = no pain, 10 = maximum pain) scores report that the mean fentanyl CPof 0.3 to 0.7 ng/ml and 0.5 to 1.2 ng/ml during PCA correlate with VAS scores at rest of 3 or 4 [19]and 2 to 4, [16]respectively. Scores of 1 to 3 are associated with a CPof 1 or 2 ng/ml in different postoperative patient populations (thoracotomy, [17,18]cesarean section, [38]knee surgery [39]) treated by a bolus dose plus infusion of fentanyl. However, measurements of the CPassociated with effective analgesia often are obtained while patients are at rest; at a similar CP, VAS scores markedly increase with movement or coughing. [39]The observed variability in the analgesic CPreported for fentanyl in large part is caused by differences in study design and in individual pharmacodynamic responses. Analgesic requirements of individual patients and different surgical populations vary over a sixfold range for fentanyl and other opioids. [15,37,40]With respect to study design, the residual presence of anesthetic drugs and possible coadministration of central nervous system depressants affect the relation between doses or the C (P) of fentanyl and the intensity of analgesia and side effects. The degree of drug interaction also varies by study design. The types of surgical procedure also alter the degree of postoperative pain, and thereby the analgesic requirement: With a similar study design, we would expect a higher analgesic requirement in patients undergoing thoracotomy than hysterectomy. Different measurements of analgesic effect are used, including descriptive terms, [14]MEC, [37]CPassociated with 50% reduction in pain intensity, [33]and VAS score. [17-19,38]The timing of blood sampling also differs: Some investigators sample at predetermined intervals, correlating these results with analgesic effect, [38]whereas others measuring MEC sample just before the patient administers the next bolus. [15,36,37]Intravenously administered fentanyl produces effective analgesia in patients after operation at CPvalues ranging from 0.6-3.0 ng/ml. Pain control at rest is satisfactory within this range, but the analgesic effect diminishes with movement or coughing, [39]suggesting that a higher CPmay be required if analgesia is intended to promote either of these responses.Plasma Fentanyl Concentration and Respiratory Depression. Studies investigating the connection between fentanyl CPand ventilatory effect show a concentration-effect relation. [33,41], [double dagger] With intravenous bolus elimination, a CPof 3 or 4 ng/ml produces a 50% decrease in the slope of minute ventilation (VE) versus end-tidal carbon dioxide concentration. [20,21,42]However, these measured plasma concentrations may not reflect effect-site concentrations of fentanyl, as a result of the hysteresis between these values with bolus administration. Other studies using prolonged infusions or loading dose/maintenance infusions thus provide a better reflection of the steady state concentration-effect relations for fentanyl, [33]and these report clinically significant respiratory depression in both patients undergoing surgery [1,34,43]and volunteers [33]at a steady state CPof 2 ng/ml or more. For this review, we define clinically significant respiratory depression as a requirement for intervention with naloxone administration, resuscitation, or cessation of fentanyl treatment.Fentanyl-induced respiratory depression has been measured primarily by assessing the ventilatory response to carbon dioxide using the carbon dioxide rebreathing technique. Although an altered carbon dioxide response may indicate depression of central respiratory control, this approach may be impractical in patients after operation because it relies on patient cooperation and is significantly affected by alertness and arousal, conditions that are likely to vary among patients. [44]Continuous measurement of ventilation therefore is preferable, particularly to detect the occurrence of apnea, hypopnea, slow respiratory rate, or hypoxemia, the development of which will not be detected by discrete measurement. [44]Respiratory inductive plethysmography and pulse oximetry have been used to monitor the occurrence of episodes of apnea (tidal volume < 100 ml for > 15 s in adults) and slow respiratory rate (< 8 breaths/min for > 5 min). [45-47]Using these methods, Sandler et al. [18]reported a baseline occurrence of three apnea episodes per hour before operation in patients undergoing thoracotomy. In the postoperative period, a steady state CPof 1 or 2 ng/ml was associated with VAS pain scores of 2 at rest, a moderate increase in apneic episodes and slow respiratory rates, and the partial pressure of carbon dioxide arterial blood levels of 47-49 mmHg. This degree of respiratory depression did not require intervention.There is a direct concentration-effect relation between the CPfentanyl and respiratory depression. Plasma concentrations greater than 2 ng/ml are associated with clinically significant respiratory depression. However, the degree of respiratory depression is affected by various factors, including the types of surgical population, level of noxious stimulation, age, and individual pharmacodynamic responses. Thus, a threshold greater than 2 ng/ml should serve primarily as a guideline for clinicians.Therapeutic Window. The therapeutic window for fentanyl analgesia is the range between the minimally effective analgesic concentration and that associated with respiratory depression. [48]Studies in volunteers allow the complex relations among analgesic effect, side effects, and fentanyl C (P) to be evaluated under highly controlled conditions. In volunteers, [33]as in patients, the magnitude of analgesia and respiratory depression has a direct relation to the fentanyl CP. The lowest concentration producing slight, but measurable analgesia, without having significant ventilatory effect in volunteers [33]and patients [14]is 0.6 ng/ml. At plasma concentrations at which pain intensity decreases by 50%(CPassociated with 50% reduction in pain intensity = 1.4 ng/ml), fentanyl decreases the slope of the VEversus end-tidal carbon dioxide concentration curve in volunteers by 33% and VEby 12%. At a CPof 3 ng/ml, fentanyl produces profound analgesia and decreases this slope by 54% and VEby 23%. Thus, the therapeutic margin in volunteers correlates reasonably well with that just described for patients after operation.There is a direct concentration-effect relation between fentanyl C (P) and analgesia and respiratory depression. In volunteers and patients, the range of fentanyl CPproviding analgesia without clinically significant respiratory depression is 0.6-2 ng/ml. Factors including type of surgical procedure, surgical population (e.g., elderly patients), interaction with other central depressive drugs, and individual pharmacodynamic and pharmacokinetic differences can markedly influence this window and should be considered when the suggested therapeutic range is applied.Modes of Administration. Fentanyl can be administered intravenously for postoperative analgesia using a loading (bolus) dose with a continuous fixed or variable infusion, a fixed background infusion with PCA, or PCA alone.Continuous Background Intravenous Fentanyl Infusion. Continuous intravenous infusions of fentanyl have been used to provide postoperative analgesia after abdominal, [14,35,49]peripheral orthopedic, [35,39,50]and major spinal surgery [51]; thoracotomy [17,18,50,52]; and cesarean section delivery [38](Table 2).Dose Requirements. An intravenous bolus of fentanyl (1 or 2 [micro sign]g/kg) usually is administered before the start of infusion. If variable, the infusion rate is 1 or 2 [micro sign]g [middle dot] kg-1[middle dot] h-1(Table 2) and may be adjusted upward or downward as required by fluctuations in analgesic requirements or increasing side effects. Before the infusion rate is increased, small bolus doses of fentanyl are administered to increase the CPrapidly. [17,18,38,39]If the infusion rate is fixed, a supplementary analgesic technique, either bolus or PCA doses of nonsteroidal antiinflammatory drugs, fentanyl, or morphine (Table 2), is used to meet the therapeutic demand. [35,50,51]Analgesic Efficacy. Infusion of fentanyl, especially at rates of 1.5-2.5 [micro sign]g [middle dot] kg-1[middle dot] h-1, can provide good-to-excellent postoperative analgesia (Table 2). At rest, the quality of analgesia remains stable; with movement (ambulation, coughing), it decreases significantly, even with higher infusion rates. [39,52]The fentanyl CPrelates directly to the infusion rate, [50]with good analgesia at rest associated with concentrations ranging from 0.5-2.3 ng/ml.Side Effects. Nonrespiratory side effects can occur. The incidence of nausea and vomiting after fentanyl infusion varies from 20-60%. Pruritus occurs in 0-30% of patients, and urinary retention occurs in 40-45%. The latter values may over- or underestimate the actual incidence of urinary retention, because many studies use postoperative indwelling urinary catheters that preclude measurement of urinary retention.Respiratory depression is common after fentanyl infusion, but most events are not significant. Only three studies [17,50,51]have reported clinically significant respiratory depression. Comparing these three with other studies (Table 2) reveals similar infusion doses, types of surgery, and other factors (e.g., systemic morphine supplementation), making it unclear why the incidence of respiratory depression differed significantly. The methods of detection and measurement of respiratory depression include intermittent or continuous measurement of respiratory rate, pulse oximetry, respiratory inductive plethysmography, and intermittent arterial blood sampling.Continuous intravenous fentanyl infusion provides good-to-excellent analgesia (particularly at rest) at doses of 1 or 2 [micro sign]g [middle dot] kg-1[middle dot] h-1. Naturally occurring variations in postoperative analgesic requirements can be managed by adjusting the fentanyl infusion rate upward or downward, as needed, assuming a variable infusion technique, or by parenteral administration of bolus doses of opioid or nonsteroidal antiinflammatory drugs to supplement a fixed infusion.Continuous Background Intravenous Infusion with Patient-Controlled Analgesia. A background low-dose intravenous infusion of fentanyl may be combined with PCA to provide satisfactory analgesia with potentially fewer adverse effects. [15,36,53-58]Dose Requirements. Patient-controlled analgesia bolus doses typically range from 7-50 [micro sign]g. Background infusion rates may be fixed, ranging from 4-60 [micro sign]g/h, or be variable, adjusted up and down according to clinical criteria [54,55](Table 3). Generally, the larger the background infusion rate, the smaller the PCA bolus dose. Lockout intervals (minimum time period between doses) range from “on demand”(i.e., no lockout) to 15 min, the most common interval being 1-5 min (Table 3).No study directly compares the use of intravenous fentanyl infusion with and without fentanyl PCA. However, examination of the data in Table 2and Table 3reveals a smaller dose requirement for continuous infusion plus PCA than for infusion alone, despite variability in infusion rate, PCA dose, and lockout interval. The type of surgery also influences the dose requirement; that is, thoracotomy generates higher requirements than does orthopedic or lower abdominal surgery. [59]Analgesic Efficacy. The technique of background infusion plus PCA produces excellent postoperative pain relief for abdominal, [15,37,54,56,57]orthopedic [15]and peripheral vascular surgery [54]and for thoracotomy. [55,58]Consistent with the primary fentanyl infusion studies, pain has been measured in patients at rest [15,58]and increased markedly with movement. [55]Studies of the concentration-effect relation with this technique have shown a MEC value for fentanyl for abdominal and orthopedic surgery that varies from 0.63-1.54 ng/ml. [15,36,37]Side Effects. Nonrespiratory side effects can occur, but data regarding the incidence of adverse effects with this technique are limited. Nausea and vomiting are estimated to occur in approximately 30-40% of patients. Only two studies have investigated the incidence of pruritus, reporting a range of 7-13%, [55,58]and none have studied the occurrence of urinary retention.Of nine studies, only five report the incidence of respiratory depression, and none show evidence of clinically significant respiratory depression requiring treatment.Compared with continuous infusion alone, the use of a background fentanyl infusion with PCA fentanyl provides excellent postoperative analgesia, with a lower total dose consumption. The incidence of side effects with the two techniques is difficult to compare because of the limited data published for background infusion.Patient-Controlled Analgesia. Fentanyl is rarely used alone for PCA, most likely because of the widespread belief in its brief duration of action. The opioids most commonly administered are morphine and meperidine. Consequently, only a few studies have compared the efficacy and safety of PCA fentanyl with those of other opioids, [60-62]but other investigators have used PCA fentanyl only as a control in clinical trials comparing it with other analgesic techniques [16,19,63-67](Table 4).Dose Requirements. Consistent with other opioids used for PCA, [60,62]fentanyl dose requirements vary widely. [36,68]Bolus doses range from 20-50 [micro sign]g with lockout intervals from “on demand” to 10 min. Theoretically, the lockout interval should relate to the time from drug administered to peak effect so that patients can experience the full effect of a dose before receiving a subsequent dose. [61]Because of fentanyl's short latency to peak effect, [68]a lockout interval of 5 or 6 min is reasonable.Maximum hourly PCA dosage varies from 120-600 [micro sign]g/h, and mean hourly requirements vary from 48-83 [micro sign]g/h (Table 4), less than those for the continuous infusion technique (Table 2). Despite fentanyl's brief duration of action, patients typically require only one to three doses/h and rarely administer more than two bolus doses/h. [63,69,70]At bolus doses of 20-50 [micro sign]g, fentanyl therefore might be suitable for PCA use.Analgesic Efficacy. Good analgesia can be achieved with PCA fentanyl alone, with efficacy comparable to that of morphine and meperidine. [61,62]Only two studies, [60,67]both using small bolus doses (20-25 [micro sign]g) and a long lockout interval (10 min), report inadequate analgesia.No study has directly compared the influence of a background infusion on the efficacy of intravenous fentanyl delivered by PCA. Comparing individual studies in Table 3and Table 4suggests that PCA fentanyl alone produces similarly effective analgesia with similar dose requirements as PCA with a background infusion. Most studies of other opioids fail to show any benefit to adding a background infusion to PCA. [71-74]Furthermore, the use of such an infusion increases opioid requirements [71-73,75]and is associated with an increased risk for severe respiratory depression. [76-78]Therefore, it may be prudent to avoid using background infusions with PCA fentanyl.Depending on the dose and lockout interval set for the PCA device, relatively effective analgesic fentanyl CPcan be achieved and maintained with PCA fentanyl alone. In an unblinded trial of 11 patients undergoing upper abdominal surgery, [16]a bolus dose of 20 [micro sign]g with a lockout interval of 6 min resulted in a mean fentanyl CPof 1.4 +/− 0.7 ng/ml (mean +/− SD) 12 h after operation, which decreased to 0.5 +/− 0.2 ng/ml at 48 h. Mean VAS pain scores at rest at 12 and 48 h were acceptable at 4 and 3, respectively. Comparing PCA fentanyl administered through the epidural route with PCA intravenous fentanyl in patients undergoing lower limb orthopedic or abdominal surgery, Glass et al. [19]conducted a randomized, double-blind, crossover trial using the same 20-[micro sign]g bolus dose and 6-min lockout interval. Fentanyl CPfor the first 6 h in the intravenous PCA group ranged from 0.2-0.4 ng/ml, resulting in mean VAS scores for this period of 2 to 4 at rest (i.e., moderate-to-good analgesia).Side Effects. Only a few studies have reported the incidence of nonrespiratory side effects with PCA fentanyl alone. Nausea and vomiting occur in 20-60% of patients and pruritus occurs in 0-40%.There are no reports of clinically significant respiratory depression with PCA fentanyl alone. However, all these studies thus far monitored respiratory depression solely by respiratory rate, which correlates poorly with ventilatory insufficiency. [44]Patient-controlled analgesia fentanyl provides analgesia comparable to that of other intravenous modes of administration. Despite fentanyl's short duration of action, most patients require only one to three bolus doses/h. The addition of a background infusion offers no benefit to the quality of analgesia and potentially increases the risk of respiratory depression. Compared with continuous infusion, average dose consumption is less with PCA alone.Transdermal delivery of fentanyl has been investigated extensively. This modality is simple, noninvasive, and allows continuous release of fentanyl into the systemic circulation. The major barrier to the entry of transdermally administered drug into the systemic circulation is the stratum corneum of the epidermis. [79]This layer of skin has a “brick-and-mortar” arrangement of kiratin-rich cells embedded in a lipid matrix arranged in broad sheets forming multiple layers. However, fentanyl's lipid-soluble properties allow it to diffuse through the stratum corneum via the intercellular lipid medium. [80]Permeability of the stratum corneum may be affected by various factors, including body site, skin temperature, skin damage, ethnic group, or age. To ensure a predictable rate of drug transfer, the transdermal delivery system minimizes the influence of skin in transfer by incorporating a rate-controlling membrane more impermeable than skin.The Therapeutic Transdermal System (TTS; ALZA Corp., Palo Alto, CA) uses the membrane permeation model. [81]This transdermal fentanyl patch is available in four sizes and provides sustained release of fentanyl at rates of approximately 25, 50, 75, and 100 [micro sign]g/h for periods of 48-72 h. The patch is attached to the skin by a contact adhesive, adjacent to which is a microporous membrane that controls the rate at which fentanyl is transferred from the drug reservoir to the skin (Figure 3). The reservoir is a shallow compartment with a gel matrix containing as much as 10 mg fentanyl, intended to provide a sufficiently high concentration gradient for diffusion across the skin. To prevent escape of the fentanyl matrix into the environment, the reservoir has a backing.An important feature of the TTS design is that it takes advantage of the substantial capacity of the skin layers to act as a secondary reservoir. The presence of skin depot has several implications: It dampens the fluctuations of fentanyl effect, needs to be reasonably filled before significant vascular absorption occurs, and contributes to a prolonged residual fentanyl CPafter patch removal. [45]The amount of fentanyl remaining within the system and skin depot after removal of the patch is substantial: At the end of a 24-h period with a TTS fentanyl patch releasing drug at the rate of 100 [micro sign]g/h, 1.07 +/− 0.43 mg fentanyl (approximately 30% of the total delivered dose from the patch) remains in the skin depot. [24]Pharmacokinetics. Pharmacokinetic studies have examined absorption, plateau systemic concentrations, time to peak concentration, and appa