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PA I N M E D I C I N E

Volume 8

•

Number 8

•

2007

Blackwell Publishing IncMalden, USAPMEPain Medicine1526-23752006 Blackwell Publishing Ltd? 200788657668Original Article

Efficacy and Safety of Fentanyl ITSMinkowitz et al.

Reprint requests to:

Harold S. Minkowitz, MD, Department of Anesthesiology, Memorial Hermann Memorial City Hospital, 921 Gessner Rd, Houston, TX 77024, USA. Tel: 713-932-3436; Fax: 713-242-3664; E-mail: [email protected]. The current multicenter study was conducted at 39 cen- ters, which are listed, along with the principal investigator at each center, in Appendix 1.

Efficacy and Safety of the Fentanyl Iontophoretic Transdermal System (ITS) and Intravenous Patient-Controlled Analgesia (IV PCA) with Morphine for Pain Management Following Abdominal or Pelvic Surgery

Harold S. Minkowitz, MD,* James P. Rathmell, MD,

†

Sue Vallow, RPh, MBA, MA,

‡

Kathryn Gargiulo, RN, MPA,

C. V. Damaraju, PhD,

and David J. Hewitt, MD

*Department of Anesthesiology, Memorial Hermann Memorial City Hospital, Houston, Texas;

†

Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;

‡

Outcomes Research and Primary Care, Ortho-McNeil Janssen Scientific Affairs, LLC, Titusville, New Jersey;

Medical Affairs, Ortho-McNeil,

A B S T R A C T

Inc., Raritan, New Jersey;

Biostatistics, Ortho-McNeil Janssen Scientific Affairs, LLC, Raritan, New Jersey, USA

ABSTRACT

Objective.

The fentanyl HCl iontophoretic transdermal system (ITS) has effectively managed pain following several types of surgery. This study evaluated the efficacy, safety, and ease of care associated with fentanyl ITS and morphine intravenous patient-controlled analgesia (IV PCA) for pain management following abdominal or pelvic surgery.

Design.

This open-label, multicenter, randomized, active-controlled, parallel-group, phase IIIb study enrolled 506 postoperative patients at 39 U.S. sites. Patients received fentanyl ITS (40

g fentanyl/dose) or morphine IV PCA (1 mg morphine/dose). The primary efficacy measure was demonstrating equivalence on the patient global assessment (PGA) of the method of pain control in the first 24 hours of treatment between the groups.

Results.

Percentages of patients in the fentanyl ITS and morphine IV PCA groups reporting PGA ratings of “good” or “excellent” in the first 24 hours were statistically equivalent (84.9% vs 84.3%, respectively; difference

0.7%, 95% CI:

−

5.6% to 7.0%). Equivalence was also demonstrated based on mean last pain intensity scores in the first 24 hours (3.0 vs 2.9, respectively; difference

0.1, 95% CI:

−

0.28 to 0.43). Overall discontinuation rates were not significantly different between groups (16.7% vs 11.8%, respectively;

0.128). Patients and nurses reported better ease-of-care ratings for fentanyl ITS than for morphine IV PCA. Commonly occurring adverse events were similar between groups.

Conclusions.

Fentanyl ITS and morphine IV PCA were comparable methods of pain control fol- lowing abdominal or pelvic surgery; however, fentanyl ITS was rated better than morphine IV PCA for ease of care by patients and nurses.

Key Words

. Pain Management; Fentanyl ITS; Postoperative; Acute Pain

Introduction

ver the past two decades, considerable efforts to improve the treatment of postoperative

pain have led to the development and implemen- tation of pain management guidelines [1–4] and the establishment of acute pain services in numer- ous hospitals [5,6]. However, results of recent studies indicate that postoperative pain remains inadequately managed [7–9].

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Minkowitz et al.

Patient-controlled analgesia (PCA) using the intravenous (IV) route is commonly used to manage acute, moderate-to-severe pain following major surgery. IV PCA allows patients to self- administer small fixed doses of analgesic (e.g., morphine) according to their individual require- ments for pain relief. In addition, use of IV PCA avoids the adverse events associated with peaks in serum opioid concentrations and severe pain asso- ciated with troughs in serum opioid concen- trations that may occur with intermittent administration of large bolus doses. Patient satis- faction is high with the PCA approach, and studies have shown that patients prefer IV PCA to con- ventional intramuscular or IV bolus-dosing strat- egies [10,11].

A novel PCA therapy that utilizes fentanyl has been developed to address limitations associated with PCA administered via the IV route, including programming errors, mobility restrictions, and risk of needlestick injuries. The fentanyl HCl iontophoretic transdermal system (fentanyl ITS; IONSYS

™

, Ortho-McNeil, Inc., Raritan, NJ) is a needle-free, self-contained, patient-controlled analgesic delivery system. The compact system is applied to a patient’s upper outer arm or chest, reducing constraints on patient mobility. The fen- tanyl ITS administers a preprogrammed dose (40

g) of fentanyl via iontophoresis, a noninva- sive process by which ionized drug molecules are driven across intact skin using a low-intensity elec- trical field [12]. Sathyan and colleagues [13] dem- onstrated that delivery of a 40-

g fentanyl dose from the fentanyl ITS resulted in a mean C

max

of 1.954

g/L and a mean absorption of 39.5

g fen- tanyl per 10-minute dose delivery period. Similar mean half-lives (11.0 vs 12.6 hours) have been cal- culated for fentanyl (40

g) administered intrave- nously vs fentanyl delivered using fentanyl ITS, respectively [13]. In addition, serum concentra- tions of fentanyl administered via these routes decrease at similar rates [13], suggesting that use of the fentanyl ITS does not result in a fentanyl depot in the skin. Further, fentanyl does not induce histamine release and has no active or toxic metabolites [14,15].

A previous study of patients who underwent a variety of major surgical procedures demonstrated that the fentanyl ITS was comparable as a method of pain control to morphine IV PCA [16]. The current study included additional measures that assessed therapeutic elements beyond pain con- trol, including the ease of use/care and satisfaction with the method of pain control from the perspec-

tives of patients and nurses. This study was also designed to demonstrate the safety and efficacy of fentanyl ITS in the treatment of postoperative pain following two specific types of surgery, abdominal and pelvic surgery. These patients were considered to represent a more homogeneous sur- gical population than previously studied and were expected to share a similar postoperative pain experience.

Methods

Patients

Patients were screened both pre- and postopera- tively for participation in this study. Patients were initially screened for eligibility up to 3 weeks prior to enrollment, during which time patients pro- vided their medical history, underwent a physical examination, signed an informed consent form, and received preoperative education on both the fentanyl ITS and morphine IV PCA. Patients who were eligible for study participation were

≥

18 years of age; American Society of Anesthesi- ologists physical status I, II, or III; scheduled to undergo elective abdominal or pelvic surgery; expected to require

≥

24 hours of hospitalization after surgery; and expected to experience moder- ate-to-severe postoperative pain.

A second screening was performed in the post- anesthesia care unit following surgery. Eligible patients were titrated to comfort using intermit- tent IV bolus doses of opioids (morphine, hy- dromorphone, fentanyl, sufentanil, or alfentanil). Patients were included if they were awake, alert, breathing spontaneously with a respiratory rate of 8–24 breaths per minute and an oxygen saturation (SpO

) of

≥

90%, were comfortable for

≥

30 minutes in the postanesthesia care unit, and had attained a pain score of

≤

4 (numerical rating scale [NRS], 0

no pain to 10

worst possible pain). Patients were excluded if they were known to be opioid- tolerant or met any

Diagnostic and Statistical Man- ual of Mental Disorders IV

(DSM-IV-TR™) criteria for substance dependence [17]. Opioid tolerance was defined as taking any dose of strong opioids (e.g., fentanyl, morphine, hydromorphone) or short-acting opioid or combination of short- acting opioids greater than codeine 120 mg daily, hydrocodone 40 mg daily, tramadol 200 mg daily, or oxycodone 40 mg daily for 4 consecutive days prior to surgery. Patients who had active skin dis- ease, were expected to receive postoperative anal- gesia supplied by a continuous regional technique, were expected to require intensive care postoper-

Efficacy and Safety of Fentanyl ITS

659

atively, would likely require additional surgical procedures within 72 hours, or were intubated at the time of final screening were excluded. Patients were also excluded if they had received long-acting intraoperative spinal anesthesia (other than bupi- vacaine without epinephrine) or epidural anes- thesia, local anesthetics in the surgical area, nonsteroidal anti-inflammatory drugs preopera- tively or postoperatively, or opioids other than morphine, hydromorphone, fentanyl, sufentanil, or alfentanil. Patients who satisfied these require- ments were assigned a five-digit identification number; the first two digits represented the inves- tigator at the site, and the last three digits were assigned in ascending sequential order according to the time of enrollment. Patients were random- ized (1:1) to receive the fentanyl ITS or morphine IV PCA based on their five-digit identification number using a centralized, computer-generated randomization schedule that was prepared before initiation of the study; patients were not random- ized 1:1 at each study site.

Patients were considered enrolled upon ran- domization. Hour 0 was the time of application of the fentanyl ITS or attachment and enabling of the morphine IV PCA pump. Supplemental anal- gesia with IV fentanyl (fentanyl ITS group) or IV morphine (morphine IV PCA group) was available during the first 3 hours following initiation of treatment; patients in both treatment groups could receive either IV fentanyl or IV morphine if the appropriate analgesic for the assigned treatment group was unavailable. Patients who requested supplemental analgesia

3 hours after enrollment were withdrawn from the study due to inadequate analgesia.

Study Design

This open-label, randomized, multicenter, active- controlled, parallel-group phase IIIb study was conducted from May 18, 2004, to April 11, 2005, at 39 sites in the United States. Study protocols were approved by the institutional review board at each study site.

The fentanyl ITS delivered a fixed dose of fen- tanyl (40

g) over a period of 10 minutes upon patient activation. The system is preprogrammed to deliver up to 6 doses per hour for up to 24 hours or a maximum of 80 doses, whichever occurs first. The fentanyl ITS is activated and an audible beep occurs when the patient double-clicks the recessed, on-demand dosing button. A red light from a light-emitting diode remains illuminated during the 10-minute dose delivery period, during

which time additional doses of fentanyl cannot be administered. The cumulative number of doses administered by each system may be estimated by the number of light flashes that appear following administration of a dose.

IV PCA pumps were programmed to deliver a 1-mg bolus dose of morphine, with a 5-minute lockout interval between doses. A maximum of 10 doses was available per hour for up to 24 hours, for an overall maximum of 240 doses (240 mg/ 24 hours). Due to differences in hospital policies or PCA pump limitations, approximately half of the sites were granted exemptions to use a 6- minute lockout interval.

Efficacy Assessments

The primary efficacy measure was ratings of suc- cess (“good” or “excellent”) on the patient global assessment (PGA) of the method of pain control in the first 24 hours (4-point categorical scale [“excellent,” “good,” “fair,” or “poor”]). To per- form this assessment, a member of the investiga- tor’s staff read aloud the following question to the patient: “Overall, would you rate this method of pain control during the last 24 hours as being excellent, good, fair, or poor?” The PGA was per- formed at the 24-, 48-, and 72-hour time points for patients who remained in the study or upon early termination.

Equivalence between groups was also deter- mined based on the mean last pain intensity scores in the first 24 hours. Pain intensity was measured on the NRS. A member of the investigator’s staff read aloud the following question to the patient: “On a scale from 0 to 10, where 0 means no pain and 10 means the worst possible pain, rate the pain that you have now.” A baseline pain assessment was performed at hour 0 and repeated at hours 0.5, 1, 2, 3, 4, 6, and 8 and every 4 hours thereafter throughout the remainder of the study or upon early termination. Sleeping patients were not awakened, and no pain intensity score was recorded at those time points. Additional efficacy measures included the percentage of patients who withdrew early from the study, the percentage of patients who required supplemental analgesia dur- ing the first 3 hours of the study, and the number of supplemental analgesic doses of IV fentanyl and IV morphine that were administered to patients. In addition, the mean number of doses of analgesic that were activated by the patient in the first 6, 12, and 24 hours was also noted; the number of on- demand doses administered by the fentanyl ITS was estimated using the following equation: esti-

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Minkowitz et al.

mated number of doses

number of light flashes)

−

2. A validated Patient Ease-of-Care Question-

naire, developed to evaluate the ease of use and satisfaction with patient-controlled therapies for the management of postoperative pain [18], was completed by patients after 72 hours or upon dis- continuation of study medication. The question- naire included 28 items, grouped according to the following subscales: Confidence with Device, Comfort with Device, Movement, Dosing Confi- dence, Pain Control, Knowledge/Understanding of the Device, and Satisfaction. All items in the Patient Ease-of-Care Questionnaire, except Satis- faction items, were scored on a 6-point Likert scale, which ranged from 0

“not at all” to 5

“a very great deal.” The Overall Patient Ease-of- Care score was calculated as the mean of scores on the subscales, excluding Satisfaction. Higher scores on all Patient Ease-of-Care subscales indi- cated more favorable results.

Validated Nurse Ease-of-Care Questionnaires, developed to evaluate the ease of care and satisfac- tion with patient-controlled therapies for postop- erative pain management [19], were completed by nurses following the completion of

≥

10 patients or when all patients completed the study at their respective sites. The Nurse Ease-of-Care Ques- tionnaire included subscales that assessed satisfac- tion and the time-efficiency and convenience of patient-care tasks due to the device. The Overall Nurse Ease-of-Care score was calculated using the mean of scores on the scales that assessed time- efficiency and convenience: items in these sub- scales were rated on a 6-point Likert scale, from 0

“not at all” to 5

“a very great deal,” with a lower value indicating greater ease of care.

Safety Assessments

Throughout the study, adverse events and system- related events, defined as problems related to the analgesic system that must be addressed by health care providers (e.g., device malfunction or failure, patient could not locate button, infiltration of the IV line, air in line, low battery, and IV line inad- vertently pulled out), that led to an interruption in pain control or the use of health care resources, were recorded as they occurred. An analgesic gap was defined as an interruption in the method of pain control that resulted in a period of time dur- ing which analgesia was not available. System- related events that led to an interruption in pain control were noted on the system-related events checklist, along with information pertaining to

whether the system-related event resulted in an analgesic gap.

Vital signs and oxygen saturation levels were recorded at 0.5, 1, 2, 3, 4, 6, and 8 hours and every 4 hours thereafter until 72 hours of treatment or patient withdrawal from the study. Respiratory function was assessed as the primary measure of systemic safety. Patients were monitored for clin- ically relevant respiratory depression (defined as respiratory rate

8 breaths per minute and exces- sive sedation). If the patient was asleep, the respi- ratory rate, heart rate, oxygen saturation, and number of on-demand doses delivered were recorded. Sleeping patients with a respiratory rate of

8 breaths per minute were awakened and assessed for excessive sedation. In addition, Ram- say Sedation Scale scores were recorded 8 hours after enrollment and every 8 hours thereafter until 72 hours or upon early termination [20].

Statistical Analyses

All analyses were performed based on the intent- to-treat (ITT) population, which included all patients randomized to receive study medication. Randomized patients who received at least 3 hours of treatment with either modality comprised the evaluable-for-efficacy population. The entire ITT population was used for analyses of efficacy and safety endpoints to include patients who discon- tinued the study prior to the 3-hour time point. For patients who withdrew early, a PGA, a pain intensity score, and any adverse events were recorded upon withdrawal and were included in efficacy and safety analyses for the ITT popula- tion. The sample size for this study was deter- mined based on the primary efficacy endpoint of difference in success rates between the treatment groups for the PGA assessed at 24 hours and was calculated to achieve a power of 80%, while con- trolling the Type 1 error rate at

0.05 using a two-sided 95% confidence interval (CI) procedure with an equivalence margin of

0.10. The suc- cess rate,

0.83 based on results of previous studies, was assumed to be equal in both random- ized treatment groups. Based on these assump- tions, the sample size required per group was approximately 250, taking into account that some patients would discontinue before receiving treat- ment for 3 hours and would not be included in the evaluable-for-efficacy population.

Between-group differences in patient charac- teristics were analyzed using

anova

with treat- ment as a factor for continuous variables and an uncorrected chi-square test or Fisher’s exact test

Efficacy and Safety of Fentanyl ITS

661

for categorical variables, where appropriate. Anal- ysis of the primary efficacy measure involved the construction of a two-sided 95% CI for the differ- ence in the percentages of PGA successes (ratings of “good” or “excellent”) in the first 24 hours between the fentanyl ITS and morphine IV PCA groups. The two treatments were considered equivalent methods of pain control if the two- sided 95% CI for the difference in the percent- ages of PGA successes fell within

10%. For patients who withdrew from the study or com- pleted the study prior to the 24-hour time point, PGA ratings that were recorded at the time of discontinuation were used to calculate the PGA in the first 24 hours. If no data were available, a rat- ing of “poor” on the PGA was assumed for statis- tical analyses; a rating of “fair” or “poor” was classified as a failure. The percentages of PGA success ratings were also analyzed across patient subpopulations, including age (

65 vs

≥

65 years), body mass index (BMI;

25, 25–29, 30–39, and

≥

40 kg/m

), and surgery type (abdominal or pelvic).

Equivalence was also determined for the sec- ondary efficacy measure of pain intensity in the first 24 hours, which required that the two-sided 95% CI for the difference between treatment groups in the 24-hour mean pain intensity scores was within

1.0. Between-group differences in mean pain intensity scores recorded during the first 12 hours were analyzed using

anova

with treatment as a factor. An uncorrected chi-square test was used to evaluate between-group differ- ences in the percentages of patients who required supplemental analgesia. Differences in the number of supplemental analgesic doses that were admin- istered to patients in each treatment group were evaluated using a general linear model with treat- ment as a factor. Between-group differences in PGA ratings of excellent, patient withdrawals from the study, the number of patients with inter- ruptions in pain control due to a system-related

event, the incidence of adverse events, and the incidence of treatment-related adverse events were analyzed using a Fisher’s exact test. No adjustment (to significance level) was applied for multiplicity of comparisons made. Between-group differences in the Ease-of-Care Questionnaires were evaluated using a two-sample

-test (patients) or a mixed-model approach (nurses who had expe- rience with one or both modalities), in which the treatment and type of nurse (staff nurse, research nurse, or study coordinator) were fixed effects, and the individual nurse who completed the Ease- of-Care Questionnaire was considered a random effect. Further, to summarize the ordinal res- ponses for the multiple items in each subscale, the respondents were dichotomized based on a strict requirement of consistent responses across all items of a subscale, thus dividing respondents into two broad categories: 1) responder: a respondent who responded with the top 3 responses of the Likert scale on all items of a subscale; and 2) non- responder: a respondent who did not respond with the top 3 responses of the Likert scale on at least one item of a subscale. Therefore, patients who reported a “3,” “4,” or “5” for all items included in the mean Overall Ease-of-Care were classified as responders, while nurses who reported a “0,” “1,” or “2” for all items included in the mean Overall Ease-of-Care were responders.

Results

A total of 506 patients were enrolled and random- ized to receive the fentanyl ITS (n

252) or mor- phine IV PCA (n

254) for postoperative pain management (Figure 1). Patient characteristics were similar at baseline between the treatment groups (Table 1). Patients were predominantly female, Caucasian, and

65 years of age, with a mean age of 50.3 years. The mean BMI was sim- ilar between the groups, and pelvic surgery was the most common procedure.

Figure 1

Flow of patients through the open-label, randomized, active-con- trolled trial. This diagram accounts for the flow of patients through the study, including the number of patients who were randomized and received treat- ment, as well as those who withdrew from the study or completed the study. ITS

iontophoretic transdermal sys- tem; IV PCA

intravenous patient- controlled analgesia.

210 Completed study 167 No further need for parenteral opioid 36 Completed 72 hours of treatment 7 Discharged from hospital

224 Completed study 184 No further need for parenteral opioid 32 Completed 72 hours of treatment 8 Discharged from hospital

42 Discontinued study 23 Inadequate analgesia 14 Adverse event 4 Withdrawal of consent 1 Other

252 Received the fentanyl ITS (intent-to-treat population) 254 Received morphine IV PCA (intent-to-treat population)

30 Discontinued study 7 Inadequate analgesia 19 Adverse event 1 Protocol violation 1 Withdrawal of consent 2 Other

506 Randomized

662

Minkowitz et al.

There was no statistical difference in the overall withdrawal rate between the fentanyl ITS and morphine IV PCA treatment groups (16.7% vs 11.8%,

0.128; Table 2). A higher percentage of patients in the fentanyl ITS group vs morphine IV PCA group discontinued treatment due to inadequate analgesia (9.1% vs 2.8%, respectively;

0.002). Similar percentages of patients in the fentanyl ITS and morphine IV PCA groups with- drew from the study due to an adverse event (5.6% vs 7.5%, respectively;

0.472). A larger propor- tion (43.5%) of patients in the fentanyl ITS group who discontinued due to inadequate analgesia dis- continued between 3 and 12 hours of treatment, compared with 28.6% of patients who received morphine IV PCA and discontinued due to inad- equate analgesia during this time.

Efficacy

The fentanyl ITS and morphine IV PCA were equivalent methods of pain control, based on the

primary efficacy measure of the percentages of patients who reported a rating of success on the PGA of the method of pain control in the first 24 hours (84.9% vs 84.3%, respectively; difference

0.7%, 95% CI:

−

5.6% to 7.0%) (Figure 2). A higher percentage of patients in the fentanyl ITS group than in the morphine IV PCA group reported a PGA rating of “excellent” (50.0% vs 40.2%, respectively;

0.039) in the

Table 1

Baseline characteristics and patient demographics

Fentanyl ITS (n

252) Morphine IV PCA (n

254) Total (N

506)

value*

Sex, n (%) Female 212 (84.1) 213 (83.9) 425 (84.0) 0.934 Male 40 (15.9) 41 (16.1) 81 (16.0)

Age (years), mean (SEM) 50.2 (0.9) 50.4 (0.9) 50.3 (0.6) 0.875

65, n (%) 206 (81.7) 208 (81.9) 414 (81.8) 0.967

≥

65, n (%) 46 (18.3) 46 (18.1) 92 (18.2) Ethnicity, n (%)

Caucasian 187 (74.2) 188 (74.0) 375 (74.1) 0.943 Black 48 (19.0) 48 (18.9) 96 (19.0) Hispanic 13 (5.2) 16 (6.3) 29 (5.7) Asian 2 (0.8) 1 (0.4) 3 (0.6) Other 2 (0.8) 1 (0.4) 3 (0.6)

BMI (kg/m

), mean (SEM) 29.3 (0.5) 29.6 (0.4) 29.4 (0.3) 0.606 Surgery type, n (%)

Pelvic 159 (63.1) 173 (68.1) 332 (65.6) 0.813 Abdominal 93 (36.9) 81 (31.9) 174 (34.4)

* P value was calculated using ANOVA with treatment as a factor for continuous variables and an uncorrected chi-square test for categorical variables. Fisher’s exact test was used to analyze the between-group difference in ethnicity. ITS = iontophoretic transdermal system; IV PCA = intravenous patient-controlled analgesia; SEM = standard error of the mean; BMI = body mass index.

Table 2 Reasons for withdrawal from the study

Fentanyl ITS (n = 252) n (%)

Morphine IV PCA (n = 254) n (%) P value*

Discontinued prematurely 42 (16.7) 30 (11.8) 0.128 Inadequate analgesia 23 (9.1) 7 (2.8) 0.002 Adverse event 14 (5.6) 19 (7.5) 0.472 Protocol violation 0 (0.0) 1 (0.4) 1.00 Withdrawal of consent 4 (1.6) 1 (0.4) 0.215 Other 1 (0.4) 2 (0.8) 1.00

* P values were calculated using a Fisher’s exact test. ITS = iontophoretic transdermal system; IV PCA = intravenous patient- controlled analgesia.

Figure 2 Ratings of success on the PGA of the method of pain control in the first 24 hours of treatment. The primary efficacy endpoint in this study was the percentage of patients who reported ratings of success (“good” or “excel- lent”) on the PGA of the method of pain control in the first 24 hours of treatment. The assessment consisted of a cat- egorical evaluation, in which the method of pain control (fentanyl ITS or morphine IV PCA) was rated as “excellent,” “good,” “fair,” or “poor.” The distribution of categorical responses of “good” or “excellent” for intent-to-treat patients in each treatment group is presented. Difference = 0.7%, 95% CI: −5.6% to 7.0%; P = 0.835. ITS = iontophoretic transdermal system; IV PCA = intravenous patient- controlled analgesia; PGA = patient global assessment.

100

Pe rc

en ta

ge o

f p at

ie nt

Fentanyl ITS Morphine IV PCA

84.9 84.3

34.9 Good

50.0 Excellent 40.2

Excellent

44.1 Good

Efficacy and Safety of Fentanyl ITS 663

first 24 hours (Figure 2). Similar percentages of patients in the fentanyl ITS and morphine IV PCA treatment groups reported a PGA rating of failure (“fair,” 10.7% vs 12.2%, respectively; “poor,” 4.0% vs 2.4%, respectively).

The fentanyl ITS and morphine IV PCA were comparable methods of pain control across several patient subpopulations. For patients <65 years of age, a similar PGA rating of success was reported for the fentanyl ITS vs morphine IV PCA treat- ment groups (83.5% vs 85.1%, respectively; difference = −2.8%, 95% CI: −9.8% to 4.1%), while 91.3% of patients who were ≥65 years of age reported a PGA rating of success for the fentanyl ITS, compared with 80.4% of patients who received morphine IV PCA (difference = 12.9%, 95% CI: −0.7% to 26.5%).

Patients in each BMI group (i.e., <25, 25–29, 30–39, and ≥40 kg/m2) provided comparable 24- hour PGA ratings for the two modalities (Table 3). The percentages of patients who underwent abdominal surgery and reported a PGA rating of success for the fentanyl ITS or morphine IV PCA were 79.6% vs 84.0%, respectively (difference = −4.6%, 95% CI: −15.8% to 6.7%), while 88.1% vs 84.4% of patients who underwent pelvic sur- gery reported a PGA rating of success for the fentanyl ITS vs morphine IV PCA, respectively (difference = 2.7%, 95% CI: −4.6% to 10.0%). A higher percentage of patients in the fentanyl ITS group than in the morphine IV PCA group reported a PGA rating of success at 48 hours

(91.3% vs 85.3%, respectively) and 72 hours (98.4% vs 87.5%, respectively).

Patients reported similar pain intensity scores at treatment initiation in the fentanyl ITS and morphine IV PCA groups (3.5 vs 3.6, respectively). Equivalence was demonstrated for the mean last pain intensity scores in the first 24 hours (3.0 vs 2.9; difference = 0.1, 95% CI: −0.28 to 0.43) for the fentanyl ITS vs morphine IV PCA groups, respectively. Comparable pain intensity scores were also recorded at the last observation during the 72-hour study period (2.6 vs 2.5; difference = 0.1, 95% CI: −0.27 to 0.47) and at 12-hour time points throughout the study for patients who received the fentanyl ITS or mor- phine IV PCA, respectively (Figure 3). Mean pain intensity scores during the first 12 hours of the study (recorded at up to 9 time points), with the exception of scores recorded at hour 3 (P = 0.018), were also comparable.

More patients in the fentanyl ITS vs morphine IV PCA group received supplemental analgesia in the first 3 hours of treatment (20.6% vs 12.2%, respectively; P = 0.011); the mean number of sup- plemental analgesic doses of IV fentanyl (2.3 vs 1.5, respectively; P = 0.492) and IV morphine (2.3 vs 1.8, respectively; P = 0.264) per patient was sim- ilar between groups. The mean number of on- demand doses administered during the first 6 hours (11.9 vs 14.5), 12 hours (20.4 vs 22.8), and 24 hours (35.0 vs 39.2) was also similar for patients

Table 3 Patient global assessment of the method of pain control by body mass index group in the first 24 hours

Fentanyl ITS (n = 252) n (%)

Morphine IV PCA (n = 254) n (%) 95% CI (Difference)

<25 kg/m2 Success 67 (82.7) 61 (82.4) −11.7% to 12.2% (0.3%) Failure 13 (16.0) 13 (17.6) Missing 1 (1.2) 0 (0.0)

25–29 kg/m2

Success 68 (88.3) 61 (79.2) −2.5% to 20.7% (9.1%) Failure 9 (11.7) 14 (18.2) Missing 0 (0.0) 2 (2.6)

30–39 kg/m2

Success 59 (85.5) 44 (91.7) −16.4% to 4.0% (6.2%) Failure 10 (14.5) 7 (8.3) Missing 0 (0.0) 0 (0.0)

≥40 kg/m2 Success 20 (80.0) 15 (78.9) −11.7% to 12.2% (0.3%) Failure 5 (20.0) 3 (15.8) Missing 0 (0.0) 1 (5.3)

ITS = iontophoretic transdermal system; IV PCA = intravenous patient- controlled analgesia; CI = confidence interval.

Figure 3 Pain intensity scores reported during the study. Pain intensity was scored on a numerical rating scale (NRS) from 0 = no pain to 10 = worst possible pain. Mean pain intensity scores are shown for hour 0 (initiation of treatment) and for each 12-hour time point postenrollment, up to 72 hours (study completion), for intent-to-treat patients in the fentanyl ITS vs morphine IV PCA groups. Error bars represent the standard error of the mean. The number of patients in each treatment group who reported pain in- tensity scores at the indicated time points is given. ITS = iontophoretic transdermal system; IV PCA = intravenous patient-controlled analgesia.

251 251

38 31

82 52

76 67

195 193

180 192

4.0

Pa in

in te

ns ity

(N R

S, 0

–1 0) Fentanyl ITS

Morphine IV PCA3.0

2.0

1.0

Hours of treatment

Fentanyl ITS, n Morphine IV PCA, n

664 Minkowitz et al.

who received the fentanyl ITS or morphine IV PCA, respectively.

Ease of Care Patients who received the fentanyl ITS reported significantly higher (better) mean Overall Ease-of- Care scores than patients who received morphine IV PCA (4.47 vs 4.18, respectively; P < 0.001). A higher percentage of patients who received the fentanyl ITS were responders for Overall Ease-of- Care compared with patients who received mor- phine IV PCA (41.5% vs 28.9%, respectively; P = 0.004). In addition, a greater proportion of patients who received the fentanyl ITS were responders for the Movement subscale compared with patients in the morphine IV PCA treatment group (96.7% vs 74.7%, respectively; P < 0.001). Nurses reported lower (better) mean Overall Ease-of-Care scores with the fentanyl ITS com- pared with morphine IV PCA (0.47 vs 1.09, respectively; P < 0.001). A significantly higher percentage of nurses who cared for patients with the fentanyl ITS were responders for Overall Ease-of-Care compared with nurses who cared for patients with morphine IV PCA (83.5% vs 55.9%, respectively; P < 0.001).

Safety The most commonly reported adverse events were nausea (48.0% vs 44.1%, P = 0.422), head- ache (16.7% vs 10.6%, P = 0.053), fever (14.3% vs 11.0%, P = 0.287), pruritus (7.9% vs 13.8%, P = 0.045), and vomiting (12.7% vs 9.8%, P = 0.328) for the fentanyl ITS and morphine IV PCA treatment groups, respectively (Table 4). The percentage of patients who experienced at least one treatment-related adverse event was similar between patients who received fentanyl ITS vs morphine IV PCA (77.4% vs 72.4%, respectively; P = 0.219). No significant between- group differences were observed for patients who experienced adverse events relevant to the use of opioids, including cardiovascular system (8.3% vs 8.7%, P = 1.00), nervous system (11.5% vs 8.3%, P = 0.236), respiratory system (7.5% vs 12.2%, P = 0.101), or urogenital system-related adverse events (3.2% vs 6.7%, P = 0.099) during treat- ment with the fentanyl ITS vs morphine IV PCA, respectively. Treatment-related adverse events (≥5%) were nausea (41.7% vs 39.4%, P = 0.651), headache (13.9% vs 9.1%, P = 0.095), vomiting (11.9% vs 9.1%, P = 0.313), and pruri- tus (7.1% vs 12.6%, P = 0.052) in the fentanyl ITS and morphine IV PCA treatment groups,

respectively. Application-site reactions, reported in 14.7% of patients treated with the fentanyl ITS, were mild-to-moderate in severity and resolved without specific treatment. IV insertion- site reactions were reported in 1.6% of patients who received morphine IV PCA. No cases of clinically relevant respiratory depression were reported in the fentanyl ITS group, while one case was reported in the morphine IV PCA group following 7.3 hours of treatment. A similar percentage of patients with two or more consecu- tive vital signs out of the normal range and in the same direction was noted, with 1.6% and 2.4% of patients with low or high pulse in the fentanyl ITS and morphine IV PCA treatment groups, respectively.

The percentage of patients with ≥1 system- related event related to study medication and the method of pain control was similar for patients in the fentanyl ITS vs morphine IV PCA groups (21.4% vs 22.0%, respectively). However, fewer patients who received the fentanyl ITS experi- enced an interruption in pain control resulting in an analgesic gap as a result of a system-related event compared with patients who received mor- phine IV PCA (6.0% vs 12.6%, respectively; P = 0.014).

Table 4 Reported adverse events (≥2%)

Adverse event

Fentanyl ITS (n = 252) n (%)

Morphine IV PCA (n = 254) n (%)

Nausea 121 (48.0) 112 (44.1) Headache 42 (16.7) 27 (10.6) Fever 36 (14.3) 28 (11.0) Pruritus 20 (7.9) 35 (13.8) Vomiting 32 (12.7) 25 (9.8) Application-site reaction—erythema 24 (9.5) 0 (0.0) Application-site reaction—itching 14 (5.6) 0 (0.0) Dizziness 13 (5.2) 11 (4.3) Back pain 13 (5.2) 7 (2.8) Anemia 3 (1.2) 12 (4.7) Abdominal pain 11 (4.4) 4 (1.6) Urinary retention 4 (1.6) 9 (3.5) Pharyngitis 3 (1.2) 9 (3.5) Tachycardia 2 (0.8) 9 (3.5) Insomnia 8 (3.2) 4 (1.6) Hypoxia 4 (1.6) 8 (3.1) Dyspepsia 7 (2.8) 1 (0.4) Application-site reaction—vesicles 7 (2.8) 0 (0.0) Hypertension 5 (2.0) 6 (2.4) Ileus 6 (2.4) 3 (1.2) Oliguria 1 (0.4) 6 (2.4) Hypotension 5 (2.0) 5 (2.0) Constipation 5 (2.0) 3 (1.2) Hypoventilation 3 (1.2) 5 (2.0)

ITS = iontophoretic transdermal system; IV PCA = intravenous patient- controlled analgesia.

Efficacy and Safety of Fentanyl ITS 665

Discussion

The fentanyl ITS was effective in managing acute postoperative pain following pelvic or abdominal surgery and was demonstrated to be a statistically equivalent method of pain control when compared with a standard dosing regimen of morphine IV PCA based on results of the last PGA in the first 24 hours. In addition, more patients in the fenta- nyl ITS treatment group rated the method of pain control as “excellent” compared with ratings of patients in the morphine IV PCA group. The results of the current study support clinical effi- cacy findings that were previously observed in a study of postoperative pain management with the fentanyl ITS or morphine IV PCA in a large pop- ulation of patients who had undergone a diverse range of surgical procedures [16]. Equivalence, based on analgesic efficacy, between these two sys- tems was also suggested based on last pain inten- sity scores in the first 24 hours. Results also suggest that the fentanyl ITS had certain advan- tages, based on fewer analgesic gaps due to sys- tem-related events, and improved ease of care compared with morphine IV PCA.

Results of Patient and Nurse Ease-of-Care Questionnaires suggested greater ease of use and ease of patient care, respectively, with the fentanyl ITS compared with morphine IV PCA. In addi- tion, the higher proportion of patient and nurse responders for Overall Ease-of-Care in the fenta- nyl ITS treatment group provides further support for the greater ease of use and/or ease of care afforded by this modality. The higher percentage of patient responders on the Movement subscale of the Patient Ease-of-Care Questionnaire for the fentanyl ITS compared with morphine IV PCA suggested that the compact size and simplicity of the fentanyl ITS may reduce restrictions to patient movement that commonly occur with IV PCA.

The current findings also support the accept- able safety profile documented in previous placebo- and active-controlled trials evaluating the fentanyl ITS [16,21,22]. The most frequently reported adverse events were those commonly associated with opioid administration (i.e., nausea, vomiting, pruritus) [11] and were similar between the treatment groups. Patients in the fentanyl ITS treatment group had a significantly lower inci- dence of pruritus compared with patients who received morphine IV PCA, which may be a result of morphine-induced histamine release [14]. Application-site reactions reported for the fenta- nyl ITS treatment group, including erythema,

itching, vesicles, and edema, were generally mild- to-moderate in severity and resolved without spe- cific treatment. The low incidence of IV insertion- site reactions for patients who received morphine IV PCA may be a result of underreporting of ecchymosis, because this side effect is commonly observed for patients with IV lines. Importantly, there were no incidents of clinically relevant res- piratory depression (<8 breaths per minute and excessive sedation) in patients treated with the fen- tanyl ITS in the current study, which is consistent with results of previous controlled trials (N = 714) [16,21,22].

Results from the current study suggest that the fentanyl ITS is appropriate, safe, and effective for the management of acute postoperative pain in a wide range of postsurgical patient populations. Patients across age subgroups (<65 and ≥65 years of age) and BMI subgroups reported comparable PGA ratings between treatment groups in the first 24 hours. These results further support previous conclusions that the system may be safe and appropriate for postoperative pain management across a wide range of patient ages. The system also appears to provide effective analgesia among patients of varying BMI. Because the population of morbidly obese patients (BMI ≥ 40 kg/m2) in this study is relatively small, further investigation of the efficacy of the fentanyl ITS in this popula- tion is warranted.

A higher percentage of patients in both treat- ment groups rated their method of pain control as a success compared with success rates reported in the previous active-controlled trial (73.7% [fenta- nyl ITS] vs 76.9% [morphine IV PCA]) [16]. This may be due to an important difference in the design of the current study, namely, the require- ment for patients to have a pain intensity score of ≤4 on a scale of 0–10 prior to study enrollment, which was not specified in the previously con- ducted, active-controlled trial [16]. This inclusion criterion ensured that patients were titrated to comfort prior to study enrollment, allowing a comparison of the modalities’ ability to maintain analgesia. Compared with previous studies, lower overall rates of discontinuation and lower rates of discontinuation due to inadequate analgesia were observed [16,22,23]. Together, these results emphasize the importance of establishing patient comfort prior to the initiation of PCA.

Mean pain intensity scores recorded at frequent time points, such as those recorded during the first 12 hours of the study, are difficult to compare, especially in isolation. For instance, the significant

666 Minkowitz et al.

difference observed at the single time point at hour 3 in this study may be due to the discontin- uation of supplemental analgesia at hour 3 or patient withdrawals from the study between the hour 2 and hour 3 time points and is therefore of doubtful clinical relevance. A more valid compar- ison of pain intensity scores over the duration of the study suggests that there are no meaningful between-group differences.

A higher percentage of patients who received fentanyl ITS in the current study discontinued due to inadequate analgesia compared with patients who received morphine IV PCA. The reason for this difference is unclear but may be due to the design of the study, even though other endpoints (e.g., PGA and pain intensity) suggest that fenta- nyl ITS and morphine IV PCA are comparable methods of pain control. Patients in the fentanyl ITS group were aware that they were using a novel analgesic delivery system and may have been influ- enced by the recognition that they would be switched to the standard therapy of morphine IV PCA if they discontinued fentanyl ITS. Subjects receiving morphine IV PCA may have felt more comfortable with their method of pain control, as they knew they were receiving standard therapy, which may have resulted in patient bias toward morphine IV PCA. This view is supported by the observation that patients in the fentanyl ITS treat- ment group who discontinued due to inadequate analgesia did so early (between 3 and 12 hours). Patients who received fentanyl ITS also did not take as many doses as were available to them and took fewer total doses during the first 24 hours than patients receiving morphine IV PCA. The exclusion of supplemental analgesia following the initial 3-hour treatment period, as well as the exclusion of multimodal therapy, which is com- monly used for postoperative pain management, may have artificially increased discontinuations due to inadequate analgesia in both groups. None- theless, 24-hour PGA success ratings were equiv- alent, overall rates of discontinuation were not statistically different between the treatment groups, and pain intensity scores were comparable at all time points during the study (Figure 3).

Despite numerous benefits, some safety and practical limitations are related to IV PCA use. For example, the requirement for manual pro- gramming of the PCA pump by members of the hospital staff introduces the risk of overdose due to programming errors, which have resulted in excessive sedation and death in some cases [24,25]. In addition, IV PCA introduces the risk of needle-

related complications for patients and health care providers. Patient mobility may also be restricted, because the patient is tethered by IV tubing, an IV pole, and the PCA pump apparatus. Morphine, the most commonly used analgesic for IV PCA, induces histamine release [14], which contributes to the development of pruritus and is metabolized to morphine-6-glucuronide, which may accumu- late in patients with renal dysfunction [15].

The fentanyl ITS gives patients the ability to control their pain, providing efficacy similar to that of a standard regimen of morphine IV PCA. In contrast to morphine IV PCA, the fentanyl ITS is preprogrammed, thus eliminating the danger of errors in PCA infusion pump programming and/ or drug preparation that may occur [24,26]. Because the fentanyl ITS is needle-free, it reduces the risk of staff needle injury, by which bloodborne infections may be transmitted to patients, as well as to members of the clinical staff [27]. Further, results of both Patient and Nurse Ease-of-Care Questionnaires suggest that patients and nurses are more satisfied with pain management with the fentanyl ITS. The simplicity of the fentanyl ITS system may help explain the fact that fewer patients experienced analgesic gaps associated with system-related events compared with patients who received morphine IV PCA. These results demonstrate that the fentanyl ITS is an effective and safe method of pain control that is similar to a standard regimen of morphine IV PCA but less invasive and with potentially important advantages for the management of acute postoperative pain.

Acknowledgments

Ortho-McNeil, Inc. (Raritan, New Jersey) supported this study in its entirety.

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Appendix 1

Oscar A. Aguirre, MD, Rose Medical Center, Denver, CO; Shireen Ahmad, MD, Prentice Women’s Hospital, Chicago, IL; Jolene Bean- Lijewski, MD, Scott and White Memorial Hospi- tal and Clinic, Temple, TX; Alex Bekker, MD, PhD, NYU Medical Center, New York, NY; Christine Brody, MD, Tri City Medical Center, Oceanside, CA; Donald C. Carmichael, MD, Cit- rus Memorial Hospital, Inverness, FL; Ralph L. Corsetti, MD, Tulane University Medical Center, New Orleans, LA; Robert D’Angelo, MD, For-

668 Minkowitz et al.

syth Medical Center–Sara Lee Center for Women’s Health, Winston Salem, NC; Scott E. Eder, MD, Capital Health System at Mercer, Trenton, NJ; James W. Fleshman, MD, Barnes Jewish Hospital BJC, Inc., St. Louis, MO; T. J. Gan, MD, Duke University Medical Center, Durham, NC; Irwin Gratz, DO, The Cooper Health System, Camden, NJ; Neil Hyman, MD, Fletcher Allen Health Care, Burlington, VT; Joel O. Johnson, MD, PhD, Columbia Regional Hos- pital and University of Missouri Health Care, Columbia, MO; R. Kevin Jones, MD, Saddleback Memorial Medical Center, Laguna Hills, CA; Daniel Katz, MD, South Coast Medical Center, Laguna Beach, CA; Robert Kauffman, MD, Northwest Texas Healthcare System, Amarillo, TX; Samia Khalil, MD, Memorial Hermann Hos- pital, Houston, TX; David A. Krusch, MD, Uni- versity of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY; Bruce J. Levine, MD, Virtua Memorial Hospital, Mt. Holly, NJ; Emmy Lu, MD, The Stamford Hospi- tal, Stamford, CT; Timothy I. Melson, MD, Helen Keller Hospital, Sheffield, AL; Harold

Minkowitz, MD, Memorial Hermann Memorial City Hospital, Houston, TX; Kanagasabai Muthu, MD, Western Pennsylvania Hospital, Pittsburgh, PA; James T. Norwood, MD, Baylor University Medical Center, Dallas, TX; Vasudev M. Patel, MD, The Monroe Clinic, Monroe, WI; Derek K. Paul, MD, FACS, Indian River Memorial Hospi- tal, Vero Beach, FL; Steven Pliskow, MD, FACOG, Palms West Hospital, Loxahatchee, FL; Paul Satwicz, MD, Newton-Wellesley Hospital, Newton, MA; D. Paul Shackelford, MD, Pitt County Memorial Hospital, Greenville, NC; Ray- mond Sinatra, MD, PhD, Yale–New Haven Hos- pital, New Haven, CT; Adam B. Smith, DO, Osteopathic Medical Center of Texas, Fort Worth, TX; Thomas Stavoy, MD, Halifax Medical Cen- ter, Daytona Beach, FL; Robert B. Steinberg, MD, PhD, Baystate Medical Center, Springfield, MA; W. Brian Sweeney, MD, St. John’s Hospital, Maplewood, MN; Denis Tarakjian, MD, Sharp Mary Birch Hospital for Women, San Diego, CA; Thomas Witkowski, MD, Thomas Jefferson Uni- versity Hospital, Philadelphia, PA; Joel Yarmush, New York Methodist Hospital, Brooklyn, NY.