Patient-Controlled Transdermal Fentanyl vs IV Morphine
Patient-Controlled Transdermal Fentanyl vs IV Morphine
Patient-controlled analgesia (PCA) with intravenous morphine is commonly used to control moderate-to-severe postoperative pain. The US FDA recently approved a transdermal system for patient-controlled iontophoretic delivery of fentanyl as an alternative treatment. Aside from the route of administration, other differences between these systems may result in differing adverse-effect profiles. This review compares the clinical utility of these two modalities. MEDLINE, Cinahl and Google Scholar searches for clinical trials (1982 through to July 2007) were performed. Search terms included transdermal analgesia, iontophoresis, patient-controlled analgesia, IONSYS™ and E-TRANS. All trials comparing intravenous morphine PCA with the transdermal iontophoretic fentanyl system (fentanyl ITS) were included. CONSORT diagrams and adverse-event frequencies were available in all cases. Results demonstrated that fentanyl ITS and intravenous PCA morphine are equally effective analgesics for the management of acute postoperative pain. Fentanyl ITS is associated with fewer treatment failures due to adverse events (p=0.046), less pruritus (p=0.001) and less somnolence (p=0.055). Intravenous PCA morphine is associated with fewer treatment failures due to inadequate analgesia (p=0.001). It was concluded that fentanyl ITS is an equally safe and effective alternative to intravenous PCA morphine. Advantages favoring fentanyl ITS include convenience and ease-of-care.
Patient-controlled intravenous (iv.) delivery of opioids has often been considered the gold standard for management of acute postoperative pain. Patient-controlled analgesia (PCA) allows the patient to self-administer small aliquots of analgesic medication, usually an opioid, as required (after an analgesic state has been initially established) to control their pain. In 2006, the US FDA approved a novel, transdermal delivery system for patient-controlled administration of fentanyl (IONSYS™; Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ, USA) for the management of postoperative pain in hospitalized patients. Although the product is not yet available on the market, a number of reviews have already been published.
A needleless system, without a bulky external pump, may avoid a number of the limitations associated with iv. PCA use. The need to maintain an iv. line, interrupt therapy for administration of other medications through the iv. line, program the PCA pump, or maintain the pump itself are all obviated. The potential pharmacoeconomic advantages in eliminating the PCA pump have not yet been fully investigated. Moreover, enhanced safety through the avoidance of programming errors is another area that has not yet been defined. However, patient satisfaction, improved function and ease-of-care are areas of interest where some data do exist.
The rapid delivery of a drug across intact skin is accomplished using iontophoresis. In iontophoresis, a small, imperceptible current is applied to generate an electric field to drive the ionized drug through the dermis. The positively charged drug is repulsed from the drug reservoir at the anode, but is also transported by electro-osmotic bulk flow of the solvent. With the transdermal iontophoretic fentanyl system (fentanyl ITS), a current density of 62µA/cm is generated by a 3V lithium battery. Each successful activation of the system results in the active transport of approximately 40 µg of fentanyl (44.4 µg fentanyl HCl). The amount of fentanyl absorbed following activation is only 40% of the dose delivered in the first hour of system use, but reaches full effect at 10h. Therefore, as with iv. PCA administered opioid and other methods for maintenance of analgesia, prior to initiating therapy adequate analgesia must first be established with bolus loading doses. Supplemental rescue analgesia should also be provided as required, especially in the first hours of treatment. Importantly, with the current density employed by this system, the dose of fentanyl delivered is directly proportional to the current applied (170 µA). Consequently, unlike passive transdermal fentanyl patches, no clinically significant amount of drug is delivered unless the system is activated; nor is there a significant subcutaneous reservoir of drug after discontinuation of the system.
IONSYS is a small self-contained system that is attached directly to the chest or upper outer arm for consistent and effective absorption and easy patient access. The system is affixed to an area of bare, intact, clean, dry skin (hair may be clipped but should not be shaved). Should the adhesive fail to establish skin contact properly, the system will not function since the circuit required to establish the electric field will not be completed. Unlike the typical iv. PCA pump apparatus, this system is not programmable and is not capable of providing a basal infusion. As such, it is ideally used in opioid-naive patients, where standard dosing is likely to be effective. The patient must press the button twice within a 3s period in order to activate the system, thus minimizing accidental drug delivery.
A fixed dose of fentanyl 40µg is delivered following activation over the 10min lock-out period. Following activation, a brief audible tone is produced and a light-emitting diode (LED) illuminates continuously during drug delivery. The system is effective for 80 doses or 24h, whichever comes first. If the system becomes dislodged, losing effective skin contact and therefore the required electrical circuit, the LED will flash and a longer (20s) tone will be emitted. Unlike typical iv. PCA pumps, the system cannot be easily queried for delivery history. However, pressing the button only once results in a single flash for each five successful drug deliveries giving a rough approximation of opioid use. As with all opioids, proper drug accountability and disposal are required. For disposal the system separates into two components: the electronics (with battery) and the drug reservoir (residual fentanyl).
Two large, placebo-controlled, clinical trials with fentanyl ITS document efficacy. The first was a randomized, double-blinded, placebo-controlled trial in 205 post-operative subjects following intra-abdominal, intrathoracic and major orthopedic surgery. Subjects were randomized to receive active versus placebo treatment in a 3:1 ratio. Significantly more placebo patients withdrew due to inadequate pain control. These findings were confirmed in a second randomized, double-blinded, placebo-controlled trial in a similar population of 484 subjects. Importantly, this second study used an active to placebo ratio of 1:1 and controlled for pain levels at the time of randomization. To date, no double-blind, double-dummy trial has been performed to control for the novelty of the new system, however, several open-label trials have been performed comparing the system with iv. PCA morphine.
Viscusi etal. performed the first randomized trial comparing fentanyl ITS with iv. PCA morphine. Subjects were randomized in a 1:1 ratio (n=636). The primary efficacy variable was the patient global assessment (PGA) of the method of pain control (poor, fair, good or excellent) over the first 24 h following intra-abdominal, intrathoracic and major orthopedic surgery. The majority of patients in both groups rated their pain control as good or excellent (fentanyl ITS: 73.7%; intravenous morphine: 76.9%). The between-treatment difference in good/excellent scores was -3.2% (95% confidence interval [CI]: -9.9-3.5%; p=0.36) satisfying the apriori definition of equivalence. However, a minimum pain intensity was not required for study entry, suggesting that some subjects may not have had adequate pain control when the maintenance procedures were established and the study initiated.
In a second large randomized trial, Hartrick etal. addressed uniformity of pain stimulus at randomization and into the post-operative period in 799 subjects following primary, unilateral total hip arthroplasty. As in the aforementioned comparison study, randomization was performed in a 1:1 ratio and the primary efficacy outcome measure of success were good or excellent ratings on the PGA at 24 h. PGA success rates were 83% for fentanyl ITS and 82.2% in the iv. morphine group. The between-group difference was 0.9% (95% CI: -4.4-6.1%) which again met the a priori definition of equivalence. A higher percentage of subjects reported excellent PGA scores in the fentanyl ITS group at 24h (50.9 vs 35.9%).
A third randomized trial by Grond et al. compared fentanyl ITS with iv. PCA morphine in 660 subjects. While the study population included both major abdominal and major orthopedic surgical patients, similar findings were reported. Randomization in a 1:1 ratio resulted in PGA success ratings at 24h (good to excellent) of 86.2% for fentanyl ITS and 87.5% for iv. PCA morphine. The between-group difference of -1.3% (95% CI: -6.5-3.9%) was not significant. Finally, Minkowitz etal. performed a fourth randomized comparison (1:1 ratio) of fentanyl ITS to iv. PCA morphine in 506 subjects following major abdominal or pelvic surgery. PGA ratings of success at 24h were 84.9 and 84.3% for fentanyl ITS and iv. morphine, respectively. Once again, the predefined criterion for equivalency was satisfied with a between-group difference of 0.7% (95%CI:-5.6-7.0%). A higher percentage of subjects reported excellent PGA scores at 24 h in the fentanyl ITS group (50 vs 40.2%; p=0.039).
In both aforementioned placebo-controlled trials, the administration of fentanyl ITS resulted in side effects that are typically seen with opioid analgesia. Nausea and pruritus were increased over placebo in two studies, while vomiting was increased over placebo in only one study. However, despite direct comparison in over 2500 subjects, differences in tolerability between fentanyl ITS and iv. PCA morphine with regard to adverse events (AE) are not yet clear. The purpose of this review is to further define any differences that may exist by combining available studies using a meta-analysis approach.
Patient-controlled analgesia (PCA) with intravenous morphine is commonly used to control moderate-to-severe postoperative pain. The US FDA recently approved a transdermal system for patient-controlled iontophoretic delivery of fentanyl as an alternative treatment. Aside from the route of administration, other differences between these systems may result in differing adverse-effect profiles. This review compares the clinical utility of these two modalities. MEDLINE, Cinahl and Google Scholar searches for clinical trials (1982 through to July 2007) were performed. Search terms included transdermal analgesia, iontophoresis, patient-controlled analgesia, IONSYS™ and E-TRANS. All trials comparing intravenous morphine PCA with the transdermal iontophoretic fentanyl system (fentanyl ITS) were included. CONSORT diagrams and adverse-event frequencies were available in all cases. Results demonstrated that fentanyl ITS and intravenous PCA morphine are equally effective analgesics for the management of acute postoperative pain. Fentanyl ITS is associated with fewer treatment failures due to adverse events (p=0.046), less pruritus (p=0.001) and less somnolence (p=0.055). Intravenous PCA morphine is associated with fewer treatment failures due to inadequate analgesia (p=0.001). It was concluded that fentanyl ITS is an equally safe and effective alternative to intravenous PCA morphine. Advantages favoring fentanyl ITS include convenience and ease-of-care.
Patient-controlled intravenous (iv.) delivery of opioids has often been considered the gold standard for management of acute postoperative pain. Patient-controlled analgesia (PCA) allows the patient to self-administer small aliquots of analgesic medication, usually an opioid, as required (after an analgesic state has been initially established) to control their pain. In 2006, the US FDA approved a novel, transdermal delivery system for patient-controlled administration of fentanyl (IONSYS™; Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ, USA) for the management of postoperative pain in hospitalized patients. Although the product is not yet available on the market, a number of reviews have already been published.
A needleless system, without a bulky external pump, may avoid a number of the limitations associated with iv. PCA use. The need to maintain an iv. line, interrupt therapy for administration of other medications through the iv. line, program the PCA pump, or maintain the pump itself are all obviated. The potential pharmacoeconomic advantages in eliminating the PCA pump have not yet been fully investigated. Moreover, enhanced safety through the avoidance of programming errors is another area that has not yet been defined. However, patient satisfaction, improved function and ease-of-care are areas of interest where some data do exist.
The rapid delivery of a drug across intact skin is accomplished using iontophoresis. In iontophoresis, a small, imperceptible current is applied to generate an electric field to drive the ionized drug through the dermis. The positively charged drug is repulsed from the drug reservoir at the anode, but is also transported by electro-osmotic bulk flow of the solvent. With the transdermal iontophoretic fentanyl system (fentanyl ITS), a current density of 62µA/cm is generated by a 3V lithium battery. Each successful activation of the system results in the active transport of approximately 40 µg of fentanyl (44.4 µg fentanyl HCl). The amount of fentanyl absorbed following activation is only 40% of the dose delivered in the first hour of system use, but reaches full effect at 10h. Therefore, as with iv. PCA administered opioid and other methods for maintenance of analgesia, prior to initiating therapy adequate analgesia must first be established with bolus loading doses. Supplemental rescue analgesia should also be provided as required, especially in the first hours of treatment. Importantly, with the current density employed by this system, the dose of fentanyl delivered is directly proportional to the current applied (170 µA). Consequently, unlike passive transdermal fentanyl patches, no clinically significant amount of drug is delivered unless the system is activated; nor is there a significant subcutaneous reservoir of drug after discontinuation of the system.
IONSYS is a small self-contained system that is attached directly to the chest or upper outer arm for consistent and effective absorption and easy patient access. The system is affixed to an area of bare, intact, clean, dry skin (hair may be clipped but should not be shaved). Should the adhesive fail to establish skin contact properly, the system will not function since the circuit required to establish the electric field will not be completed. Unlike the typical iv. PCA pump apparatus, this system is not programmable and is not capable of providing a basal infusion. As such, it is ideally used in opioid-naive patients, where standard dosing is likely to be effective. The patient must press the button twice within a 3s period in order to activate the system, thus minimizing accidental drug delivery.
A fixed dose of fentanyl 40µg is delivered following activation over the 10min lock-out period. Following activation, a brief audible tone is produced and a light-emitting diode (LED) illuminates continuously during drug delivery. The system is effective for 80 doses or 24h, whichever comes first. If the system becomes dislodged, losing effective skin contact and therefore the required electrical circuit, the LED will flash and a longer (20s) tone will be emitted. Unlike typical iv. PCA pumps, the system cannot be easily queried for delivery history. However, pressing the button only once results in a single flash for each five successful drug deliveries giving a rough approximation of opioid use. As with all opioids, proper drug accountability and disposal are required. For disposal the system separates into two components: the electronics (with battery) and the drug reservoir (residual fentanyl).
Two large, placebo-controlled, clinical trials with fentanyl ITS document efficacy. The first was a randomized, double-blinded, placebo-controlled trial in 205 post-operative subjects following intra-abdominal, intrathoracic and major orthopedic surgery. Subjects were randomized to receive active versus placebo treatment in a 3:1 ratio. Significantly more placebo patients withdrew due to inadequate pain control. These findings were confirmed in a second randomized, double-blinded, placebo-controlled trial in a similar population of 484 subjects. Importantly, this second study used an active to placebo ratio of 1:1 and controlled for pain levels at the time of randomization. To date, no double-blind, double-dummy trial has been performed to control for the novelty of the new system, however, several open-label trials have been performed comparing the system with iv. PCA morphine.
Viscusi etal. performed the first randomized trial comparing fentanyl ITS with iv. PCA morphine. Subjects were randomized in a 1:1 ratio (n=636). The primary efficacy variable was the patient global assessment (PGA) of the method of pain control (poor, fair, good or excellent) over the first 24 h following intra-abdominal, intrathoracic and major orthopedic surgery. The majority of patients in both groups rated their pain control as good or excellent (fentanyl ITS: 73.7%; intravenous morphine: 76.9%). The between-treatment difference in good/excellent scores was -3.2% (95% confidence interval [CI]: -9.9-3.5%; p=0.36) satisfying the apriori definition of equivalence. However, a minimum pain intensity was not required for study entry, suggesting that some subjects may not have had adequate pain control when the maintenance procedures were established and the study initiated.
In a second large randomized trial, Hartrick etal. addressed uniformity of pain stimulus at randomization and into the post-operative period in 799 subjects following primary, unilateral total hip arthroplasty. As in the aforementioned comparison study, randomization was performed in a 1:1 ratio and the primary efficacy outcome measure of success were good or excellent ratings on the PGA at 24 h. PGA success rates were 83% for fentanyl ITS and 82.2% in the iv. morphine group. The between-group difference was 0.9% (95% CI: -4.4-6.1%) which again met the a priori definition of equivalence. A higher percentage of subjects reported excellent PGA scores in the fentanyl ITS group at 24h (50.9 vs 35.9%).
A third randomized trial by Grond et al. compared fentanyl ITS with iv. PCA morphine in 660 subjects. While the study population included both major abdominal and major orthopedic surgical patients, similar findings were reported. Randomization in a 1:1 ratio resulted in PGA success ratings at 24h (good to excellent) of 86.2% for fentanyl ITS and 87.5% for iv. PCA morphine. The between-group difference of -1.3% (95% CI: -6.5-3.9%) was not significant. Finally, Minkowitz etal. performed a fourth randomized comparison (1:1 ratio) of fentanyl ITS to iv. PCA morphine in 506 subjects following major abdominal or pelvic surgery. PGA ratings of success at 24h were 84.9 and 84.3% for fentanyl ITS and iv. morphine, respectively. Once again, the predefined criterion for equivalency was satisfied with a between-group difference of 0.7% (95%CI:-5.6-7.0%). A higher percentage of subjects reported excellent PGA scores at 24 h in the fentanyl ITS group (50 vs 40.2%; p=0.039).
In both aforementioned placebo-controlled trials, the administration of fentanyl ITS resulted in side effects that are typically seen with opioid analgesia. Nausea and pruritus were increased over placebo in two studies, while vomiting was increased over placebo in only one study. However, despite direct comparison in over 2500 subjects, differences in tolerability between fentanyl ITS and iv. PCA morphine with regard to adverse events (AE) are not yet clear. The purpose of this review is to further define any differences that may exist by combining available studies using a meta-analysis approach.