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The Safety and Efficacy of Fentanyl Iontophoretic Transdermal System Compared with Morphine Intravenous Patient-Controlled Analgesia for Postoperative Pain Management: An Analysis of Pooled Data from Three Randomized, Active-Controlled Clinical Studies

Section Editor(s): Liu, Spencer S.Viscusi, Eugene R. MD*; Siccardi, Matthew MS; Damaraju, C V. PhD; Hewitt, David J. MD; Kershaw, Paul MD

doi: 10.1213/01.ane.0000281913.28623.fd
Analgesia: Research Report
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BACKGROUND: Postoperative pain is often managed using IV patient-controlled analgesia (PCA). In this analysis of pooled data, we compared the safety and efficacy of the fentanyl iontophoretic transdermal system (ITS) with morphine IV PCA.

METHODS: Data were obtained from three multicenter, randomized, active-controlled trials (N = 1941). The primary efficacy measure was success (“good”/“excellent” ratings) on the 24-h patient global assessment of the method of pain control. Pain intensity, relative dosing ratios, discontinuation rates, and adverse events were assessed. Efficacy was evaluated across age, surgery type, and body mass index (BMI).

RESULTS: Comparable percentages of patients reported success on the 24-h patient global assessment of the method of pain control (fentanyl ITS, 80.5%; morphine IV PCA, 81.0%; difference = −0.5%; 95% confidence interval, −4.0% to 3.0%). Mean last pain intensity scores in the first 24 h were comparable (fentanyl ITS, 3.1; morphine IV PCA, 3.0; difference = 0.07; 95% confidence interval, −0.14 to 0.29). Relative dosing ratios of fentanyl to morphine overall and in subpopulations (age, BMI) were comparable over 6, 12, and 24 h. Fentanyl ITS was equally effective when compared with morphine IV PCA for patient subpopulations (age, surgery type, and BMI). Discontinuation rates and the incidence of adverse events were similar between groups.

CONCLUSIONS: These pooled data represent one of the largest head-to-head comparisons of fentanyl versus morphine in a postoperative acute pain setting. Results suggest that fentanyl ITS is effective across subpopulations defined by age and BMI, and support a consistent safety and efficacy profile of fentanyl delivered by fentanyl ITS for postoperative pain management.

IMPLICATIONS: This analysis of pooled data from three multicenter, randomized, active-controlled trials (n = 1941) of similar design is one of the largest studies comparing the safety and efficacy of fentanyl and morphine in an acute postoperative pain management setting. Findings from the analysis demonstrate that fentanyl delivered using the fentanyl HCl iontophoretic transdermal system and morphine administered via IV patient-controlled analgesia provide comparably safe and effective postoperative pain control for patients, regardless of age or body mass index.

From the *Department of Anesthesiology, Thomas Jefferson University, Philadelphia, Pennsylvania; †Ortho-McNeil Janssen Scientific Affairs, LLC; and ‡Johnson & Johnson Pharmaceutical Services, Raritan, New Jersey.

Accepted for publication July 9, 2007.

Supported by Ortho-McNeil, Inc., Raritan, New Jersey.

Address correspondence and reprint requests to Eugene R. Viscusi, MD, Department of Anesthesiology, Thomas Jefferson University, 111 South 11th St., Suite G-8490, Philadelphia, PA 19107. Address e-mail to eugene.viscusi@jefferson.edu.

IV patient-controlled analgesia (PCA) is commonly used to manage moderate-to-severe postoperative pain. Although morphine is often the mainstay analgesic for IV PCA, other opioids, including fentanyl, are also administered for postoperative pain management. Morphine and its active metabolites, morphine-3-glucuronide and morphine-6-glucuronide, may accumulate in patients with renal impairment and have toxic effects (1). Morphine also induces histamine release (2), which may contribute to pruritus; and administration of IV bolus doses of morphine has been associated with an increased risk of hypotension (3). Fentanyl has no active metabolites (1), does not induce histamine release (4,5), and is safe for pain management in patients with renal impairment (6).

The fentanyl HCl iontophoretic transdermal system (fentanyl ITS; IONSYS™; Ortho-McNeil, Inc., Raritan, NJ) is a preprogrammed, needle-free, self-contained analgesic delivery system approved for acute postoperative pain management in hospitalized adults requiring opioid analgesia and has a similar pharmacokinetic profile to IV fentanyl. One pharmacokinetic study (7) demonstrated that the tmax (0.65 vs 0.58 h), t1/2 (11.0 vs 12.6 h), and Cmax (1.37 vs 1.82 μg/L) were similar for 80 μg fentanyl delivered by fentanyl ITS (two 40-μg doses per hour) compared with 80 μg IV fentanyl delivered per hour, respectively. Mean serum fentanyl concentrations were also comparable from 20 to 48 h for both delivery methods (7). Those pharmacokinetic findings suggest that fentanyl administered using the fentanyl ITS is comparable to IV fentanyl and that the safety and efficacy of fentanyl and morphine for postoperative pain management may be compared using fentanyl ITS and morphine IV PCA.

This analysis of pooled data comprises one of the largest studies comparing the safety, efficacy, and potency of fentanyl and morphine for postoperative pain management in a diverse patient population. The safety and efficacy of fentanyl ITS and morphine IV PCA for postoperative pain management in the overall population and in subpopulations defined by age, body mass index (BMI), and/or surgery type were evaluated.

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METHODS

Data were pooled from three multicenter, open-label, randomized, active-controlled, parallel-group clinical studies conducted in Canada and the United States. Patients were enrolled following orthopedic, thoracic, pelvic, abdominal, and breast surgeries (8); total hip replacement (9); and abdominal and pelvic surgeries (10) (Table 1).

Table 1

Table 1

Patients were titrated to comfort after surgery with bolus doses of IV opioids (morphine, hydromorphone, fentanyl, sufentanil, or alfentanil). Eligible patients were ≥18 yr; ASA physical status I, II, or III; awake, alert, and breathing spontaneously for ≥30 min in the postanesthesia recovery unit with an oxygen saturation (Spo2) of ≥90%; and comfortable [defined as a pain score of ≤4 on a numerical rating scale from 0 = “no pain” to 10 = “worst possible pain” (9,10); in one study (8), no specific entry criterion for pain intensity was defined]. Patients were expected to require parenteral opioids and hospitalization for ≥24 h.

Patients were ineligible for study enrollment if they were opioid-tolerant or opioid-dependent, expected to require intensive care or postoperative analgesia supplied by a continuous regional technique, or had active skin disease. Patients were also ineligible if they received long-acting intraoperative spinal or epidural anesthesia, local anesthetics in the surgical area, or opioids other than morphine, hydromorphone, fentanyl, sufentanil, or alfentanil. Patients who satisfied inclusion and exclusion criteria were randomized (1:1) in each study using a permuted block design to receive fentanyl ITS or morphine IV PCA for postoperative pain management. This method of randomization ensured a good balance of patients between the two groups.

Bolus doses of IV fentanyl or morphine were provided upon patient request within the first 3 h of treatment to patients who received fentanyl ITS or morphine IV PCA, respectively, and disallowed thereafter. If the analgesic that was specified according to the patient's treatment group was unavailable at the time of the request, patients in either treatment group could receive IV fentanyl or IV morphine.

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Dosing Regimens

The fentanyl ITS delivered a 40-μg dose of fentanyl upon patient activation over a period of 10 min. The system delivered up to 6 doses per hour for up to 24 h or a maximum of 80 doses per system, whichever occurred first. The total number of doses delivered was estimated by the number of light flashes that occurred after administration of a dose or upon system query. Each flash indicated the delivery of a maximum of five doses.

PCA pumps were programmed to deliver 1 mg morphine upon patient activation, with a lockout interval of 5 min between doses (maximum of 10 doses per hour for 24 h, up to 240 doses or 240 mg/24 h). In two of the studies, approximately half of the sites were granted exceptions to use a 6-min lockout interval, because of pump-specific issues or hospital policy. The total number of doses delivered by a PCA pump was determined by system query.

Concomitant medications (i.e., steroids, nonsteroidal antiinflammatory drugs, and long-acting analgesics) were prohibited, with the exception of oral rofecoxib (25 mg, 2–4 h before surgery and each postoperative day during the study), which was administered to approximately 50% (n = 381) of patients who underwent total hip replacement (9).

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Outcome Measures—Efficacy

In this analysis of pooled data and in each of the three studies, the primary efficacy measure was the patient global assessment (PGA) of the method of pain control in the first 24 h (categorical scale [“excellent,” “good,” “fair,” “poor”]). A member of the clinical staff read aloud the following question to the patient: “Overall, would you rate this method of pain control during the last 24 h as excellent, good, fair, or poor?” The percentages of patients who rated the treatment modality as a success (“good” or “excellent”) on the PGA in the first 24 h were compared between treatment groups. Between-group differences in PGA success ratings were also compared at 48 and 72 h.

Pain intensity was included as a secondary efficacy measure in the current analysis of pooled data. Pain intensity scores measured at the time of fentanyl ITS placement or patient attachment to the morphine IV PCA pump (Hour 0) and at Hours 0.5, 1, 2, 3, 4, 6, 8, and every 4 h up to the 72-h time point were included in this analysis. In two of the studies (9,10), a member of the investigator's staff read aloud the following question to the patient: “On a scale from 0 to 10, where 0 means no pain and 10 means the worst possible pain, rate the pain that you have now.” In the other study (8), patients were instructed to make a mark on a 100-mm ungraded visual analog scale to indicate their level of pain as follows: “Rate the pain you have at this time. On a scale of “no pain” to “worst possible pain,” rate where you feel your pain is at this moment.” Pain intensity scores from the latter study were divided by 10 before the pooling of data to maintain consistency with the pain intensity scale used in the other two studies.

The relative dosing ratio of the amount of fentanyl administered during a given time period to the amount of morphine administered during that time period was determined at Hours 6, 12, and 24. The cumulative number of doses administered by all patients in the fentanyl ITS group was estimated at the appropriate time point and multiplied by 40 μg; for patients in the morphine IV PCA group, the cumulative number of doses at each time point was determined and multiplied by 1 mg. The relative dosing ratio was calculated by dividing the resulting value for patients who received fentanyl ITS by the value for patients who received morphine IV PCA. The percentages of patients who withdrew early from the study for any reason, including inadequate analgesia or adverse events, were also compared between groups.

Analyses were conducted in subpopulations defined by BMI (<25, 25 to <30, and ≥30 kg/m2), age (≤65, 66–75, and >75 yr), and surgery type (abdominal, orthopedic, pelvic, total hip replacement). The percentages of patients who reported a rating of success on the PGA of the method of pain control in the first 24 h, mean last pain intensity scores in the first 24 h, and relative dosing ratios were compared between treatment groups within these subpopulations.

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Safety

The safety of fentanyl ITS versus morphine IV PCA was evaluated by comparing the incidence of adverse events, including the number of cases of clinically relevant respiratory depression (defined in the three clinical trial protocols as the simultaneous occurrence of bradypnea [<8 breaths/min] and excessive sedation [patient not easily aroused]). The incidence of adverse events was also evaluated in subpopulations defined by age (≤65, >65, and >75 yr) in both treatment groups.

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Statistical Analyses

Statistical analyses of the pooled data were performed using the intent-to-treat population, which included all randomized patients who were treated with study medication. Pooled subpopulation analyses used the same criteria for equivalence that were prespecified in the three individual studies. Between-group differences in the percentages of patients who reported success ratings on the PGA in the first 24 h were analyzed, and a two-sided 95% confidence interval (CI) for the difference was constructed. The two treatment methods were considered statistically equivalent if the two-sided 95% CI was within ±10%. Missing ratings on the PGA at 24, 48 (included PGA reported between >24 and ≤48 h), or 72 h (included PGA reported between >48 and ≤72 h) were assigned a conservative rating of “poor.” Differences in the percentages of PGA success ratings at 48 and 72 h for the overall population and in the first 24 h for the subpopulations of age, BMI, and surgery type were analyzed by construction of a two-sided 95% CI.

Between-group differences in the mean last pain intensity scores in the first 24 h were analyzed using ANOVA for the overall population and for the subpopulations (age, BMI, and surgery type). A two-sided 95% CI for the between-group difference in mean pain intensity scores was calculated. Analgesic efficacy based on pain intensity was considered statistically equivalent if the two-sided 95% CI was within ±1 on the 0–10 pain rating scale. Mean pain intensity scores for both treatment groups were graphed versus time, and the area under the curve (AUC) values for 0 through 6, 0 through 12, and 0 through 24 h were calculated using the numerical integration (i.e., trapezoidal) method. Between-group differences in AUC values were determined using ANOVA with treatment as a factor. Between-group differences in the rates of patient discontinuation from the studies and the incidence of adverse events were analyzed using the Fisher exact test.

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RESULTS

A total of 1943 patients were enrolled and randomized in the three studies; two randomized patients discontinued before receiving study medication. The remaining patients (n = 1941) received either fentanyl ITS (n = 963) or morphine IV PCA (n = 978) for acute postoperative pain management (Fig. 1). Patient characteristics were similar between the treatment groups (Table 2). Patients were predominantly female and Caucasian, and most patients received fentanyl ITS or morphine IV PCA after total hip replacement or pelvic surgery. Approximately 50% (n = 381) of patients in the trial involving total hip replacement received rofecoxib before its recall.

Figure 1

Figure 1

Table 2

Table 2

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Efficacy

Statistically equivalent percentages of patients who received fentanyl ITS or morphine IV PCA reported ratings of success (“good” or “excellent”) on the PGA of the method of pain control in the first 24 h (80.5% vs 81.0%, respectively; difference = −0.5%; 95% CI, −4.0% to 3.0%; Fig. 2); the 95% CI also met the prespecified criterion set for equivalence in the three separate studies (8–10). A higher percentage of patients who received fentanyl ITS versus morphine IV PCA reported a PGA rating of “excellent” (46.6% vs 36.3%, respectively; P < 0.001). Follow-up beyond the first 24-h period for those patients continuing in the study supported continued high success rates on the PGA of the method of pain control for patients who received fentanyl ITS. High percentages of patients continuing at 48 h (91.1% vs 85.8%; difference = 5.3%, 95% CI, 1.5%–9.1%) and at 72 h (93.5% vs 84.5%; difference = 9.0%, 95% CI, 2.6%–15.4%) reported PGA ratings of success for fentanyl ITS and morphine IV PCA, respectively.

Figure 2

Figure 2

The mean last pain intensity scores reported in the first 24 h were equivalent for patients who received fentanyl ITS versus morphine IV PCA (3.1 vs 3.0, respectively; difference = 0.07; 95% CI, −0.14 to 0.29). The mean pain intensity scores were also comparable between the patients who remained in the treatment groups at each time point during the first 24 h of treatment and after 48 and 72 h of treatment (Fig. 3). Comparable pain control, based on pain intensity, was demonstrated by the AUC of pain intensity scores from 0 through 6, 0 through 12, and 0 through 24 h for patients who received fentanyl ITS and morphine IV PCA (Table 3). The mean number of doses activated during the first 24 h was lower for patients who received fentanyl ITS compared with patients who received morphine IV PCA (31.9 vs 39.8 doses, respectively). The relative dosing ratios of fentanyl to morphine were consistent for the overall population over time (Hour 6 [28.6:1]; Hour 12 [31.4:1]; Hour 24 [31.9:1]).

Figure 3

Figure 3

Table 3

Table 3

No significant differences were observed in the overall discontinuation rates (fentanyl ITS, 19.3%; morphine IV PCA, 17.1%; P = 0.217). A significantly lower percentage of patients who received fentanyl ITS compared with morphine IV PCA withdrew because of an adverse event (4.5% vs 6.5%, respectively; P = 0.047), whereas a significantly higher percentage of patients who received fentanyl ITS withdrew because of inadequate analgesia (11.9% vs 6.3%, respectively; P < 0.001).

For the subpopulations defined by age and BMI, similar percentages of patients in each treatment group reported ratings of success on the PGA of the method of pain control in the first 24 h (Table 4). PGA success ratings were also comparable across most surgery types. Patients in each age and BMI group who received fentanyl ITS reported comparable mean last pain intensity scores in the first 24 h (Table 5). Similar mean last pain intensity scores in the first 24 h were also observed after most surgery types (Table 5). The relative dosing ratios were similar among patient subpopulations of age and BMI (Table 6).

Table 4

Table 4

Table 5

Table 5

Table 6

Table 6

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Safety

The incidence of overall adverse events was generally comparable between treatment groups (Table 7). Commonly reported adverse events were those that are generally associated with opioid use. A significantly lower percentage of patients who received fentanyl ITS experienced pruritus compared with those who received morphine IV PCA (6.3% vs 11.1%, respectively; P < 0.05), whereas a significantly higher percentage of patients who received fentanyl ITS experienced headache (11.1% vs 7.3%, respectively; P < 0.05; Table 7). The percentages of patients who experienced treatment-related hypoxia (3.6% vs 3.7%) and hypotension (2.7% vs 4.3%) were similar for patients in the fentanyl ITS and morphine IV PCA groups, respectively (P ≥ 0.06). A total of 6.3% of patients who received fentanyl ITS experienced application-site reaction—erythema, and 2.5% experienced application-site reaction—itching. No patient in the fentanyl ITS group experienced clinically relevant respiratory depression; four cases were reported in the morphine IV PCA group.

Table 7

Table 7

The incidence of overall adverse events in each treatment group was similar in the subgroups divided by age and was similar to those observed in the overall population. Nausea, fever, anemia, and headache were the most commonly reported adverse events in subgroups divided by age (Table 8). A lower incidence of nausea and fever was observed in patients >65 yr than patients ≤65 yr in the fentanyl ITS group, whereas a lower incidence of headache was observed in patients >65 yr in both treatment groups. The highest incidence of somnolence and confusion was observed in patients who received morphine IV PCA and were >75 yr. The incidence of hypotension was highest in patients >65 yr who received morphine IV PCA. Pruritus was most common in patients ≤65 yr who received morphine IV PCA (Table 8).

Table 8

Table 8

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DISCUSSION

This analysis of pooled data from three clinical studies (8–10) of similar design demonstrated that fentanyl ITS is as safe and effective as a standard regimen of morphine IV PCA, and that fentanyl and morphine delivered via these methods were comparably safe and effective. The similarity in pain control allowed for the development of relative dosing ratios between morphine and fentanyl. These ratios are important in helping clinicians who are more comfortable with morphine IV PCA to use fentanyl ITS safely and effectively. A similar incidence of adverse events was observed overall for patients who received fentanyl ITS and morphine IV PCA. However, important differences in both somnolence and hypotension were observed between the treatment groups among patients >65 yr, and a significant (P < 0.05) between-group difference in confusion was observed among patients >75 yr. Most adverse events were those commonly associated with opioid analgesia in postoperative settings. Importantly, no unique safety concerns were uncovered in elderly patients.

Evidence from this analysis of pooled data supports the conclusion that fentanyl ITS and morphine IV PCA are comparable methods of pain control for patients who are not opioid-tolerant or opioid-dependent based on the primary efficacy measure, the PGA of the method of pain control in the first 24 h. Comparable efficacy is further supported by the results observed with secondary efficacy measures. Similar percentages of patients in each treatment group reported ratings of success on the PGA at 24 h, and even higher percentages of patients in both treatment groups reported PGA success ratings at 48 and 72 h. In addition, similar pain intensity scores were reported throughout the study. This shows that, during the study follow-up period, fentanyl ITS successfully maintained a level of pain control that was comparable to a standard regimen of morphine IV PCA, despite the higher percentage of patients who received fentanyl ITS and withdrew from the study because of inadequate analgesia.

The mean number of doses activated in the first 24 h by patients who received fentanyl ITS was lower compared with patients who received morphine IV PCA during that same time period and did not approach the maximum of 80 doses that may be delivered by each 24-h fentanyl ITS. The need to determine the relative potency of fentanyl delivered via the transdermal route compared with IV morphine has been previously noted (11). Relative dosing ratios in this study varied around 30:1 over 6, 12, and 24 h, suggesting that approximately 30 μg fentanyl provided an equianalgesic dose compared with 1 mg morphine. Overall, the relative dosing ratio remained at approximately 30:1, regardless of age or BMI. To our knowledge, this is the first study to determine the relative potency of iontophoretic transdermal fentanyl compared with IV morphine.

An important concern with postoperative pain management is the association of opioids with respiratory depression (12). No incidents of clinically relevant respiratory depression were observed in patients who received fentanyl ITS in the clinical studies included in this analysis, whereas four incidents were noted for patients who received morphine IV PCA. Similarly, no incidents of clinically relevant respiratory depression were observed in previous placebo-controlled studies that evaluated the efficacy and safety of fentanyl ITS (13,14).

This analysis of pooled data may be limited by some methodological differences among the studies. For instance, two (9,10) of the three studies included in the analysis used a prespecified maximum allowable pain intensity score for study entry. Although overall rates of discontinuation and discontinuations due to inadequate analgesia were lower and the percentages of patients who reported ratings of success on the 24-h PGA of the method of pain control were higher in the two studies that used a prespecified pain intensity criterion, it is not expected that these differences affected the comparison of fentanyl ITS with morphine IV PCA, as the study enrollment criterion was consistent for patients in both treatment groups in each study. The analysis may also be limited by the use of a 6-min lockout interval for PCA pumps at approximately half of the sites in two of the studies versus the 5-min lockout interval used at the remaining sites (9,10). Since patients could receive the same hourly dose of morphine regardless of the pump lockout interval, it is not expected that this between-site difference affected the results of this analysis of pooled data. In addition, one of the studies (8) used a 100-point visual analog scale to assess pain intensity scores, whereas the other two studies (9,10) used an 11-point numerical rating scale. However, Breivik et al. (15) demonstrated that the two rating scales are nearly equally sensitive for measuring pain intensity, suggesting this methodological difference did not affect the results of this analysis of pooled data.

Approximately 50% of patients in one study (9) received rofecoxib. However, Hartrick et al. (9) found that PGA success ratings and mean last pain intensity scores in the first 24 h were comparable between the treatment groups with and without rofecoxib, suggesting the use of multimodal therapy did not affect the efficacy of the modalities. These results contrast previous reports of the postoperative pain-relieving benefits of rofecoxib administered in conjunction with morphine IV PCA (16,17). Additional trials are necessary to thoroughly evaluate the efficacy and safety of fentanyl ITS as part of a multimodal regimen.

Several studies (18–20) have demonstrated that acute postoperative pain is often inadequately managed, suggesting the development of novel analgesic modalities is warranted. In the current analysis of pooled data, approximately 80% of patients in each treatment group reported that fentanyl ITS or morphine IV PCA was “good” or “excellent” on the 24-h PGA of the method of pain control. Although approximately 20% of patients in each treatment group did not rate their method of pain control as a success, this success rate will likely improve as patients gain experience with the modality and when the system is used in a more natural setting in conjunction with multimodal therapy.

Fentanyl ITS may offer benefits over currently used methods of pain control, including the potential for improved patient mobility with the system, because, unlike IV PCA, the compact self-contained fentanyl ITS does not require IV tubing or an IV pole that may interfere with patient mobility. In addition, the elimination of multiple system components and the minimal time that is expected to be required for system setup may translate into cost savings. A pharmacoeconomic analysis to evaluate these potential cost savings would be warranted once the price of the system has been determined. The fentanyl ITS is also preprogrammed, which eliminates the potential for programming errors. Although the preprogrammed nature of the system precludes dosing adjustments that may be necessary due to the individual patient's opioid needs, the current analysis demonstrated that the system provided effective pain control for patients, regardless of age or BMI.

Results of this analysis of pooled data demonstrate that fentanyl ITS is safe and effective for the management of postoperative pain after a broad range of major surgical procedures and across multiple patient subpopulations receiving pain management predominantly on a standard postoperative ward. Findings also indicate that fentanyl administered using fentanyl ITS has comparable safety and efficacy to morphine delivered via IV PCA for pain management after major surgery. This may further suggest that fentanyl ITS would be effective after surgical procedures when a standard morphine IV PCA dosing regimen (1 mg morphine per 5 min) would be prescribed for postoperative pain management.

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ACKNOWLEDGMENTS

The authors thank Ashley Smithwick, PhD, for editorial assistance with this manuscript. Programming assistance was provided by Lang Lu, MS.

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