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Anesth Analg 2006;102:188-194 © 2006 International Anesthesia Research Society doi: 10.1213/01.ane.0000183649.58483.77
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Abstract |
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An iontophoretic fentanyl HCl patient-activated transdermal system (fentanyl HCl PATS) is under development for the treatment of acute postoperative pain. The fentanyl HCl PATS is a needle-free, credit card-sized, preprogrammed system that is applied to the patient's upper outer arm or chest. The fentanyl HCl PATS was demonstrated to be superior to placebo in a previous trial; however, the randomization scheme used and the lack of control of entry pain level may have contributed to the lack of robust findings. We compared the fentanyl HCl PATS with placebo for acute postoperative pain management in a larger trial that addressed the limitations of the previous study. Adult patients admitted to the postanesthesia care unit after major surgery were titrated to comfort with opioids and randomized 1:1 to receive the fentanyl HCl PATS 40 µg or placebo for 24 hours. Supplemental IV fentanyl was available to patients upon request in both treatment groups for the first 3 hours after enrollment. The primary efficacy end-point was the percentage of patients who discontinued participation in the study because of inadequate analgesia. Pain intensity scores, patient global assessments (PGA), and investigator global assessments (IGA) were collected. Four-hundred-eighty-four patients (PATS, n = 244; placebo, n = 240) were enrolled. Fewer patients receiving the fentanyl HCl PATS discontinued because of inadequate analgesia compared with placebo (28.7% versus 60.0%; P < 0.0001). Mean last pain intensity scores were 3.5 and 5.4 for the fentanyl HCl PATS and placebo groups, respectively. Patients (73.4%, PGA) and investigators (72.1%, IGA) considered the fentanyl HCl PATS a good or excellent method of pain control. Treatment-related adverse events were similar between groups. This study demonstrated the superiority of the iontophoretic fentanyl HCl PATS over placebo for acute postoperative pain management.
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Introduction |
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Patient-controlled analgesia (PCA) has become a common modality for acute pain management since it came into use two decades ago (1). The initial control of postoperative pain, usually via bolus doses of IV analgesics, is required before initiating any PCA-treatment regimen (2). The purpose of PCA is to maintain a mild and tolerable level of pain without impeding progress toward recovery (3,4). Currently, the most common form of postoperative PCA uses a manually programmed electronic IV PCA pump (5,6) that delivers a small analgesic bolus through an IV line when a button is pressed by the patient. Failures of this delivery method because of programming errors, IV line occlusions, and IV catheter infiltration into the subcutaneous tissue have been reported (2,7,8).
An iontophoretic fentanyl HCl patient-activated transdermal system (PATS) that addresses many limitations of currently available PCA systems is under development. This preprogrammed, self-contained, credit card-sized, needle-free system (Fig. 1) does not require tubing, poles, or a pump apparatus, which may hinder patient mobility. The PATS uses an imperceptible, low-intensity electric current to transfer 40 µg of fentanyl from a hydrogel reservoir across the skin into the systemic circulation. The amount of fentanyl delivered by this system is directly related to the magnitude of current applied (9); drug delivery is consistent and reproducible when the system is activated by the patient (10–12) and negligible when current is not applied (13). The 40-µg dose was chosen based on results of a fentanyl IV PCA dose-finding study, which demonstrated this dose to have the best combination of analgesic efficacy and an acceptable side effect profile (14). In addition, fentanyl delivered by this system has a pharmacokinetic profile similar to that after IV fentanyl administration (13).
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The fentanyl HCl PATS adheres to the upper outer arm or chest, is activated when the patient double-presses the button, and communicates system status using light flashes and beeps. The system provides on-demand delivery of 40 µg of fentanyl for 10 min, with up to six doses available per hour. The PATS operates for 24 hours or until a maximum of 80 doses are delivered, whichever occurs first. During dose delivery, the system will not respond to requests for additional doses, and delivery cannot be interrupted or extended beyond 10 min. A single beep and illumination of the red light indicate the beginning of a dose, and the red light remains on during dose delivery. The number of doses delivered by the PATS is approximated by the number of light flashes between dosing deliveries. One flash represents 1–5 doses, two flashes represent 6–10 doses, and so forth. The maximum number of flashes is 16, corresponding to 76–80 doses delivered.
Recently, the results of a randomized, controlled trial demonstrated the superiority of the fentanyl HCl PATS over placebo for acute postoperative pain management; however, results of primary and secondary efficacy end-points were not as robust as would be expected (P = 0.049 and P = 0.047) (15). Several study limitations, including the lack of control of pain intensity at study entry (i.e., the maximum level of pain intensity patients could have before enrollment was not defined), as well as a 3:1 fentanyl-to-placebo randomization scheme, most likely contributed to the lack of a robust effect. In that study, approximately 19% of patients who received the fentanyl HCl PATS entered the study with a Visual Analog Scale (VAS) pain score of 
75 on a scale from 0 to 100, which is indicative of severe pain. Disproportionately, more patients with a pain score of 75 were assigned to the fentanyl HCl PATS group (15), which may have impacted the findings from that study.
The objectives of this study were to compare the safety and efficacy of the fentanyl HCl PATS with placebo, in a 1:1 randomization scheme, for the management of moderate-to-severe pain in patients initially titrated to comfort (as assessed by a VAS score of <5) with IV opioids for immediate postoperative pain control and to evaluate more personal aspects of pain management via patient questionnaires that assessed patient satisfaction, ease of use, and convenience of the delivery modality.
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Methods |
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This prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted from November 2001 to March 2002 at 20 United States hospitals. The study protocol was approved by the IRB of each participating center. Written informed consent was obtained from each patient during the screening process within a 2-wk period before enrollment. Patients eligible for enrollment were at least 18 years of age, ASA physical status I, II, or III, expected to be admitted to the postanesthesia care unit (PACU) after general or regional anesthesia for major abdominal, orthopedic, or thoracic surgery, and expected to have moderate or severe pain requiring parenteral opioids for at least 24 h after surgery.
During screening, patients were educated regarding postoperative pain, the use of the fentanyl HCl PATS, and performance of study assessments. Postoperatively, patients were admitted to the PACU. Eligible patients were awake, alert, breathing spontaneously, able to answer questions and follow commands for at least 30 min in the PACU, and were comfortable for at least 30 min after the administration of IV opioids for immediate pain control. Patients were titrated to an acceptable comfort level with IV doses of morphine, fentanyl, sufentanil, or alfentanil, if required. During the study period, all analgesics other than IV fentanyl were disallowed, including all other opioids, local anesthetics, and nonsteroidal antiinflammatory drugs. Patients were not eligible to enroll if they had received long-lasting intraoperative regional anesthetics or spinal opioids, were expected to receive postoperative analgesia supplied by a continuous regional technique, had received intraoperative opioids other than morphine, fentanyl, sufentanil, or alfentanil (except for one dose of meperidine, allowed for shivering within 30 min of PACU arrival), were tracheally intubated at the time of final screening assessment, were known or suspected to be opioid tolerant, or had active systemic or local skin disease preventing application of the PATS.
After 30 min, patients were asked to assess their pain; those with a pain score <5 (on an 11-point scale, with 0 defined as the absence of pain and 10 as the worst possible pain) were randomized to treatment. Vital signs, oxygen saturation, and last reported pain score were immediately recorded, and the study period was considered to have begun (Hour 0). Immediately after assessments, the active PATS or placebo system was applied, and the patient was considered enrolled. The patient was again instructed in the use of the fentanyl HCl PATS; only the patient was permitted to activate the system. The placebo and active systems used in this study were identical in appearance; however, the electronic circuitry of the placebo system was modified to prevent production of the electric current required for drug delivery. Upon request, rescue medication (IV bolus doses of fentanyl) was administered to patients in both the fentanyl HCl PATS and placebo groups through an existing IV line for the first 3 h after system application and disallowed thereafter. During the study, patients who felt their pain was not adequately controlled with the allowed interventions could withdraw from the study at any time. Patient withdrawal from the study could be initiated by the patient or by the physician, and reasons for withdrawal could include inadequate analgesia, administration of disallowed study medication, occurrence of adverse event, no requirement for further parenteral opioid analgesic, and patient withdrawal of consent for any reason, among others.
Vital signs, oxygen saturation, pain intensity scores, and the number of PATS flashes were assessed at Hours 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24. Patient global assessments (PGA), investigator global assessments (IGA), and questionnaires to assess patient satisfaction, ease of use, and convenience of the fentanyl HCl PATS were administered at 24 hours or upon withdrawal from the study, whichever came first.
Study staff monitored patients and recorded patient-reported adverse events, along with their relation to study medication. Application sites were monitored for erythema and other reactions during the study, and skin erythema was assessed again 24 h after system removal. Patients who reported adverse events or skin reactions were observed until symptoms resolved or until the condition became medically stable. Respiratory depression was the primary measure of systemic safety, and clinically relevant respiratory depression (CRRD) was defined as the simultaneous occurrence of bradypnea (respiration rate <8 breaths/min) and excessive sedation (patient not easily aroused).
Pain intensity was measured on the verbal numerical scale of 0–10 described previously. Patients were instructed to take a deep breath and cough 5 min before each assessment but were not awakened if sleeping at the scheduled assessment time. Pain intensity scores were recorded at study termination for those who did not complete 24 h of treatment. PGAs and IGAs asked responders to rate the method of pain control as poor, fair, good, or excellent. Each patient questionnaire used a different 5-point scale: satisfaction with the fentanyl HCl PATS for pain management (1 = "very dissatisfied" to 5 = "very satisfied"), ease of use of the fentanyl HCl PATS (1 = "very hard" to 5 = "very easy"), and convenience of the fentanyl HCl PATS (1 = "very inconvenient" to 5 = "very convenient").
Demographic and clinical variables (ASA status, surgery type, etc.) were summarized by treatment group for all randomized patients. All statistical tests for the final efficacy analyses were performed at the 0.05 significance level, and those for the analysis of baseline data were performed at the 0.10 significance level.
The primary efficacy variable was the proportion of patients who withdrew from the study because of inadequate pain relief during the 24-hour treatment period. Efficacy data were analyzed for the intent-to-treat population (all patients enrolled). The 
2 test was used to compare the proportion of patients who withdrew from the study between treatment groups.
Secondary efficacy end-points included study withdrawal for any reason, mean last pain intensity scores, PGA, and IGA. Study withdrawal for any reason was analyzed using the 2 test. A two-sample t-test was used to determine if the last recorded pain intensity scores were significantly different between treatment groups. For patients who withdrew from the study before 24 h, the pain scores at withdrawal were used in a last observation carried forward analysis. Analysis of variance was used to analyze categorical PGA and IGA data. The estimated number of doses delivered was calculated by the formula ([number of PATS light-emitting diode (LED) flashes] x 5 – 2).
Enrollment of up to 474 patients was planned to allow for a 10% withdrawal rate before patients became evaluable. This would result in a sample size of 430 evaluable patients, providing approximately 90% power to detect a 15% difference in withdrawal rate because of inadequate analgesia between groups, with a significance level of 
= 0.05.
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Results |
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Of the 630 patients screened for study enrollment, 16 withdrew consent, and 130 failed to meet inclusion criteria. The most common reasons for exclusion from the study were a pain score of 5 or more at the time of screening (n = 52) and postoperative administration of long-lasting regional anesthesia or continuous regional analgesia (n = 20). Patients enrolled in the study (n = 484) were randomized 1:1 to receive the fentanyl HCl PATS (n = 244) or placebo (n = 240). At least 3 h of treatment were completed by 235 patients receiving the active treatment and 204 patients receiving placebo. The disposition of all patients is summarized in Figure 2. The most common reason for study withdrawal in both groups was inadequate analgesia; other reasons included withdrawn consent, adverse events, and protocol violations. Of the six study withdrawals caused by adverse events among patients receiving active treatment, three were attributed to study medication (nausea, n = 2; pruritus, n = 1). Patient demographics were not significantly different between treatment arms (Table 1). There was no significant difference in the distribution of surgery type between randomized and treated patients or between treatment groups.
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One-hundred-forty-four patients in the placebo group (60.0%) withdrew from the study because of inadequate analgesia compared with 70 patients receiving the active fentanyl HCl PATS (28.7%; P < 0.0001). The mean duration of treatment before withdrawal was similar between groups, with an average of 7.3 h (sem = 0.70) in the active treatment group and 6.5 h (sem = 0.43) in the placebo group. Figure 3 shows the cumulative dropout rate because of inadequate analgesia in each group.
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When compared with patients receiving the active system, a significantly larger proportion of patients receiving placebo discontinued the study for any reason (36.9% versus 68.3%, respectively; P < 0.001). Similar significant differences were found between treatment groups in last pain intensity score, PGA, and IGA (Table 2). Mean pain intensity scores were significantly higher for patients in the placebo group than for patients in the fentanyl HCl PATS group at the last pain assessment (P < 0.0001) and throughout the 24-h treatment period (Fig. 4). The results from the patient satisfaction questionnaire showed that the majority of the 484 patients in both treatment groups found the PATS to be very convenient (79.8%) and very easy to use (87.0%). However, only 32.1% of patients receiving placebo were very satisfied with the pain management provided by the system, compared with 61.5% of patients in the active treatment group.
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At each measured time point, patients using the placebo system activated more doses per hour than patients receiving the active treatment, and the frequency of dosing decreased in both groups from Hour 1 to Hour 24 (data not shown). In addition, the cumulative number of doses activated per patient was higher at each measured time point from Hours 1–24 for patients receiving placebo than for patients receiving the fentanyl HCl PATS. At Hours 8 and 24 after enrollment, patients in the placebo group received approximately 16.2 doses (n = 125) and 40.7 doses (n = 66) per patient, respectively, whereas patients in the fentanyl HCl PATS group received approximately 14.4 doses (n = 186) and 36.7 doses (n = 148) per patient, respectively. A significantly larger percentage of patients receiving placebo required rescue medication in the first 3 h of the study than patients receiving the active treatment (57.5% versus 45.5%, respectively; P = 0.008).
Adverse events judged as possibly or probably related to treatment and reported by at least 2% of patients are summarized in Table 3. The incidence of opioid-related side effects was more frequent in the active treatment group. Two serious adverse events were judged to be possibly related to study medication because two patients from the active treatment group experienced ileus after system removal. Ileus was diagnosed 15 h after system removal in one case and 20 min after system removal in the other case. No patient experienced CRRD in this study. Application site reactions were reported by 11 patients (4.5%) using the active fentanyl HCl PATS versus 3 patients (1.3%) receiving placebo. All reactions were mild or moderate. Erythema 24 h after system removal was observed in 120 of 484 (24.8%) patients, with most of those (64.2%) being classified as mild. None of these patients required treatment, and the erythema resolved in 4 wk or less.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The purpose of this study was to compare the efficacy and safety of the iontophoretic fentanyl HCl PATS with placebo for the management of acute postoperative pain. The smaller percentage of patients withdrawing from this study because of inadequate analgesia in the active treatment group demonstrates the superior efficacy of the PATS. The results of the secondary efficacy analyses support this conclusion.
There were no episodes of CRRD in this study, although it was not adequately powered to detect the incidence of such events, estimated to be <1% with opioid treatment (16). Most adverse events were rated as mild or moderate in severity and are commonly experienced by patients receiving opioid analgesia and by patients in the immediate postoperative period (4).
These findings are more robust than the results from an earlier multicenter clinical trial that demonstrated the superior efficacy of the fentanyl HCl PATS compared with placebo in the management of postoperative pain (15). Corroboration of the results from this earlier study was important, owing to the smaller treatment difference observed between groups in that study (15%) and the marginal significance of its primary efficacy end-point (P = 0.049). These outcomes were most likely caused by the combined effects of a 3:1 active treatment-to-placebo randomization scheme and a lack of control for a maximum level of pain allowed for study entry. These two factors resulted in more patients with high baseline pain scores being enrolled into the fentanyl HCl PATS group and a greater probability of a perceived treatment effect in the placebo group because patients were aware of a 75% chance of receiving the active treatment (15). These factors were addressed in the design of the current study.
The current study does have limitations. As previously mentioned, patients were enrolled only if their pain score was <5 (on a scale of 0–10) at screening; therefore, it is conceivable that patients were without pain upon enrollment. However, the fentanyl HCl PATS was not designed to treat the intense levels of pain immediately after surgery, but rather to deliver frequent small doses of drug to maintain analgesia once initial pain control has been established. This is consistent with the manner in which PCA is currently used in the clinical postoperative setting. Another limitation may be that patients in both groups were prohibited from receiving additional analgesia after three hours, which does not represent a "real world" situation, because bolus dosing for breakthrough pain may occasionally be required in the clinical setting. In addition, analgesia in this study was dependent upon opioids alone, which also may not reflect current practice, given the increasing use of nonsteroidal antiinflammatory drugs as co-analgesics in the postoperative period. This study also did not control for the particular opioid used during the initial titration of analgesia; the two most frequently used opioids were morphine and fentanyl, with morphine having a longer duration of action, as well as a potent metabolite, morphine-6-glucuronide (2). These differences in pharmacokinetics could potentially affect the demand for additional opioids within the first three hours of treatment.
There are several potential advantages to the iontophoretic fentanyl HCl PATS. The system provides pain control comparable to that of a standard regimen of IV PCA morphine, without the PCA pump, IV lines, tubing, and pump apparatus required for IV PCA (17). Preprogramming of the fentanyl HCl PATS device eliminates the potential for drug administration errors observed with manually programmed IV PCA devices. Further, the fentanyl HCl PATS should not require significant coordination between nursing, pharmacy, and biomedical engineering services, as do IV PCA systems. In this study, most patients were very satisfied with the pain control provided by the PATS, and most patients characterized the system as very convenient and very easy to use. There are limitations of the device, however; patients unable to operate the device because of deficiencies in upper extremity mobility or comprehension would be excluded from this treatment modality as they would be with any existing patient-activated therapy. Whereas individual patients may require varying amounts of drug based on differences in weight, opioid tolerance, or their perception of pain, the possible limitations of a preprogrammed 40-µg dose may be overcome by more frequent dosing because patients are able to self-initiate from 40 to 240 µg/h, depending upon their analgesic requirements.
In conclusion, the fentanyl HCl PATS provided pain control superior to that of placebo in the first 24 hours after major surgical procedures. The system provides the advantages of PCA through a self-contained, needle-free, compact delivery system. Further studies examining other patient populations for whom this pain management system would be appropriate are warranted. In addition, an extensive comparative cost-benefit analysis incorporating the potential for improved safety and decreased demand for resources would provide further insights into the potential advantages of the iontophoretic fentanyl HCl PATS.
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Footnotes |
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Accepted for publication August 5, 2005.
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References |
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- Bennett RL, Batenhorst RL, Bivins BA, et al. Patient-controlled analgesia: a new concept of postoperative pain relief. Ann Surg 1982;195:700–5.[Web of Science][Medline]
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[Abstract/Free Full Text] - Vicente KJ, Kada-Bekhaled K, Hillel G, et al. Programming errors contribute to death from patient-controlled analgesia: case report and estimate of probability. Can J Anaesth 2003;50:328–32.[Web of Science][Medline]
- Gupta SK, Bernstein KJ, Noorduin H, et al. Fentanyl delivery from an electrotransport system: delivery is a function of total current, not duration of current. J Clin Pharmacol 1998;38:951–8.[Abstract]
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- Sathyan G, Zomordi K, Gidwani S, Gupta S. The effect of dosing frequency on the pharmacokinetics of a fentanyl HCl patient-controlled transdermal system (PCTS). Clin Pharmacokinet. 2005;44(Suppl 1):17–24.
- Sathyan G, Jaskowiak J, Evashenk M, Gupta S. Characterisation of the pharmacokinetics of the fentanyl HCl patient-controlled transdermal system (PCTS): effect of current magnitude and multiple-day dosing and comparison with IV fentanyl administration. Clin Pharmacokinet 2005;44(Suppl 1):7–15.
- Camu F, Van Aken H, Bovill JG. Postoperative analgesic effects of three demand-dose sizes of fentanyl administered by patient-controlled analgesia. Anesth Analg 1998;87:890–5.
[Abstract/Free Full Text] - Chelly JE, Grass J, Houseman TW, et al. The safety and efficacy of a fentanyl patient-controlled transdermal system for acute postoperative analgesia: a multicenter, placebo-controlled trial. Anesth Analg 2004;98:427–33.
[Abstract/Free Full Text] - Etches RC. Respiratory depression associated with patient-controlled analgesia: a review of eight cases. Can J Anaesth 1994;41:125–32.[Web of Science][Medline]
- Viscusi ER, Reynolds L, Chung F, et al. Patient-controlled transdermal fentanyl hydrochloride vs intravenous morphine pump for postoperative pain: a randomized controlled trial. JAMA 2004;291:1333–41.
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