PA I N M E D I C I N EVolume 8•Number 8.docx

PA I N M E D I C I N E
Volume 8
•
Number 8
•
2007
© American Academy of Pain Medicine 1526-
2375/07/$15.00/657 657–668 doi:10.1111/j.1526-
4637.2006.00257.x
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
µ
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;
P
=
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].
O
658
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

µ
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-
µ
g fentanyl dose
from the fentanyl ITS resulted in a mean C
max
of
1.954
µ
g/L and a mean absorption of 39.5
µ
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
µ
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
2
) 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
µ
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-
660
Minkowitz et al.

mated number of doses
=
(5
×
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
α
=
0.05 using a
two-sided 95% confidence interval (CI) procedure
with an equivalence margin of

δ
=
0.10. The suc-
cess rate,
π
=
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
2
), 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
t
-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%,
P
=
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;
P
=
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;
P
=
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;
P
=

0.039) in the
Table 1
Baseline characteristics and patient demographics
Fentanyl ITS
(n
=
252)
Morphine IV PCA
(n
=
254)
Total
(N
=
506)

P
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
2

), 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.

patient-
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.
0
100
80
60
Pe
rc
en
ta
ge
o
f p

at
ie
nt
s
20
40
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)
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.
0
251
251
72
38
31
60
38
31
48
82
52
36
76
67
24
195
193

12
180
192
0
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)
patient-
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

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-
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.

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