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The Safety and Efficacy of a Fentanyl Patient-Controlled Transdermal System for Acute Postoperative Analgesia: A Multicenter, Placebo-Controlled Trial

Jacques E. Chelly, MD PhD, MBA^*, Jeffrey Grass, MD, Timothy W. Houseman, MD, Harold Minkowitz, MD, and Alex Pue, MD^||

*University of Pittsburgh Medical Center and The Western Pennsylvania Hospital, Pittsburgh, Pennsylvania, Thomas Hospital, Fairhope, Alabama, Memorial City Hospital, Houston, Texas, and the ||Mary Birch Hospital for Women, San Diego, California

Address correspondence and reprint requests to Jacques E. Chelly, MD, PhD, MBA, Professor of Anesthesiology and Orthopedic Surgery, and Vice Chairman of Clinical Research, Director of Orthopedic Anesthesia and Acute Pain Services Department of Anesthesiology, Pittsburgh School of Medicine, A-1305 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261. Address email to chelje{at}anes.upmc.edu

	Abstract

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A noninvasive method of delivery of parenteral opioids for management of acute pain may offer logistic advantages for patients and nursing staff. A patient-controlled transdermal system (PCTS) under development consists of a preprogrammed, self-contained drug-delivery system that uses electrotransport technology (E-TRANS®, ALZA Corp, Mountain View, CA) to deliver 40 µg of fentanyl HCl over 10 min per on-demand dose for patient-controlled analgesia (PCA). In this randomized, double-blinded, placebo-controlled trial we compared the efficacy and safety of on-demand fentanyl HCl PCTS 40 µg against placebo for postoperative pain up to 24 h after major abdominal, orthopedic, or thoracic surgery in 205 patients. The primary efficacy measurement was the percentage of patients withdrawn from the study because of inadequate analgesia after completing at least 3 h of treatment. Secondary efficacy measures included mean pain intensity (using visual analog scales), patient global assessments, and investigator global assessments. Of 189 patients considered evaluable for efficacy, 25% of patients in the fentanyl HCl PCTS 40 µg group withdrew because of inadequate analgesia, compared with 40.4% of the placebo group (P < 0.05). Use of fentanyl HCl PCTS 40 µg was associated with lower VAS scores and higher mean patient and investigator global assessment scores compared with placebo. No patient experienced clinically relevant respiratory depression. This study showed that a fentanyl HCl PCTS 40 µg for PCA was superior to placebo and well tolerated for the control of moderate to severe postoperative pain for up to 24 h after major surgery.

IMPLICATIONS: This multicenter, randomized, double-blinded, placebo-controlled trial showed that an on-demand fentanyl HCl patient-controlled transdermal system (PCTS) was superior to placebo and well tolerated for the control of moderate to severe postoperative pain for up to 24 h after major surgery. This fentanyl HCl PCTS is a preprogrammed, needle free, self-contained drug-delivery system that uses electrotransport technology (iontophoresis) to deliver 40 µg of fentanyl per on-demand dose.

	Introduction

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Potent opioids are commonly used for moderate to severe pain after major surgical procedures (1). Traditionally, opioids are administered IM or IV using intermittent regimens; however, as this pain is constant, it is often inadequately controlled because of infrequent administration and variability in drug absorption (2–4). Advances in the delivery of analgesic drugs and the development of additional analgesic medications have not entirely solved this problem, and many patients continue to experience poor control of their acute postoperative pain (4–7). A major improvement in postoperative pain management is the use of patient-controlled analgesia (PCA). However, the typical delivery system requires technical expertise of nursing staff and venous access.

Fentanyl has been commonly used for analgesia during the postoperative period for several decades. Furthermore, the safety and efficacy of IV fentanyl PCA have been demonstrated with doses ranging from 10 to 60 µg using lockout intervals ranging from 1 to 10 minutes (8–15). Because of its high potency and lipid solubility, fentanyl can also be administered via the transdermal route (16,17). Iontophoresis (electrotransport) delivers ionizable drugs, such as fentanyl HCl, into or through the skin by application of an external electrical field (18,19) and allows on-demand drug administration. Using this technology, a fentanyl HCl patient-controlled transdermal system (PCTS) is being developed that is a preprogrammed, self-contained, self-adhesive, on-demand drug-delivery system (Fig. 1). The system uses low electrical current proprietary electrotransport technology (E-TRANS® ALZA Corp, Mountain View, CA) to deliver 40 µg fentanyl over a 10-min period without the requirement for venous access. The objective of this randomized study, conducted in 205 patients, was to assess the efficacy and safety of fentanyl HCl 40 µg PCTS for the management of the first 24 h of postoperative pain.

View larger version (86K): [in this window] [in a new window]   Figure 1. Fentanyl HCl patient-controlled transdermal system (PCTS). Button for patient activation of dose. Light-emitting diode (LED) or light.

	Methods

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Patients were excluded if their postsurgical recovery was complicated (e.g., requiring treatment with vasoactive substances or admission to an intensive care unit), if they received long-lasting intraoperative regional anesthesia or opioids other than morphine, fentanyl, sufentanil, or alfentanil, or if they had a history of substance or alcohol abuse, allergy or sensitivity to fentanyl, or tolerance to or dependence on opioids. Other exclusion criteria included skin disease that could interfere with fentanyl HCl PCTS administration or an inability to operate the system.

Patients were consented, screened for entry into the study, and trained to use the system at a preoperative visit. Postoperatively in the postanesthesia care unit (PACU), patients were titrated to comfort with IV opioids (bolus IV doses of fentanyl 25 or 50 µg were typically used in amounts indicated by the nurse or doctor as necessitated by the patient’s pain intensity score and pain relief achieved). After at least 30 min, patients, if awake and alert, were assessed for pain intensity, vital signs, and oxygen saturation. Those who were comfortable were considered eligible to enter the study and were randomized to fentanyl HCl PCTS 40 µg or placebo in a 3:1 ratio. The use of this 3:1 ratio minimizes the number of patients exposed to the placebo treatment. The system was applied to the patient’s upper, outer arm, or chest and the correct operation of the system was again explained. Only the patient was permitted to activate the system. Because supplemental IV fentanyl was allowed during the first 3 h of the study, patients were considered evaluable for efficacy if they remained in the study for at least 3 h. Patients could withdraw from the study at any time for any reason and were immediately given appropriate analgesia.

Fentanyl HCl PCTS provides a maximum of 6 10-min doses per hour and operates for 24 h or delivers up to 80 doses, whichever occurs first. The placebo systems used in this study were identical to the active systems except that electrical current was not applied to the drug reservoir and therefore no drug was delivered. As the current applied was very small (170 microamperes), patients would not perceive any difference between the fentanyl HCl PCTS and the placebo system.

Preliminary trials were conducted to determine the appropriate dose for this study. In a postoperative study in which patients were randomized to IV PCA of 20, 40, or 60 µg of fentanyl infused over 10 min, the 40 µg/dose and 60 µg/dose controlled pain better than the 20 µg/dose; however, the 60 µg/dose was associated with an increase in adverse respiratory effects compared with the 40 µg/dose (20). Further, in an open-label clinical study, fentanyl HCl PCTS 40 µg provided better pain control than fentanyl HCl PCTS 25 µg without causing additional adverse events in adult patients with moderate to severe postoperative pain.¹ Finally, the 40 µg dose was used in a single-center, placebo-controlled trial with positive results.² Consequently, fentanyl HCl PCTS 40 µg was chosen as the dose for this double-blinded study.

The primary efficacy measurement was the percentage of patients in each treatment group who withdrew from the study because of inadequate pain control 3 h or more after application of the system. The overall number of patients who withdrew from treatment for any reason, except hospital discharge or no further need for parenteral opioids, during the 24-h treatment period was also determined.

In addition, pain intensity was measured immediately before the system was applied (hour 0), 0.5, 1, 2, 3, 4, 6, and 8 h after application and every 4 h thereafter until 24 h, using a 100-mm ungraded visual analog scale (VAS) that ranged from no pain (0 mm) to the worst possible pain (100 mm). The last available pain intensity record was used as an efficacy measure. Patients and investigators made global assessments at the end of the 24-h study period or at the time of withdrawal using a categorical scale with assigned values (1 = poor; 2 = fair; 3 = good; 4 = excellent) to indicate their evaluation of the method of pain control. Pain was both assessed and treated according to hospital standards.

The number of doses used by a patient was estimated by recording the number of light flashes displayed by the system at defined study intervals. Each flash represented the delivery of 1 to 5 doses (e.g., 1 flash represented 1 to 5 doses, 5 flashes represented 21 to 25 doses). The estimated number of doses was calculated as 5 times the number of displayed light flashes minus 2 to obtain the midrange dose number (e.g., 5 flashes would give an estimated number of doses of 23; 5 times 5 minus 2). Information regarding the clinical use of the fentanyl HCl PCTS 40 µg was obtained from the estimated number of doses of study medication delivered by the patient and the average number of doses per hour for the first 6 h and for the remainder of the study. The number of patients requiring rescue medication during the first 3 h and the total number of doses of rescue medication administered were also recorded. Finally, the percentage of the system area adhering to the application site was assessed just before removal.

All adverse events were solicited and recorded at the time of each assessment and also recorded when spontaneously reported by the patient. Oxygen saturation and vital signs, including blood pressure, heart rate and respiratory rate, were also measured at each assessment time. Respiratory function was the main measure of systemic safety. Clinically relevant respiratory depression was defined as bradypnea (respiratory rate <8 breaths per minute sustained for 1 min) simultaneous with excessive sedation (patient not easily aroused). The application site was monitored for erythema after removal of the system or at the time of discharge. Erythema was assessed using a 4-point scale (0 = none; 1 = noticeable redness; 2 = well-defined redness; 3 = beet redness). Other application site reactions that occurred during this period were also recorded.

All statistical tests for efficacy measures were performed at the = 0.05 level using a two-tailed test. The power analysis indicated that a sample size of 164 patients was necessary to provide 90% power to detect a 30% event rate difference between the discontinuation rates of the 2 treatment groups. Patients were evaluable for efficacy analyses if they received at least 3 h of treatment with the system. Logistic regression analysis was used to evaluate the potentially confounding factors of age, treatment, gender, race, pain score before entry (PACU score), and patient requirement for rescue medication within the first 3 h after system application.

The ² test was used to compare the proportion of patients discontinuing because of inadequate pain control in the fentanyl HCl PCTS 40 µg and placebo groups. The means scores for patient and investigator global assessments and mean last pain intensity scores were compared between treatments using analysis of variance. The estimates of the total number of doses of fentanyl HCl PCTS 40 µg and placebo activated by each patient were summarized. The average number of doses per hour for the first 6 h and for 24 h were summarized and compared with the number of doses of study medication available. Use of rescue medication, adverse events, and safety data were summarized or tabulated.

	Results

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A total of 205 postoperative patients were enrolled, randomized and treated in this study and 189 patients were evaluable for efficacy with 142 randomized to fentanyl HCl PCTS 40 µg and 47 to placebo. Most evaluable patients were female (68.8%) and Caucasian (81.5%) and had an ASA physical status of II (64.0%). Lower abdominal surgical procedures were the most common (51.3%). Patient demographics (age, height, weight, and body mass index) were similar between the 2 groups at baseline (data not shown).

Before removal, the system was checked for adherence to the application site; good adherence (at least 90% adherence with no edges unattached) was achieved for 90% of patients. The system fell off of 3 patients (1.5%), and another 4 patients required additional taping. Two patients had a second system applied after fall off and continued the study with no further incidents. The third patient withdrew from the study.

Inadequate analgesia was more common with placebo than fentanyl HCl PCTS 40 µg; 25.4% of patients in the fentanyl HCl PCTS 40 µg group withdrew because of inadequate pain control 3 h or longer after application of the system, compared with 40.4% of the placebo group (P < 0.05). The mean time to withdrawal because of inadequate pain control was similar between treatments (6.6 h with fentanyl HCl PCTS 40 µg versus 6.5 h with placebo), but a larger proportion of placebo-treated patients had withdrawn by that time (Fig. 2). Thus, fentanyl HCl PCTS 40 µg provided significantly better pain control than placebo as assessed by the primary efficacy end-point. The proportion of patients who withdrew from the study for any reason was 32% of the fentanyl HCl PCTS 40 µg group (n = 46) and 53% of the placebo group (n = 25) (P = 0.011). Reasons for early withdrawal are summarized in Table 1. Mean last pain intensity scores, as measured by VAS, were 30.9 ± 2.4 (SEM) for fentanyl HCl PCTS 40 µg versus 40.8 ± 4.6 (SEM) for placebo, P = 0.047. Pain intensity VAS scores at each assessment time are shown in Figure 3. The mean global assessment score of the method of pain control was significantly higher with fentanyl HCl PCTS 40 µg than with placebo as judged by patients (3.0 versus 2.6, P = 0.047) and investigators (3.1 versus 2.6, P = 0.007).

View larger version (10K): [in this window] [in a new window]   Figure 2. Cumulative percentage of evaluable patients who withdrew from treatment because of inadequate pain control at least 3 h after application of the patient-controlled transdermal system (PCTS) over the 24-h study period.

View larger version (43K): [in this window] [in a new window]   Figure 3. Pain intensity visual analog scale (VAS) scores by time after application of the patient-controlled transdermal system (PCTS) or placebo. Only patients with a pain intensity score at the given time are included in the calculation of the mean. Up to 31% of patients did not contribute a score because patients were not awakened for pain assessment. Missing data rendered an analysis of pain scores at each time unjustified. *P = 0.0474 for fentanyl HCl PCTS versus placebo.

A total of 154 patients treated with fentanyl HCl PCTS 40 µg and 51 patients treated with placebo were evaluated for safety. At least one adverse event was experienced by 64% of the fentanyl HCl PCTS 40 µg recipients and 51% of placebo recipients. The most common adverse events related to study medication are summarized in Table 2. Adverse events that were considered by the investigator to be related to the study medication were experienced by 46% of patients who received fentanyl HCl PCTS 40 µg and by 33% of those who received placebo. Only 1 patient had a serious adverse event that was considered to be treatment-related. This patient experienced moderate nausea and vomiting and severe urinary retention. Thirteen patients discontinued study treatment because of an adverse event, 8 (5.6%) who received fentanyl HCl PCTS 40 µg and 5 (10.6%) who received placebo.

View this table: [in this window] [in a new window]   Table 2. Most Common Adverse Events Related to Study Medication (2% of patients)

Cardiovascular and respiratory measurements were similar in each treatment group at all times. Oxygen saturation remained more than 90% in all patients given placebo and in 97.4% of patients treated with fentanyl HCl PCTS 40 µg. Two patients had isolated oxygen saturations of 87% and 89%. One patient with chronic obstructive pulmonary disease had 5 episodic oxygen saturations of 87%–89% recorded, and another patient with renal failure had 2 records of oxygen saturations of 89%. However, none of these were associated with slow respiratory rates (16–20 bpm). No patient had clinically relevant respiratory depression.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In this study, fentanyl HCl PCTS was shown to be effective in the management of moderate to severe acute pain after major surgery by its superiority to placebo in the following measures: significantly fewer patients who received fentanyl HCl PCTS than those who received placebo withdrew from treatment because of inadequate pain control or for any reason; the final mean pain intensity score was significantly lower in the fentanyl HCl PCTS group than in the placebo group; and both patients and investigators reported greater satisfaction with fentanyl HCl PCTS than with placebo. Therefore, analgesic success from a preprogrammed, non-adjustable device appeared to be adequate, especially as additional analgesic medicines (e.g., nonsteroidal antiinflammatory drugs, other opioids, acetaminophen) were not allowed. The prohibition of other analgesics could, however, explain the withdrawal rate observed in this trial. Furthermore, the need for fentanyl on-demand doses was most frequent during the first 6 hours after application, confirming that requirements for opioids during the postoperative period decrease with time (15).

Reported adverse events in the fentanyl HCl PCTS group were those commonly seen in postoperative recovery or generally associated with opioid therapy, such as nausea and pruritus (15). The majority of adverse effects observed were judged to be mild or moderate in intensity. Topical adverse events were also mostly mild. Importantly, no patient experienced clinically relevant respiratory depression; in fact, in no patient did the respiratory rate decrease to less than 8 breaths per minute. However, this study was not powered to detect an incidence of significant respiratory depression of <1% (the likely rate of such an event) (21).

As previously indicated, the E-TRANS® technology in the fentanyl HCl PCTS uses low-intensity direct electrical current to move charged fentanyl molecules through the skin to the dermal circulation on activation by the patient. The dose of fentanyl delivered is proportional to the applied current that is preset by the manufacturer (22) and absorption is not influenced by patient demographics (ethnicity, gender, body weight, or age). Further, the fentanyl pharmacokinetics from a PCTS dose are similar to those of the same dose of IV fentanyl infused over 10 minutes, although the skin appears to attenuate the increase and decrease of plasma fentanyl concentrations (22). Fentanyl HCl has low solubility in skin and absorption is negligible if current is not applied (22). Because dosing can be intermittent, the PCTS is suitable for management of acute pain in opioid naïve patients.

These and other features distinguish the fentanyl HCl PCTS from the passive fentanyl transdermal system, Duragesic®. The latter transdermal system is marketed for chronic nonmalignant and cancer pain requiring continuous delivery of fentanyl for weeks, months, or years. Because fentanyl is delivered at a constant rate and has a long plasma half-life, Duragesic® is not suitable for acute or postoperative analgesia and is in fact contraindicated for this condition (23).

This study has two limitations with regard to assessment of the efficacy of this transdermal PCA system. The first limitation is attributable to the observation that 19% of patients entered the study with PACU pain scores of 75. Although the mean pain intensity scores at study entry were similar between groups, disproportionately more patients (5:1) were randomized to fentanyl HCl PCTS with baseline pain intensity scores 75 relative to the placebo group. This was problematic because early withdrawal was more likely in patients with a VAS pain score at study entry of 75 (odds ratio, 2.3) and may explain the small differences between groups for discontinuation for inadequate analgesia. Because PCA is a maintenance treatment it is important to achieve analgesic comfort before relying solely on PCA for pain management. Future studies should test the efficacy of PCA when a defined pain score (e.g., <50 mm on a 100-mm VAS) is required for study enrollment.

The second limitation is to understand how the efficacy of the fentanyl HCl PCTS compares to that of IV PCA. Recently, Viscusi et al. (24) reported that the effectiveness of fentanyl PCTS 40 µg was comparable to a standard IV PCA morphine regimen.

This study demonstrated that fentanyl HCl PCTS 40 µg was superior to placebo for the management of acute postoperative pain after major surgery. Fentanyl HCl PCTS 40 µg was well tolerated and provided a convenient, patient-controlled, noninvasive approach that uses a preprogrammed and self-contained transdermal system.

	Acknowledgments

 
Sponsored by ALZA Corporation, Mountain View, California.

The authors wish to acknowledge the contributions of Wafik Abdou MD, Mitchell Research Group of Bakersfield, California; Brian Ginsberg MD, Duke University Medical Center, Durham, North Carolina; Spencer Liu, MD, VA Mason Medical Center, Seattle, Washington; Charles Ripp, MD, Penrose Hospital, Colorado Springs, Colorado; B. King Tipton, MD, Lee Neurosurgery, Fort Myers, Florida, and their research staffs.

	Footnotes

 
None of the authors is compensated by or has a financial interest in ALZA Corporation.

"Fentanyl HCl PCTS" refers to transdermal systems using ALZA Corporation’s proprietary E-TRANS® technology.

¹ Brown CR, Moodie JE, Bisley EJ, et al. Dose-ranging study of Transfenta for postoperative pain [abstract]. 17th Annual Scientific Meeting of the American Pain Society 1998;Abstract 888:193.

² Brown CR, Moodie JE, Bisley EJ. Safety and efficacy of Transfenta in the treatment of postoperative pain: a double-blind, single-center, placebo-controlled trial [abstract]. 17th Annual Scientific Meeting of the American Pain Society 1998;Abstract 886:192.

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