Orthopedics

Feature Article 

Patient-Controlled Transdermal Fentanyl Versus Intravenous Morphine Pump After Spine Surgery

Emily M. Lindley, PhD; Kenneth Milligan, BS; Ryan Farmer, MD; Evalina L. Burger, MD; Vikas V. Patel, MD

Abstract

Patient-controlled analgesia (PCA) is regularly used to manage pain following major surgery. The fentanyl hydrochloride iontophoretic transdermal system (ITS) was developed to overcome some of the limitations of intravenous (IV) PCA. The small, self-adhesive, needle-free disposable system is applied to the skin on the upper arm or chest and is controlled by patients clicking a button on the device. The authors identified patients who were underwent spinal surgery from 2 prior multicenter, randomized studies and analyzed their data. Of the 1296 patients in the original trials, 170 underwent spine surgery procedures: 90 were randomized to the fentanyl ITS (40 mcg/activation) and 80 to IV PCA morphine (1 mg/dose). More patients treated with the fentanyl ITS rated their method of pain control as “excellent” across all time points, but differences did not reach statistical significance. However, investigators’ ratings of “excellent” satisfaction with study treatment were significantly higher for the fentanyl ITS. Discontinuation rates and overall adverse event rates were similar between groups. The only significant difference was that patients treated with the fentanyl ITS had a higher rate of application site reactions than infusion site reactions in the IV PCA morphine group; the reactions were typically mild-to-moderate erythema that resolved shortly after removal of the fentanyl ITS device and did not require further treatment. Ratings of satisfaction with pain control method were consistently higher for the fentanyl ITS than the IV PCA morphine. The 2 groups had a similar safety profile. These results suggest that the fentanyl ITS appears to be a safe, efficacious alternative to IV PCA in spine surgery patients. [Orthopedics. 2015; 38(9):e819–e824.]

The authors are from the Department of Orthopedics, University of Colorado, Anschutz Medical Campus, Denver, Colorado.

The authors have no relevant financial relationships to disclose.

Dr Patel was not involved in the peer review of this manuscript.

Correspondence should be addressed to: Emily M. Lindley, PhD, Department of Orthopedics, University of Colorado, Anschutz Medical Campus, 13001 E 17th Pl, Mail Stop F432, Aurora, CO 80045 ( Emily.lindley@ucdenver.edu).

Received: September 30, 2014
Accepted: January 06, 2015

Abstract

Patient-controlled analgesia (PCA) is regularly used to manage pain following major surgery. The fentanyl hydrochloride iontophoretic transdermal system (ITS) was developed to overcome some of the limitations of intravenous (IV) PCA. The small, self-adhesive, needle-free disposable system is applied to the skin on the upper arm or chest and is controlled by patients clicking a button on the device. The authors identified patients who were underwent spinal surgery from 2 prior multicenter, randomized studies and analyzed their data. Of the 1296 patients in the original trials, 170 underwent spine surgery procedures: 90 were randomized to the fentanyl ITS (40 mcg/activation) and 80 to IV PCA morphine (1 mg/dose). More patients treated with the fentanyl ITS rated their method of pain control as “excellent” across all time points, but differences did not reach statistical significance. However, investigators’ ratings of “excellent” satisfaction with study treatment were significantly higher for the fentanyl ITS. Discontinuation rates and overall adverse event rates were similar between groups. The only significant difference was that patients treated with the fentanyl ITS had a higher rate of application site reactions than infusion site reactions in the IV PCA morphine group; the reactions were typically mild-to-moderate erythema that resolved shortly after removal of the fentanyl ITS device and did not require further treatment. Ratings of satisfaction with pain control method were consistently higher for the fentanyl ITS than the IV PCA morphine. The 2 groups had a similar safety profile. These results suggest that the fentanyl ITS appears to be a safe, efficacious alternative to IV PCA in spine surgery patients. [Orthopedics. 2015; 38(9):e819–e824.]

The authors are from the Department of Orthopedics, University of Colorado, Anschutz Medical Campus, Denver, Colorado.

The authors have no relevant financial relationships to disclose.

Dr Patel was not involved in the peer review of this manuscript.

Correspondence should be addressed to: Emily M. Lindley, PhD, Department of Orthopedics, University of Colorado, Anschutz Medical Campus, 13001 E 17th Pl, Mail Stop F432, Aurora, CO 80045 ( Emily.lindley@ucdenver.edu).

Received: September 30, 2014
Accepted: January 06, 2015

The effective management of postoperative pain is an essential component of perioperative patient care. Inadequate control of postoperative pain is not only a source of great anxiety for patients, but can also lead to delays in mobilization and discharge and can increase the risk for deep venous thrombosis, pneumonia, pulmonary embolism, poor wound healing, tachycardia, hypertension, and the development of chronic pain.1–6 Postoperative pain following spine surgery is primarily due to dissection of soft tissues and muscles at the surgery site. Surgical exposures typically disrupt highly innervated and dense muscle layers that then ultimately involve the periosteum, which contains nerves that possess a lower threshold for pain than other nerve fibers in this deep layer of tissue.7,8

Current standard of care for postoperative pain management of spine surgery patients typically includes systemic administration of opioids via intravenous (IV) patient-controlled analgesia (PCA) for 24 to 48 hours postoperatively, with subsequent conversion to oral opioids and nonsteroidal anti-inflammatory drugs (NSAIDs).

Patient-controlled analgesia was developed in the late 1960s and has become a widely used method of postoperative pain control with equivalent efficacy and greater patient satisfaction when compared with intramuscular, epidural, or oral pain control.9,10 Intravenous PCA allows patients to self-administer fixed doses of opioid analgesics as needed for pain control. Although IV PCA is a well-established perioperative pain management tool, it is not without disadvantages.

Although some limitations primarily involve inconvenience to patients and staff, such as mobility restrictions and preparation time, others include the potential for compromises in patient safety. For example, IV catheters can become clotted off or infiltrate into the subcutaneous tissue, both of which would typically require an additional venipuncture to reestablish patent IV access.11 In addition to catheter problems, pump failures and programming errors have also been reported.12

A recent national survey of PCA practices found a startling lack of consistency in adherence to safety procedures in hospitals across the country.14 Although 70% of PCA adverse events are attributable to errors associated with PCA pump use, such as programming incorrect drug doses and concentrations, or attachment problems,13 only 1 of 10 hospitals surveyed followed recommended double checks to verify correct PCA pump programming and dosages for patients.14 Such errors associated with PCA pump use have led to oversedation, and even death.15

To overcome some of the limitations and potential safety concerns associated with IV PCA analgesic administration, new pharmaceutical technologies have been developed in recent years. One such alternative analgesic delivery system is the fentanyl iontophoretic transdermal system (ITS). Fentanyl ITS is needle-free and administers a preprogrammed dose of 40-µg fentanyl via iontophoresis, a non-invasive process by which a 170-µA current propels ionized molecules across the skin barrier and into systemic circulation.16

Previous studies have showed comparable serum fentanyl concentrations between IV and ITS administration and found that demographic variables, such as age, sex, race, and body mass index, had no significant effect on serum concentrations.17 It is also worth noting that multiple-day administration of fentanyl ITS does not affect the pharmacokinetics of drug administration.18

The efficacy and safety of fentanyl ITS for postoperative pain management has been studied in several large active-controlled clinical trials in more than 1000 patients.19–22 However, these trials included patients from a variety of surgical specialties, such as those undergoing major abdominal, orthopedic, and thoracic surgery. Thus, the purpose of the current analysis is to specifically evaluate whether fentanyl ITS is as efficacious as IV PCA morphine in managing postoperative pain control in patients who have undergone spine surgery procedures.

Materials and Methods

Study Design

This was a retrospective review of data collected prospectively in 2 multicenter, randomized, open-label, active-controlled, phase lll studies.19,21 Patients who underwent any spine surgical procedure in these 2 studies were identified and their efficacy and safety data were used for analysis. The full methodological details of the studies have been previously reported.19,21

Briefly, surgical patients were enrolled in the study if they were scheduled to undergo general anesthesia and were anticipated to require at least 24 hours of postoperative parenteral opioids for analgesia. Patients were excluded if they received a long-lasting regional or spinal anesthetic intraoperatively or if they were expected to require long-term continuous regional anesthetics, convalescence in an intensive care unit, or additional surgery within 36 hours following the initial surgery. Patients were also excluded if they received opiates other than morphine, fentanyl, sufentanil, or alfentanil (50 mg of meperidine was allowed for shivering). Patients who were intubated or who had a skin disease that would prohibit placement of the fentanyl ITS patch were also excluded.

Patients were randomized in a 1:1 fashion, stratified by location, to receive either fentanyl ITS or IV PCA morphine. Because the studies were open-label, neither patients nor investigators were blinded to the study drug treatment.

Medication Dosing Regimens

Per common practice, postoperatively patients were first titrated to comfort, if needed, with bolus doses of opioids (morphine, fentanyl, sufentanil, alfentanil). Hour 0 of the study was considered the time of IV PCA or fentanyl ITS device attachment.

Fentanyl ITS is pre-programmed to release a 40-µg dose over a 10-minute period on activation. The system is activated by depressing a dosing button on the device twice within 3 seconds, at which time an audible beep indicates activation. The system is pre-programmed to deliver up to 6 doses per hour or 80 doses in total over 24 hours, whichever occurs first. This results in a maximum of 3.2 mg of fentanyl per 24 hours. The system turns off when 80 doses or 24 hours is reached and must be replaced with a new ITS device if additional opioid analgesia is needed.

Intravenous morphine PCA pumps were programmed to deliver an on-demand 1-mg bolus of morphine with a 5-minute lockout period. Patients were allowed a maximum of 10 on-demand doses in any 1-hour period, or a total of 240 doses in a 24-hour period, equating to a maximum of 240 mg of morphine per 24 hours.

Efficacy Analyses

Patient data were included in the efficacy analyses if the PCA device was enabled for at least 3 hours. The primary efficacy endpoint in both active-controlled studies was the proportion of patients who achieved successful pain management at 24 hours postoperatively, as assessed using the Patient Global Assessment (PGA) of pain control. Participants were read the following question aloud: “Overall, would you rate this method of pain control during the last 24 hours as being poor, fair, good, or excellent?” Success was defined as a response of “good” or “excellent.” Assessments were also performed at the 48- and 72-hour timepoints for patients who remained in the study.

Other efficacy endpoints included the proportion of patients who reported “excellent” pain management on the PGA at each assessment, and patient self-reported pain intensity scores using either the visual analog scale (VAS) or numerical rating scale (NRS). Investigator global assessments of pain control were also performed at 24, 48, and 72 hours using the same PGA scale (poor, fair, good, or excellent).

For the VAS, participants marked the intensity of their pain by drawing a line perpendicular to a 100-mm scale, with 0 mm equating to “no pain” and 100 mm equating to the “worst possible pain.” For the NRS, participants rated their pain on a scale of 0 to 10, with 0 being “no pain” and 10 being the “worst possible pain.” To allow for a comparison of pain intensity across the 2 clinical trials, VAS scores were converted to a 10-point scale by dividing the VAS score by 10.

Safety Analyses

Data from all randomized spine surgery patients in the 2 studies were included in the safety analyses. Adverse events were recorded and categorized according to the MedDRA system classification and included any systemic event that led to an interruption in analgesia administration. Opioid-related adverse events included tachycardia, ileus, nausea, vomiting, constipation, somnolence, confusional state, urinary retention, dyspnea, hypoventilation, hypoxia, pruritus, and hypotension.

Statistical Analyses

Analyses presented in the current article were performed post hoc on the pooled subgroup of patients who had spinal surgeries in the 2 previously reported studies comparing fentanyl ITS to morphine IV PCA.19,21 Descriptive statistics were summarized for continuous variables. Frequencies and percentages were presented for categorical variables, such as PGA of pain control. Comparisons of the continuous variables were performed using t test; categorical variables were compared using Fisher’s exact test.

Results

Of the 1296 patients included in the original trials, 170 underwent spine surgery procedures. Of these spine surgery patients, 90 were randomized to the fentanyl ITS group and 80 were randomized to the IV PCA morphine group. The 2 groups were similar in age and sex. Mean age was 52.8 years (±13.66 years) and 49.9 years (±15.71 years) for fentanyl ITS and IV PCA morphine patients, respectively. Both groups also had a similar ratio of men to women, with 41 men and 49 women in the fentanyl ITS group and 37 men and 43 women in the IV PCA morphine group. The majority of patients in both groups completed the study (71.1% vs 78.8% for fentanyl ITS and IV PCA morphine, respectively).

The results of patient and investigator global assessments of pain control are provided in Table 1 and Table 2. Among all patients (N=170) included in this study, 87 in the fentanyl ITS group and 80 in the IV PCA morphine group had complete data for efficacy evaluation. Patients rated their pain control methods similarly across the 2 analgesic groups; no significant differences were found between the percentages of patients in the fentanyl ITS and IV PCA morphine groups who rated their pain control method as “excellent” or “excellent or good.” However, when comparing investigators’ ratings of pain control, significantly more rated fentanyl ITS as “excellent” at the final assessment as compared to IV PCA morphine (P<.01).

Global Assessment of Pain Control Method: Rated as “Excellent or Good”

Table 1:

Global Assessment of Pain Control Method: Rated as “Excellent or Good”

Global Assessment of Pain Control Method: Rated as “Excellent”

Table 2:

Global Assessment of Pain Control Method: Rated as “Excellent”

Other secondary outcome measures are shown in Table 3. Mean pain intensity scores were similar between the fentanyl ITS and IV PCA morphine groups, as were rates of rescue medication administration and early withdrawal from the study.

Secondary Outcome Measures

Table 3:

Secondary Outcome Measures

Adverse events are presented in Table 4. Overall, 74.4% of the fentanyl ITS group and 77.5% of the IV PCA morphine group experienced an adverse event (P=.721). The most common adverse event for both the fentanyl ITS and IV PCA morphine groups was nausea (37.8% vs 47.5%; P=.217) followed by vomiting (17.8% vs 15%; P=.682) and headache (13.3% vs 7.5%; P=.318). Opioid-specific adverse event rates were similar between the 2 analgesic groups (54.4% for fentanyl ITS vs 63.8% for IV PCA morphine; P=.275). The only significant differences in adverse events between the 2 groups were the rate of application site erythema (27.8% for fentanyl ITS vs 0% IV PCA morphine; P<.0001) and application site pruritus (6.7% for fentanyl ITS vs 0% for IV PCA morphine; P=.030). The reactions were typically mild to moderate with spontaneous resolution.

Adverse Events in >2% of PatientsAdverse Events in >2% of Patients

Table 4:

Adverse Events in >2% of Patients

Discussion

In the current analyses, the authors evaluated the use of fentanyl ITS for postoperative pain management in spine surgery patients from 2 phase III pivotal clinical trials. Included patients were from 2 prior prospective multi-site randomized clinical trials of patients undergoing major surgical procedures. These clinical trials compared the efficacy and safety of fentanyl ITS to that of IV PCA morphine.19,21 Although the results of the 2 clinical trials demonstrated the noninferiority of fentanyl ITS to the current gold standard, the patient population included in the trials was heterogeneous and the studies did not take into account the potential for different pain management needs among surgical groups. Thus, the purpose of the current analysis was to specifically determine whether fentanyl ITS is an appropriate alternative to IV PCA morphine in spine surgery postoperative care.

Regarding the primary outcome measure, the authors found that fentanyl ITS was as therapeutically effective as IV PCA morphine in helping patients achieve “excellent” or “good” pain control after spine surgery. In fact, a higher percentage of fentanyl ITS patients rated their method of pain control as “excellent” at all postoperative assessment time points (26.4% vs 22.5%, 28.7% vs 16.3%, 13.8% vs 7.5%, and 37.9% vs 26.3%, respectively), but the differences did not reach statistical significance. Investigators also assessed the method of pain control used in their patients, and significantly more rated fentanyl ITS as “excellent” than they did those taking IV PCA morphine.

Other secondary outcomes were also comparable between the fentanyl ITS and IV PCA morphine groups. Final patient assessments of pain intensity were similar, with both groups reporting a mean pain score of 3.2. The majority of fentanyl ITS patients did not require additional rescue medications, and the rates of rescue medications given were not different from those of patients treated with IV PCA morphine (19.5% and 17.5%, respectively). Withdrawal rates were also similar between groups, with most patients remaining in the study for the entire postoperative treatment period (71.1% fentanyl ITS and 78.8% IV PCA morphine).

When comparing the safety profiles of fentanyl ITS and IV PCA morphine, the overall rate of adverse events was similar between the 2 groups. Regardless of treatment method, the most commonly reported adverse events were those typically associated with opioid administration, such as nausea, vomiting, and headache. Other opioid-related adverse events, such as confusion, ileus, and hypotension, were low in both groups and not statistically different. Respiratory function was a primary safety outcome in the 2 original clinical trials. In the spine surgery population evaluated in the current analyses, the incidence of hypoventilation was low, with 1 case in the fentanyl ITS group and 2 in the IV PCA morphine group. The only significant difference seen between the groups with respect to adverse events was a higher rate of application site reactions in the fentanyl ITS patients. These reactions were typically mild to moderate at the site where the ITS device was placed on the skin. The reactions resolved shortly after removal of the ITS device and did not require further treatment. As described earlier, ITS devices must be replaced after 24 hours of use, or 80 administered doses. The new system should be applied to a different skin site to avoid local site reactions.

The current analysis is limited by the open design and lack of placebo and blinding in the original clinical trials. However, prior randomized, blinded, placebo-controlled clinical trials have shown the superiority of fentanyl ITS for pain control as compared to a control ITS device that did not deliver fentanyl.23 Another limitation of the clinical trials is the fact that not all participating hospitals used the same IV PCA morphine settings due to varying regulations and procedures in different countries. On the other hand, this limitation makes the studies more comparable to real-world uses of PCA in clinical practice. The ITS device itself can also been seen as limited by its lack of programming flexibility. However, this is also one of the primary advantages of the system because it eliminates the potential for programming errors and dosing mistakes.

Conclusion

Overall, the efficacy and safety results seen in spine surgery patients in the current study are consistent with the previous findings of phase III trials that showed fentanyl ITS to be superior to placebo23,24 and equally efficacious as IV PCA morphine.20–22 This analysis adds to the literature by demonstrating that fentanyl ITS is an appropriate and safe option for postoperative pain control management of spine surgery patients. The fentanyl ITS system provides at least equivalent efficacy for postoperative pain control without the limitations of PCA use. Specifically, the ITS does not require (1) any programming, (2) any mixing/preparation of medications, (3) any motorized equipment that could fail, (4) any separate power source, (5) any IV access or venipuncture, or (6) any IV tubing. These factors make the ITS dramatically less time-consuming for nursing and pharmacy staff and allow for increased postoperative freedom of the spine surgery patients. Thus, it has the potential to reduce cost, reduce resource utilization, and improve patient satisfaction while providing effective postoperative analgesia.

References

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Global Assessment of Pain Control Method: Rated as “Excellent or Good”

Postsurgery TimeNo. (%)
Pa
Fentanyl ITS (n=87)IV PCA Morphine (n=80)
Patient assessment: 24 h59 (67.8)60 (75.0).4396
Patient assessment: 48 h52 (59.8)39 (48.8).1526
Patient assessment: 72 h26 (29.9)23 (28.8).6796
Patient: final assessment63 (72.4)61 (76.3).7875
Investigator: final assessment67 (77.0)62 (77.5)1.000

Global Assessment of Pain Control Method: Rated as “Excellent”

Postsurgery TimeNo. (%)
Pa
Fentanyl ITS (n=87)IV PCA Morphine (n=80)
Patient assessment: 24 h23 (26.4)18 (22.5).3550
Patient assessment: 48 h25 (28.7)13 (16.3).0909
Patient assessment: 72 h12 (13.8)6 (7.5).4094
Patient: final assessment33 (37.9)21 (26.3).1374
Investigator: final assessment38 (43.7)18 (22.5).0123

Secondary Outcome Measures

Outcome MeasureFentanyl ITS (n=87)IV PCA Morphine (n=80)Pa
Mean Final Pain Intensity Rating, 0–10 scale3.23.2.9485
Rescue medication given, No. (%)17 (19.5)14 (17.5).8427

Adverse Events in >2% of Patients

EventNo. (%)
Pa
Fentanyl ITS (n=90)IV PCA Morphine (n=80)
Any AE reported67 (74.4)62 (77.5).721
Opioid-related AEb49 (54.4)51 (63.8).2745
MedDRA system organ class
  Eye disorders
    Diplopia02 (2.5).220
  Gastrointestinal disorders
    Abdominal pain2 (2.2)3 (3.8).667
    Constipation6 (6.7)4 (5.0).751
    Flatulence2 (2.2)1 (1.3)1.000
    Nausea34 (37.8)38 (47.5).217
    Vomiting16 (17.8)12 (15.0).682
General disorders and administration site conditions
  Application site erythema25 (27.8)0<.0001
  Application site edema3 (3.3)0.248
  Application site pruritus6 (6.7)0.030
  Application site vesicles2 (2.2)0.499
  Chest pain02 (2.5).220
  Injection site inflammation02 (2.5).220
  Injection site reaction03 (3.8).102
  Pain2 (2.2)1 (1.3)1.000
  Pyrexia8 (8.9)8 (10.0)1.000
Infections and infestations
  Pharyngitis5 (5.6)2 (2.5).449
Nervous system disorders
  Dizziness2 (2.2)4 (5.0).422
  Headache12 (13.3)6 (7.5).318
  Hypertonia2 (2.2)0.499
  Paresthesia2 (2.2)3 (3.8).667
  Somnolence3 (3.3)2 (2.5)1.000
  Tremor2 (2.2)0.499
Psychiatric disorders
  Anxiety3 (3.3)3 (3.8)1.000
  Confusional state3 (3.3)2 (2.5)1.000
Renal and urinary disorders
  Urinary retention2 (2.2)4 (5.0).4219
Respiratory, thoracic, and mediastinal disorders
  Dyspnea2 (2.2)1 (1.3)1.000
  Hypoventilation1 (1.1)2 (2.5).602
  Hypoxia2 (2.2)2 (2.5)1.000
Skin and subcutaneous tissue disorders
  Pruritus4 (4.4)7 (8.8).352
Vascular disorders
  Hypotension2 (2.2)2 (2.5)1.000

10.3928/01477447-20150902-61

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