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From the *Coalition for Pain Education Foundation, Tampa, Florida; Ortho-McNeil Janssen Scientific Affairs, LLC, Raritan, New Jersey; and Xcenda, Palm Harbor, Florida.
Address correspondence and reprint requests to Sunil J. Panchal, MD, 4911 Van Dyke Road, Lutz, FL 33558. Address e-mail to sunilpanchal2000{at}yahoo.com.
Abstract
BACKGROUND: Analgesic gaps (interruptions in analgesic delivery) contribute to ineffective postoperative pain management. In this analysis, we evaluated the incidence of analgesic gaps resulting from system-related events (SREs) for patients using the fentanyl iontophoretic transdermal system (ITS), a noninvasive patient-controlled analgesia (PCA) system, or morphine IV PCA for postoperative pain management.
METHODS: Data were pooled from two open-label, randomized, active-controlled trials that evaluated the efficacy and safety of fentanyl ITS and morphine IV PCA after total hip replacement, abdominal, or pelvic surgery. The incidence and duration of analgesic gaps resulting from SREs were assessed, along with SRE resolution times.
RESULTS: A total of 1305 patients received fentanyl ITS (n = 647) or morphine IV PCA (n = 658). Fentanyl ITS was associated with a significantly lower incidence of analgesic gaps per 100 patients compared with morphine IV PCA (5.87 vs 12.01, respectively; P < 0.001). Compared with patients receiving morphine IV PCA, patients receiving fentanyl ITS had both a numerically lower median total analgesic gap time (15.0 min vs 20.0 min) and a numerically lower median total SRE resolution time (11.0 min vs 20.0 min). Most fentanyl ITS SREs were resolved by applying a new system, whereas many different SRE resolution methods were used for morphine IV PCA.
CONCLUSIONS: Fentanyl ITS was associated with a significantly lower incidence of analgesic gaps relative to morphine IV PCA. Fentanyl ITS may provide patients with fewer interruptions and more continuous analgesic delivery.
Despite efforts to improve pain management through the development and implementation of pain management guidelines and acute pain services in many hospitals (1,2), acute postoperative pain management remains inadequate (3). The goals of the clinical practice guidelines established by the Agency for Healthcare Research and Quality (formerly the Agency for Health Care Policy and Research) include reducing the incidence and severity of postoperative pain and improving patient satisfaction and comfort to optimize pain management (4). Yet, a review of the literature found that a significant proportion of patients receiving postoperative analgesia still experienced moderate-to-severe pain after surgery (5).
One contributor to the inadequate management of postoperative pain may be the occurrence of analgesic gaps, defined as periods during which the patient does not have access to analgesia. Patients may experience analgesic gaps while waiting for nursing staff to administer bolus doses of opioid via the IV or IM route, or during the transition from one analgesic modality to another (6,7). The incidence of analgesic gaps may vary depending on the analgesic delivery system. For instance, systems that are complex, invasive, or involve multiple steps for analgesic administration may have more frequent system-related events (SREs, defined as problems related to the analgesic system that must be addressed by health care providers) that may result in interruptions in pain control. Patient-controlled analgesia (PCA) modalities may help minimize analgesic gaps, since they allow patients to control their pain according to their personal analgesic needs.
IV PCA is routinely used to manage postoperative pain and is often considered the "gold standard" for acute pain management. However, analgesic administration using IV PCA requires manual programming of the infusion pump, which introduces the potential for programming errors. IV PCA systems are also prone to patient errors and system malfunctions. In fact, the United States Food and Drug Administration recently issued a recall on the Syndeo PCA Syringe Pump (Baxter Healthcare, Deerfield, IL) due to a design defect that caused some of the infusion pumps to disrupt analgesic therapy (8). Furthermore, the complexity of the IV PCA system may increase the risk of SREs, due to problems with the infusion pump, IV line, or other components of the system.
The fentanyl HCl iontophoretic transdermal system (ITS) (IONSYSTM, Ortho-McNeil, Inc., Raritan, NJ) is a self-contained, needle-free analgesic delivery system that has been shown to be effective and safe for the management of acute postoperative pain in placebo- (9,10) and active-controlled (11–14) studies. The compact, self-adhesive system administers a preprogrammed 40-µg dose of fentanyl upon patient activation via iontophoresis.
Two recent open-label, active-controlled, parallel-group clinical trials demonstrated that fentanyl ITS is comparable in treatment efficacy and safety to morphine IV PCA for the management of acute postoperative pain (12,13). We used data from those two trials to compare the incidence and types of SREs that occurred during analgesic administration with the fentanyl ITS or morphine IV PCA.
METHODS
Study Design
Data for the current analysis were pooled from two open-label, randomized, multicenter, active-controlled, parallel-group studies of similar design that were conducted at 91 sites in the United States (12,13). The study protocol and amendments for both trials were approved by the IRB at each site. Written informed consent was obtained from all patients participating in the trials. Inclusion and exclusion criteria were as previously described (12,13).
After surgery, patients were randomized to receive either fentanyl ITS or morphine IV PCA for up to 72 h. For patients in the fentanyl ITS treatment group, a single 40-µg dose of fentanyl was delivered upon patient activation over a period of 10 min, with a maximum of six such doses per hour for 24 h or 80 doses per system, whichever occurred first. An audible beep and the illumination of a red light-emitting diode (LED) indicated that dosing had been initiated. The LED remained illuminated during the 10-min dose-delivery period, and additional doses could not be activated during this time. For patients in the morphine IV PCA treatment group, a 1-mg morphine bolus dose was administered on-demand with a 5-min lockout period. A 6-min lockout interval was allowed at some sites, depending upon site-specific policies. Patients received up to 10 doses per hour for 24 h or a maximum of 240 doses.
Supplemental analgesia was allowed for the first 3 h of treatment and disallowed thereafter. Patients in the fentanyl ITS group received IV fentanyl, whereas patients in the morphine IV PCA group received IV morphine upon request. Patients could receive IV fentanyl or IV morphine if the specified analgesic was not available. In one of the studies, patients in each treatment group were scheduled to receive oral rofecoxib (25 mg, 2–4 h before surgery, and 25 mg each day during the study) before its withdrawal from the market (12).
Nurses recorded SREs (e.g., infiltration, device malfunction or failure, pain at the IV or application site) as they occurred on an SRE checklist. Each time that an SRE occurred, the type of SRE, whether the SRE led to an analgesic gap, the duration of any analgesic gap, how the SRE was resolved, and the length of time required for its resolution were recorded.
Statistical Analyses
Data from the two studies were pooled for the current analysis. Between-group differences in the incidence of analgesic gaps that occurred as a result of SREs were evaluated using the Fisher exact test. The total number of analgesic gaps in each treatment group was also examined, since patients may have experienced more than one SRE. The relative risk of experiencing an analgesic gap was estimated as a ratio of the two incidence rates for patients with analgesic gaps (i.e., proportion of patients who experienced a analgesic gap while using morphine IV PCA divided by the proportion of patients who experienced an analgesic gap while using fentanyl ITS as the reference). Its associated 95% confidence interval (CI) was calculated using the approximate Woolf's method (15) that uses a logarithmic transformation, a linear approximation, and a normal distribution assumption.
The total duration of analgesic gaps and the total length of SRE resolution time were calculated as the sum of all gap or resolution times for each patient. The median was presented as the summary statistic for the analgesic gap time and the resolution time, since the median minimizes the effect of extreme outliers.
RESULTS
Patients (N = 1305) were randomized to receive fentanyl ITS (n = 647) or morphine IV PCA (n = 658) for acute postoperative pain management after total hip replacement, abdominal, or pelvic surgery. Patient characteristics were similar between the treatment groups (Table 1). Patients were predominantly female (64.3%) and white (84.9%).
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The incidence of analgesic gaps per 100 patients was significantly lower for fentanyl ITS (5.87) compared with that of morphine IV PCA (12.01, P < 0.001) (Fig. 1). Thus, fentanyl ITS was associated with approximately 6 fewer patients who experienced an analgesic gap per 100 patients relative to morphine IV PCA. The median total analgesic gap time (15.0 min vs 20.0 min) was numerically less for patients who received the fentanyl ITS versus morphine IV PCA, respectively. Compared with patients who received fentanyl ITS, the relative risk of experiencing an analgesic gap for patients who received morphine IV PCA was 2.04 (95% CI, 1.41–2.96). The relative risks calculated using data from each individual study supported the relative risk of an analgesic gap with morphine IV PCA as calculated using the pooled data (Fig. 2).
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The frequency of SREs that resulted in an analgesic gap in each treatment group is presented in Table 2. The total number of SREs that led to an analgesic gap was less for patients in the fentanyl ITS group (n = 41) versus the morphine IV PCA group (n = 98). Patients who received morphine IV PCA experienced a wide range of SREs that resulted in an analgesic gap, including infiltration of the IV line (n = 17), device malfunction or failure (n = 11), IV line pulled out (n = 8), and low or dead battery (n = 8). A total of 684 morphine IV PCA pumps were used during the two studies, and 17 (2.5%) of these pumps malfunctioned or failed; 11 of these SREs led to an analgesic gap.
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The most frequent SRE that resulted in an analgesic gap for patients who received the fentanyl ITS was device malfunction or failure (Table 2). Of the 1183 fentanyl ITS units used during the 2 studies, 52 (4.4%) had a device malfunction or failure; 26 of these system malfunctions or failures were associated with an analgesic gap. Manufacturer diagnostics revealed the following possible reasons for device malfunction or failure that resulted in an analgesic gap for the fentanyl ITS: no problem found (35%), battery failure (31%), switch failure (15%), and a defective LED (8%) (Table 3).
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The median total time required to resolve SREs was numerically less for patients who received fentanyl ITS versus morphine IV PCA (11.0 min vs 20.0 min). A variety of resolution methods were used to address SREs that occurred with morphine IV PCA, and included the following: started a new IV line (n = 36), new pump applied (n = 14), and reprogrammed/ stopped alarm (n = 6) (Fig. 3). In contrast, the majority of SREs that occurred with fentanyl ITS were resolved by applying a new system (n = 26). In some instances, patients underwent reeducation (n = 5) or study medication was discontinued (n = 4).
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DISCUSSION
Results from this analysis demonstrated that postoperative pain management using the fentanyl ITS was associated with a significantly lower relative risk of experiencing an analgesic gap relative to morphine IV PCA. Furthermore, the median total SRE resolution time for fentanyl ITS was nearly half that for morphine IV PCA.
For morphine IV PCA, infiltration of the IV line was the most frequently reported SRE that resulted in an analgesic gap. Infiltration at the catheter site is a problem commonly encountered with IV-related procedures, and may result in IV line failure and/or a subcutaneous depot of opioid, leading to inadequate and ineffective delivery of analgesic, as well as pain and discomfort (16). Incorrect programming and dosing errors occurred with morphine IV PCA in the two studies included in this analysis; the needle-free, preprogrammed nature of the fentanyl ITS eliminates the potential for such complications.
Many of the SREs encountered with morphine IV PCA are not possible with fentanyl ITS, as the system does not require IV access or dose adjustment. Device malfunctions or failures accounted for most of the SREs that occurred with the fentanyl ITS; however, manufacturer diagnostics found no problem with the system in 35% of these cases. Such a result may be attributed to nurses' unfamiliarity with this novel analgesic delivery system. In other words, nurses may have mistakenly diagnosed a malfunctioning or failing unit when there was no problem. Improved nurse training after product availability will likely decrease the rate of system failures.
A lower incidence of SREs and resulting analgesic gaps may impact the delivery, costs, and quality of patient care. Use of the fentanyl ITS may require fewer resources to address SREs and resulting analgesic gaps, including decreased time spent by nurses and other health care providers. Technological advances that reduce the staff time and resource consumption required for analgesic administration may be an important consideration in determining preferred analgesic modalities (17).
The fentanyl ITS may be limited by its lack of flexibility in dosing and may not appear suitable for opioid-sensitive or opioid-tolerant individuals. However, comparable safety and efficacy have been demonstrated in patients using the preprogrammed fentanyl ITS and morphine IV PCA, regardless of age or body mass index (12,13).
Our findings indicate that fentanyl ITS was associated with a significantly lower incidence of analgesic gaps that occurred as a result of SREs compared with morphine IV PCA, although fewer device malfunctions or failures occurred with morphine IV PCA. This could be a result of the manner in which device malfunctions or failures were classified in these studies, leading to the observed between-group difference. The incidence of IV line infiltrations and a low or dead battery in the morphine IV PCA group may also have been considered device malfunctions or failures but were not considered. One potential limitation of the analysis is that patients receiving fentanyl ITS may have been more closely monitored than those receiving morphine IV PCA, leading to a reduced incidence of SREs that led to an analgesic gap. However, this is highly unlikely, as the majority of SREs that led to an analgesic gap for fentanyl ITS were the result of device malfunction or failure, and it is unlikely that surveillance affected whether a system malfunctioned. It is possible that if patients receiving fentanyl ITS were more closely monitored, this may have resulted in quicker response times to SREs and shorter times required to resolve them. However, since the studies included in this analysis were conducted in a clinical trial setting, all study participants, regardless of treatment group, may have been more closely monitored than they would be in a typical clinical setting.
A pharmacoeconomic evaluation of the two modalities was beyond the scope of this analysis and, as a result, the cost implications of SREs cannot be determined. There may be a concern that replacement of a malfunctioning or failing fentanyl ITS may increase the cost of treatment compared with the cost for patients receiving morphine IV PCA. The overall costs resulting from SREs likely represent factors (i.e., the administrative costs of replacing a malfunctioning system) that were not examined in the two studies; therefore, cost implications cannot be extrapolated from the available data for fentanyl ITS and morphine IV PCA.
In summary, although both modalities are similarly safe and effective for postoperative pain management, findings from this analysis suggest that the fentanyl ITS may provide patients with access to more continuous pain relief compared with morphine IV PCA. Although data were not collected to perform a pharmacoeconomic assessment, such an assessment and a consideration of other health-related outcomes may be valuable in future studies and will help to further evaluate the utility of fentanyl ITS relative to other pain management therapies.
Footnotes
Accepted for publication June 20, 2007.
Supported by Ortho-McNeil, Inc. (Raritan, NJ).
Sunil Panchal received research funding from and is a consultant for Ortho-McNeil, Inc. C. V. Damaraju, David Hewitt, and Jeff Schein are employees of Ortho-McNeil Janssen Scientific Affairs, LLC. Winnie Nelson is a consultant for Ortho-McNeil Janssen Scientific Affairs, LLC.
REFERENCES
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