fentanyl its

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PAIN

Iontophoretic transdermal system using fentanyl compared withpatient-controlled intravenous analgesia using morphine for

postoperative pain management

S. Grond1*, J. Hall2, A. Spacek3, M. Hoppenbrouwers4, U. Richarz5 and F. Bonnet6

1Klinik fur Anasthesiologie, Martin-Luther-Universitat Halle-Wittenberg, Halle, Germany. 2Anaesthetics and

Intensive Care Medicine, Heath Park, Cardiff, UK. 3Klinik fur Anasthesie und Allgemeine Intensivmedizin,

Medizinische Universitat Wien, Wien, Austria. 4SGS Medisearch International, Mechelen, Belgium. 5Janssen-

Cilag EMEA, Baar, Switzerland. 6Departement dAnesthesieReanimation, Hopital Tenon, Assistance

Publique Hopitaux de Paris, Universite Paris VI, Paris, France

*Corresponding author: Klinik fur Anasthesiologie, Martin-Luther-Universitat Halle-Wittenberg,

Ernst-Grube-Str. 40, 06097 Halle, Germany. E-mail: [email protected]

Background. The fentanyl iontophoretic transdermal system (fentanyl ITS) enables needle-free, patient-controlled analgesia for postoperative pain management. This study compared the

efficacy, safety, and ease of care of fentanyl ITS with patient-controlled, i.v. analgesia (PCIA)

with morphine for postoperative pain management.

Methods. A prospective, randomized, multicentre trial enrolled patients in Europe after

abdominal or orthopaedic surgery. Patients received fentanyl ITS (n325; 40.0 mg fentanyl

over 10 min) or morphine PCIA [n335; bolus doses (standard at each hospital)] for 72 h.

Supplemental i.v. morphine was available during the first 3 h. The primary efficacy measure was

the patient global assessment (PGA) of the pain control method during the first 24 h.

Results. PGA ratings of good or excellent were reported by 86.2 and 87.5% of patients

using fentanyl ITS or morphine PCIA, respectively (95% CI, 26.5 to 3.9%). Mean (SD) last pain

intensity scores (numerical rating scale, 010) were 1.8 (1.77) and 1.9 (1.86) in the fentanyl

ITS and morphine PCIA groups, respectively (95% CI, 20.38 to 0.18). More patients reported

a system-related problem for fentanyl ITS than morphine PCIA (51.1 vs 17.9%, respectively).

However, fewer of these problems interrupted pain control (4.4 vs 41.3%, respectively).

Patients, nurses, and physiotherapists reported more favourable overall ease-of-care ratings for

fentanyl ITS than morphine PCIA. Study termination rates and opioid-related side-effects were

similar between groups.

Conclusion. Fentanyl ITS and morphine PCIA were comparably effective and safe.

Br J Anaesth 2007; 98: 80615

Keywords: analgesia, patient-controlled; analgesia, postoperative; analgesics opioid, fentanyl;

analgesics opioid, morphine; analgesic techniques, transdermal iontophoresis

Accepted for publication: March 7, 2007

Patient-controlled intravenous analgesia (PCIA) is often

considered the standard method of care for the treatment

of acute postoperative pain.1 7 However, the preparation

of pumps, syringes, and lines requires considerable staff

time and resources.8 Patient mobility may also be

restricted by the patient-controlled analgesia (PCA) pump

and i.v. line, and programming errors, pump failures, and

syringe errors may result in severe adverse events.9 To

overcome these problems, a new, needle-free fentanyl

Declaration of interest. Stefan Grond received honoraria from

Janssen-Cilag for providing lectures and participating in an advisory

board. Judith Hall received an honorarium from Janssen-Cilag for

providing a lecture. Anna Spacek received honoraria from Janssen-

Cilag for providing lectures and participating in an advisory board

and received travel reimbursement from Janssen-Cilag to speak at a

scientific conference. Mieke Hoppenbrouwers worked as a

biostatistician in the contract research organization that oversaw the

biometrics of the trial. Ute Richarz is an employee of Janssen-Cilag.

Francis Bonnet was funded as a consultant for Janssen-Cilag in

2006.

# The Board of Management and Trustees of the British Journal of Anaesthesia 2007. All rights reserved. For Permissions, please e-mail: [email protected]

British Journal of Anaesthesia 98 (6): 80615 (2007)

doi:10.1093/bja/aem102


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HCl iontophoretic transdermal system (fentanyl ITS,

IONSYSTM, Janssen-Cilag NV, Beerse, Belgium) has been

developed that is pre-programmed to deliver a fixed dose

of fentanyl (40.0 mg) across the skin, utilizing the process

of iontophoresis.10 It is compact, self-contained, and self-

adhesive, and it is applied to the patients upper outer arm

or chest.

While previous trials have demonstrated the fentanylITS to be superior to placebo11 12 and therapeutically com-

parable with a standard morphine PCIA dosing regimen

for postoperative pain management,1315 other elements

important to the process of patient care, such as the con-

venience of use and the associated levels of patient and

provider satisfaction, have not been thoroughly assessed.

The system was recently reviewed in this journal.16 In this

study, validated questionnaires were also included to

assess the ease-of-care (EOC)/use and the level of satisfac-

tion associated with each modality from the perspectives

of patients, nurses, and physiotherapists.17 This multicentre

European study further evaluates the efficacy and safety of

the two modalities in patients undergoing major abdominalor orthopaedic surgery to simulate its use in a standard

clinical practice setting. The primary aim of this study was

to determine whether fentanyl ITS was non-inferior to

morphine PCIA for the management of postoperative pain

using a patient global assessment (PGA) of the method of

pain control 24 h after the initiation of treatment.

Methods

This international, multicentre, open-label, randomized,

comparative, parallel-treatment, phase IIIb study was con-

ducted from June 14, 2004, to June 15, 2005, at 51 sites

in 11 European countries (Austria, Belgium, Denmark,

France, Germany, Italy, Ireland, Spain, Sweden,

Switzerland, and the UK). The study protocol was approved

by ethical committees in each country, and patients pro-

vided written consent during the screening process.

Prospective patients were screened within 2 weeks

before surgery, and medical history, physical examination,

and informed consent were obtained. Patients were

instructed in the use of the fentanyl ITS and morphine

PCIA pump, and were provided with education regarding

pain management and pain assessment. To determinethe patients pain management goal, they were asked to

indicate the postoperative pain score (0no pain to

10worst possible pain) that they felt would not inter-

fere with required activities, so that recovery could occur

more quickly. Eligible patients were 18 yr of age; ASA

status I, II, or III; and scheduled to undergo general or

regional anaesthesia (i.e. spinal anaesthetic with 4 h dur-

ation of action) for elective major orthopaedic or abdomi-

nal surgery requiring parenteral opioids for moderate or

severe pain for at least 24 h after surgery.

Patients were screened in the recovery room after the

operation, and included in the study if they were awake,

alert, and breathing spontaneously for at least 30 min, with

a ventilatory frequency of 10 24 breaths min21 and a

pulse oximetry reading (SpO2) of at least 90% (with or

without supplemental oxygen), and able to answer ques-

tions and follow commands. Patients had to be comforta-

ble [ pain intensity 4 out of 10 on a verbal numericalrating scale (NRS)].

Patients were excluded from the study if they were

known or expected to be opioid-dependent, had a chronic

pain disorder, had an active skin disease, were pregnant or

breast-feeding, were expected to require intensive care

after the operation, or would be likely to require additional

surgical procedures within 72 h.

Patients who satisfied the above requirements were ran-

domized (1:1) to receive either the fentanyl ITS or mor-

phine PCIA, utilizing an interactive voice response system

implemented before the study. Randomization was strati-

fied by country and by surgery type (orthopaedic surgery

of the lower extremities, lower abdominal surgery, upperabdominal surgery, or pelvic surgery). Patients were con-

sidered enrolled after the first application of the fentanyl

ITS or after the attachment and enabling of the morphine

PCIA pump, which occurred in the recovery room

immediately after baseline assessments at Hour 0.

In the recovery room, if required, they were titrated to

an acceptable level of comfort with i.v. bolus doses of

morphine. After at least 30 min, the study entry criteria

were assessed, and qualifying patients were randomized to

receive either fentanyl ITS or morphine PCIA. Pain man-

agement with fentanyl ITS or morphine PCIA continued

for up to 72 h. The treatment and assessment schedule is

described in Figure 1.

Fentanyl ITS was applied to the patients upper outer

arm or chest, and was activated when the patient pressed

the recessed, on-demand dosing button twice within 3 s.

An audible beep and the flash of a red light-emitting diode

(LED) indicated the initiation of dosing. The system is

pre-programmed and used an imperceptible electrical field

to deliver 40 mg fentanyl over 10 min, allowing up to six

doses per hour for 24 h or a maximum of 80 doses, which-

ever occurred first. At the end of each 24 h period or after

80 doses, the fentanyl ITS was removed from the patient

and a new system was applied to a different application

site. During delivery of each fentanyl dose, the system didnot respond to additional requests for dosing delivery.

PCA pumps were programmed for a specific dose and

lock-out period according to the standard practice of each

participating hospital. Across hospitals, the patient initiated

the delivery of a bolus dose of morphine (up to 20 mg per

2 h and a maximum of 240 mg per 24 h) by pressing the

PCA dosing button.

Supplemental analgesia (i.v. morphine bolus adminis-

tration after the routine practice of each hospital) was

available to patients in both the fentanyl ITS and the

Fentanyl ITS vs morphine PCIA

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morphine PCIA groups during the first 3 h after the

initiation of treatment on the first day of the study. Patients

requiring supplemental opioid analgesia beyond the first

3 h were discontinued from the study. Non-opioid analge-

sics, including paracetamol, non-steroidal anti-inflammatory

drugs (NSAIDs; including ketorolac), and COX-2 inhibitors

were allowed intraoperatively and during the postoperative

screening or treatment period, according to clinical judge-

ment and institutional practice per normal procedures for

each hospital.

The primary efficacy endpoint was the PGA of the

method of pain control at 24 h. The following question

was read aloud to the patient by a member of the investi-

gators staff: Overall, would you rate this patient-

controlled analgesia method of pain control during the last

24 hours as being poor, fair, good, or excellent? PGA

success was defined as a response of good or excellent.

PGAs were also performed at the 48 and 72 h time points

for patients who remained in the study. Investigator global

assessments were also performed at 24, 48, and 72 h usingthe same scale (poor, fair, good, or excellent). If the

patient withdrew from the study before any 24 h time

point, the PGA and investigator global assessment were

completed at the time of withdrawal from the study, and

scores were included in the data group for the next 24 h

point. Reasons for withdrawal from the study were

recorded and summarized, including the overall dropout

rates and dropouts because of inadequate pain control.

Pain intensity was measured on the NRS, a valid and

reliable pain rating scale18 that is consistent with the

World Health Organizations pain management standards.

The scale ranged from 0 to 10, where 0no pain and

10worst possible pain. Pain intensity scores were

recorded at the time of enrolment (Hour 0), 1, 2, 3, 4, 6,

and 8 h after the enrolment, and every 4 h thereafter until

72 h or termination. Sleeping patients were not awakened

to obtain pain intensity scores.

Additional efficacy outcomes included the mean

number of doses of study medication used by each patient

and the percentage of patients who required supplemental

analgesia. The number of doses delivered by each

modality was recorded at the same time points as the

intensity scores. The number of fentanyl doses delivered

by patients in the fentanyl ITS group was estimated

(1 LED flash15 doses).

EOC questionnaires were completed at 72 h or at the

time of study medication discontinuation for patients,

upon study completion for nurses, and after any session

during the study for physiotherapists. The items on the

patient, nurse, and physiotherapist questionnaires that con-tributed to Overall EOC scores had response choices on a

six-point Likert scale ranging from not at all (0) to

a very great deal (5). The Patient EOC Questionnaire

has previously demonstrated acceptable validity and

reliability,17 and included 23 items that are divided into

seven subscales: Comfort With Device, Dosing

Confidence, Knowledge and Understanding, Movement,

Quality of Pain Control, Confidence With Device, and

Satisfaction; higher scores indicated more favourable

results. For the Patient EOC Questionnaire, Overall EOC

Fig 1 Treatment schedule.

Grond et al.

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was defined as the mean of the mean scores for all items

on six of the subscales, excluding Satisfaction (the mean

scores on the Satisfaction subscale were reported separ-

ately). The Nurse and Physiotherapist Questionnaire has

previously demonstrated validity and reliability,17 and

included 22 items that are divided into three subscales:

Time-consuming, Bothersome, and Satisfaction. The

Overall EOC for the Nurse and Physiotherapist EOCQuestionnaires was defined as the mean of scores on

the Time-consuming and Bothersome subscales (the

Satisfaction subscale was excluded from the Overall EOC

and reported separately); lower scores indicated more

favourable results. Satisfaction with each method of pain

control was assessed for patients, nurses, and physiothera-

pists. Items on the Satisfaction subscale included response

options on a six-point Likert scale ranging from extre-

mely dissatisfied (0) to extremely satisfied (5); higher

scores indicated more favourable results.

Vital signs and oxygen saturation level were recorded at

the same time points as the intensity scores. Problems

associated with the fentanyl ITS or with the i.v. line orPCA pump with morphine PCIA were reported by the

patient and recorded by members of the hospital staff on a

separate check-list during the course of the study. Adverse

events, including the occurrence of clinically relevant res-

piratory depression, defined as the simultaneous occur-

rence of bradypnea (,8 bpm) and excessive sedation,

were recorded as they occurred. Application-site reactions

reported by the patient or noticed by the patient or

members of the hospital staff at any time were recorded.

In addition, members of the hospital staff performed a pro-

spectively defined assessment for application-site reactions

at 24, 48, and 72 h. With the exception of clinically rel-

evant respiratory depression, adverse events were classified

according to the COSTART Thesaurus.19

It was estimated that a total sample size of 590 patients,

randomized 1:1, would provide a probability of 80% to

demonstrate the non-inferiority of fentanyl ITS to mor-

phine PCIA based on the percentages of PGA ratings of

success observed in a previous study,13 with a lower limit

of 10% on the 95% CI for the difference (to detect clini-

cally relevant differences) and a significance level of

0.025 one-sided.20 To allow for a 10% dropout rate, an

enrolment of up to 650 patients was planned for this study.

Patient data were evaluated using two-way analysis of

variance (ANOVA) for numerical data, with treatment andcountry as factors, or using the CochranMantel

Haenszel general association test for categorical vari-

ables,21 controlling for country.

Efficacy and safety analyses were performed using data

from patients for whom the study treatment was applied

(intent-to-treat population). Analysis of the primary effi-

cacy outcome, PGA of the method of pain control at 24 h,

included the construction of a 95% CI of the between-

treatment difference in PGA successes (ratings of good

or excellent). Non-inferiority was concluded when the

lower bound of the 95% CI fell to the right of the pre-

selected maximum allowable difference of 210%. The

between-group difference in the percentages of patients

who reported a PGA rating of excellent was determined

using ANOVA, with treatment and country as factors. Other

efficacy measures were evaluated using tabulations and

descriptive statistics, along with the 95% CI. Data are

expressed as number of patients, mean (SD), standard errorof the mean (SEM), or median with minimum and

maximum. Probability values were considered significant

at the 5% significance level for two-tailed tests.

Results

A total of 660 patients were enrolled [fentanyl ITS group

(n325); morphine PCIA group (n335)] and progressed

through the study (Fig. 2). An average of 13 patients par-

ticipated in the study at each site (range, 141 patients).

Patient characteristics were not significantly different

between groups (Table 1). The majority of patients wereCaucasian (95.6%), mean (SD) age of 53.3 (14.6) yr, and

94.2% of the patients were ASA physical status I or II.

The distribution of type of surgery was similar between

groups. A total of 26 patients in the fentanyl ITS group

and 32 patients in the morphine PCIA group received a

spinal anaesthetic with a duration of action of 4 h.

Morphine PCIA settings varied between hospitals, but the

dosage remained within the allowed maximum of 20.0 mg

morphine every 2 h; the morphine dose ranged from 1.0 to

3.0 mg, and the lockout interval ranged from 5 to 20 min.

The percentages of patients who reported PGA ratings

of good or excellent after the first 24 h were 86.2% for

the fentanyl ITS group and 87.5% for the morphine PCIA

group (95% CI, 26.5 to 3.9%; Fig. 3). Although it was

not the primary efficacy endpoint and the study was not

powered to evaluate this variable, a higher percentage of

patients in the fentanyl ITS group reported PGA ratings of

excellent at 24 h compared with patients in the morphine

PCIA group (39.1 vs 29.9%, respectively; Fig. 3). There

was no difference in the PGA ratings of success at 48 h

(80.8 vs 84.0%, respectively; 95% CI, 29.5 to 3.3%), 72 h

(85.9 vs 82.5%, respectively; 95% CI, 24.8 to 11.5%),

and at the last assessment (88.0 vs 89.3%, respectively;

95% CI, 26.1 to 3.6%). Physicians also reported similar

investigator global assessment ratings of success betweengroups at 24 h (90.8 vs 89.9%, respectively; 95% CI, 23.6

to 5.4%), 48 h (83.0 vs 85.1%, respectively; 95% CI, 28.3

to 4.1%), 72 h (87.1 vs 83.9%, respectively; 95% CI,

24.7 to 11.0%), and at the last assessment (89.8 vs

89.3%, respectively; 95% CI, 24.1 to 5.3%).

Mean (SD) pain intensity scores on the NRS (scale, 0

10) at the last patient assessment after the first 24 h were

similar in both groups [2.5 (1.78) for fentanyl ITS and 2.4

(1.91) for morphine PCIA; 95% CI, 20.18 to 0.38;

Fig. 4]. Comparable mean (SD) pain intensity scores were


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also observed at the last patient assessment [1.8 (1.77) vs

1.9 (1.86); 95% CI, 20.38 to 0.18]. Mean pain intensity

scores were also similar in both groups at each measured

time point (Fig. 4). In addition, the percentage of patients

whose actual pain intensity scores at 24 h were less than

or equal to their pain management goal was comparable

between fentanyl ITS and morphine PCIA groups (78.3

vs 78.7%; 95% CI for the difference in response, 26.8

to 5.9%).

The estimated mean (SD) total number of on-demand,40 mg fentanyl doses per patient in the fentanyl ITS group

was 46.2 (35.63) doses (range, 0 168). The estimated

mean (SD) amount of fentanyl delivered per patient in the

fentanyl ITS group was 1.9 (1.43) mg (range, 0.06.7 mg)

over the study period (72 h). The mean (SD) amount of

morphine delivered per patient in the morphine PCIA

group was 54.7 (47.69) mg (range, 0278 mg). The pro-

portion of patients who required supplemental analgesia

was similar between the fentanyl ITS and morphine PCIA

groups (11.1 and 11.0%, respectively). The median

number of doses of supplemental morphine analgesia used

[1 dose (range, 1 10 doses) and 2 doses (range, 1 15

doses)] and the mean (SD) amount of supplemental mor-

phine used per patient [7.5 (6.45) mg and 6.5 (6.28) mg,

respectively; 95% CI, 21.93 to 3.93 mg)] were similar

between the fentanyl ITS and morphine PCIA groups. The

percentages of patients who used concomitant analgesic

medications were comparable between groups (Table 2).

The percentages of patients who dropped out of the

study because of inadequate analgesia were comparable inthe fentanyl ITS and morphine PCIA groups (3.4 and

2.4%, respectively; 95% CI, 21.6 to 3.6%), as were the

percentages of patients who withdrew for any reason (11.4

and 11.0%, respectively; 95% CI, 24.5 to 5.2%; Fig. 2).

No statistical differences in reasons for study discontinu-

ation were observed.

Patients reported higher (more favourable) mean (SEM)

Overall EOC scores for the fentanyl ITS compared with

morphine PCIA [4.3 (0.03) vs 4.1 (0.03); P,0.001;

Table 3]. Patients also reported higher (more favourable)

Fig 2 CONSORT diagram.

Grond et al.

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mean (SEM) scores for the fentanyl ITS compared with

morphine PCIA on the Movement subscale [4.8 (0.03) vs

3.7 (0.07); P,0.001; Table 3]. Nurses and physiotherapistsreported lower (more favourable) mean (SEM) Overall EOC

scores, and Bothersome and Time-consuming subscale

scores, for the fentanyl ITS compared with morphine

PCIA (Table 4). There was no significant difference in the

patient level of satisfaction between groups [mean (SEM),

4.1 (0.06), 4.1 (0.05); P0.804]. However, nurses and

physiotherapists reported higher (more favourable) mean

(SEM) Satisfaction ratings for the fentanyl ITS compared

with morphine PCIA [nurses, 3.8 (0.05), 3.5 (0.05);

P,0.001; physiotherapists, 3.7 (0.10), 3.5 (0.09);

P0.021].

The incidence of commonly occurring (2%) adverse

events was comparable between the two groups (Table 5).

The percentage of patients for whom at least one adverse

event led to study discontinuation was similar between

groups (5.5 vs 6.9%, respectively). The most frequent

adverse events leading to study discontinuation were

nausea (1.5% of fentanyl ITS patients, 2.1% of morphine

PCIA patients) and dizziness (0.3% of fentanyl ITSpatients, 1.2% of morphine PCIA patients).

In both treatment groups, fewer than 5% of patients

experienced serious adverse events (SAEs) related to study

medication. In the fentanyl ITS group, one SAE (ileus)

was judged to be possibly related to study medication,

whereas in the morphine PCIA group, three SAEs (one

event of somnolence and two episodes of hypoventilation)

were judged to be very likely related to study medication,

and one SAE (hernia) was judged to be possibly related to

study medication. One patient in the morphine PCIA

group died of brain metastasis and intracranial

Table 1 Patient and baseline characteristics. ITS, iontophoretic transdermal

system; PCIA, patient-controlled i.v. analgesia; ASA, American Society of

Anesthesiologists. P-values were calculated using ANOVA for numeric data,

with treatment and country as factors, and CochranMantel Haenszel general

association test for categorical data, controlling for country

C harac te risti c Fe nt an yl

ITS

(n5325)

Morphine

PCIA

(n5335)

Total

(n5660)

P-value

Age (yr)

Mean (SD) 53.5 (14.53) 53.0 (14.58) 53.3 ( 14.55)

Median 53.0 53.0 53.0

Range 22 89 20 88 20 89 0.736

Age subgroups

,65 yr, n (%) 240 (73.8) 251 (74.9) 491 (74.4)

65 yr, n (%) 85 (26.2) 84 (25.1) 169 (25.6) 0.864

Gender, n (%)

Male 139 (42.8) 144 (43.0) 283 (42.9)

Female 186 (57.2) 191 (57.0) 377 (57.1) 0.710

Race, n (%)

Caucasian 308 (94.8) 323 (96.4) 631 (95.6)

Black 4 (1.2) 6 (1.8) 10 (1.5)

Asian 2 (0.6) 2 (0.6) 4 (0.6)

Not allowed to ask 10 (3.1) 1 (0.3) 11 (1.7)

Other 1 (0.3) 3 (0.9) 4 (0.6) 0.122

Surgery type, n (%)

L ower a bd omin al 1 03 (31 .7 ) 9 2 (27 .5) 1 95 (29 .5)

Orthopaediclower

extremity

79 (24.3) 111 (33.1) 190 (28.8)

Pelvic surgery 42 (12.9) 39 (11.6) 81 (12.3)

Upper abdomi nal 45 (13.8) 35 ( 10.4) 80 ( 12.1)

Other 56 (17.2) 58 (17.3) 114 (17.3) 0.073

ASA physical status, n

(%)

I 127 (39.1) 137 (40.9) 264 (40.0)

II 182 (56.0) 176 (52.5) 358 (54.2)

III 16 (4.9) 22 (6.6) 38 (5.8) 0.717

Fig 4 Mean pain intensity scores over time. Pain intensity scores were

similar between groups at each measured time point throughout the study.

In addition, the 95% CI for the difference in the mean last pain intensity

scores indicated non-inferiority of the fentanyl ITS compared with

morphine PCIA after the first 24 h (95% CI, 20.18 to 0.38) and at the

last patient assessment (95% CI, 20.38 to 0.18). Error bars represent

standard deviations.

Fig 3 Distribution of categorical responses on the PGA at 24 h. The

percentages of patients who reported PGA ratings of success (excellent

or good responses) in the fentanyl ITS and morphine PCIA groups were

86.2 and 87.5%, respectively (95% CI, 26.5 to 3.9%).

Table 2 Concomitant analgesic drugs used. ITS, iontophoretic transdermalsystem; PCIA, patient-controlled intravenous analgesia; NSAIDs, non-

steroidal anti-inflammatory drugs; COX-2, cyclooxygenase-2. P-values were

calculated using the CochranMantel Haenszel general association test,

controlling for country

Medication,

n (%)

Fentanyl ITS

(n5325)

Morphine PCIA

(n5335)

P-value

Paracetamol 125 (38.5) 126 (37.6) 0.779

NSAIDs 123 (37.8) 119 (35.5) 0.326

COX-2

inhibitors

8 (2.5) 15 (4.5) 0.247


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hypertension during the study, which was judged to be

unrelated to study medication.

Respiratory function was the primary safety measure-

ment. No patient in the fentanyl ITS group experienced

clinically relevant respiratory depression (bradypnea,

,8 bpm, and excessive sedation); however, one case

occurred in the morphine PCIA group. Mean and median

vital sign values were similar for both treatment groups at

all study time points; a minimum oxygen saturation level

of,88% was recorded in 10 (3.1%) fentanyl ITS patients

and 19 (5.7%) morphine PCIA patients.

Application-site reactions, the majority of which were

erythaema, occurred in 44.3% of patients in the fentanyl

ITS group, with some patients experiencing .1 application-

site reaction. In 7 patients, there were 11 severe events (as

determined by the investigator), but all other cases were

mild to moderate in severity. All patients recovered fromthese severe application-site reactions during the study,

except for one patient who had not yet recovered at trial ter-

mination. Therapy was initiated to treat four of the severe

application-site reactions. Infusion-site reactions occurred in

6.6% of morphine PCIA patients, all of which were of

mild-to-moderate severity.

At least one problem associated with the method of

pain control was reported in 51.1% of patients in the fenta-

nyl ITS group and 17.9% of patients in the morphine

PCIA group. The most common (2%) problems in the

fentanyl ITS group were erythaema/discoloration, other

(i.e. a problem other than those listed for clinicians to

choose from), device malfunction or failure, itching, and

oedema, whereas the most common problems in the mor-

phine PCIA group were other (i.e. a problem other than

those listed for clinicians to choose from), the alarm going

off, device malfunction or failure, line pulled out, and

pain at injection site. Pain control was interrupted as a

result of 4.4% of the events reported in the fentanyl ITS

group (range, 2.0 min to 4.5 h) and in 41.3% of the events

reported in the morphine PCIA group (range, 5 min to

12 h).

Discussion

This study supports the findings of previous phase III andphase IIIb trials that demonstrated fentanyl ITS to be

superior to placebo1112 and non-inferior to a standard

regimen of PCIA with morphine.1315 In addition, this

study demonstrated that the fentanyl ITS is appropriate for

use in the context of multimodal therapy.

There was a ,2% difference in success ratings of

good or excellent between the treatments, which is well

below the predetermined 10% lower bound of the 95% CI

for the difference used to determine clinically relevant

differences on the PGA of the method of pain control. A

Table 4 Nurse and physiotherapist-reported EOC with fentanyl ITS and morphine PCIA*. EOC, ease of care; ITS, iontophoretic transdermal system; PCIA,

patient-controlled intravenous analgesia. *Lower scores represent more favourable results.Overall EOC median values represent the median of mean scores for

items from the time-consuming and bothersome subscales; median values for each subscale represent the median of the mean scores for all items within each

subscale.

P-values indicate the statistical significance between mean values

Fentanyl ITS Morphine PCIA P-value

Mean Median

Range Mean Median

Range

Nurse EOC Questionnaire

Overall EOC 0.7 0.6 0 3 1.2 1.1 0 4 ,0.001

Bothersome 0.6 0.4 0 3 1.0 0.9 0 4 ,0.001

Time-consuming 0.8 0.7 0 4 1.4 1.3 0 5 ,0.001

Physiotherapist EOC Questionnaire

Overall EOC 0.5 0.4 0 2 0.7 0.6 0 2 ,0.001

Bothersome 0.4 0.2 0 2 0.5 0.4 0 2 0.002

Time-consuming 0.6 0.6 0 3 0.8 0.8 0 2 ,0.001

Table 3 EOC with fentanyl ITS and morphine PCIA from the patients perspective*. EOC, ease of care; ITS, iontophoretic transdermal system; PCIA,

patient-controlled intravenous analgesia. *Higher scores represent more favourable results.Overall EOC median values represent the median of mean scores for

items from the six subscales that are given; median values for each subscale represent the median of the mean scores for all items within each subscale.

P-values indicate the statistical significance between mean values

Patient EOC

questionnaire

Fentanyl ITS Morphine PCIA P-value

Mean Median Range Mean Median Range

Overall EOC 4.3 4.4 2 5 4.1 4.2 3 5 ,0.001

Comfort With Device 4.3 4.4 2 5 4.3 4.4 2 5 0.913

Confidence With Device 4.8 5.0 1 5 4.7 5.0 2 5 0.032

Dosing Confidence 4.6 5.0 1 5 4.5 5.0 1 5 0.216

Knowledge/Understanding 3.9 4.0 0 5 3.7 4.0 0 5 0.127

Movement 4.8 5.0 0 5 3.7 4.0 0 5 ,0.001

Pain Control 3.6 4.0 0 5 3.8 4.0 0 5 0.164

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greater percentage of patients in the fentanyl ITS group

reported their global assessment of pain control as excel-

lent compared with those in the morphine PCIA group.

Although this was a pre-specified outcome, between-group

comparison of excellent PGA ratings was not the

primary efficacy endpoint of the trial, and the current trial

was not powered to make this comparison.

The PGA of the method of pain control may encompass

more than one aspect of pain management because it is a

global assessment. It is interesting to note, therefore, that

despite the need to replace the fentanyl ITS every 24 h,

the EOC questionnaires completed by patients, nurses, and

physiotherapists suggested that fentanyl ITS was easier to

use than morphine PCIA, which may have contributed to

the slightly higher ratings observed on the PGA for the

fentanyl ITS compared with morphine PCIA. The more

favourable responses for fentanyl ITS compared with mor-

phine PCIA on the Movement subscale of the Patient EOC

Questionnaire also suggest that the fentanyl ITS may help

to facilitate patient ambulation. Results from two phaseIIIb trials that used the same EOC questionnaires to

compare the ease of use and EOC for patients using fenta-

nyl ITS vs morphine PCIA supported the EOC results

from the current study.14 15

Results of this study compared favourably with those of

a previous active-controlled trial.13 In that study, although

patients were titrated to comfort with i.v. opioids before

study enrolment, a specific level of pain intensity at study

entry was not defined, as was the case in our study. This

resulted in comparatively higher mean pain intensity

scores at Hour 0 in that study,13 which may have contribu-

ted to the higher rates of patient withdrawal and lower

rates of PGA ratings of success observed in both treatment

groups. These findings highlight the importance of the

appropriate titration of initial pain levels and the potential

negative impact of inadequate titration on the success of

pain management during the postoperative period.

All SAEs (regardless of incidence rate) that may havebeen related to study medication are reported.

An unexpected result of this study was the higher incidence

of application-site reactions (44.3%) compared with that

reported in the previous placebo-controlled and active-

controlled trials (2.6 14.7%).1115 The most likely expla-

nation for this observed difference between the studies is that

the current study utilized a separate form specifically for the

reporting of application-site reactions, whereas previous

studies included a check box for application-site reactions on

the general adverse events form. Similar to previous studies,

however, the severity of the application-site reactions was

generally mild to moderate. Nonetheless, if pain management

requiring opioids is needed for .24 h, a new fentanyl ITSshould be applied to a different skin site to minimize the

occurrence of local erythaema.

The higher incidence of erythaema was also primarily

responsible for the between-group difference in the per-

centage of reported problems with the method of pain

control. However, a smaller percentage of these system-

related problems resulted in interruption of pain control in

the fentanyl ITS group compared with morphine PCIA,

and these problems interrupted control for a shorter period

of time. These data suggest that despite the higher inci-

dence of reported problems, fentanyl ITS may have been a

more reliable modality compared with morphine PCIA.

As respiratory function was the primary safety assess-

ment, it is worth noting that the incidence of clinically

relevant respiratory depression was rare (no cases in the

fentanyl ITS group and one in the morphine PCIA group).

In the previously published clinical trials (phase I,

phase III, or phase IIIb),1115 no cases of clinically

relevant respiratory depression were reported in the 1142

patients who were treated with fentanyl ITS. Similar to the

results from previous trials, nausea and vomiting were the

most frequent side-effects in this study,1113 with a similar

incidence observed in both the fentanyl ITS and morphine

PCIA groups.

In contrast to the previous studies comparing fentanylITS and morphine PCIA, this study aimed to be as close

as possible to clinical practice. Therefore, not all hospitals

used the same morphine PCIA settings, because hospitals

in different countries have different regulations and pro-

cedures for standard practice. Although this may be

viewed as a limitation, use of these settings was supported

by results of previous studies that have shown no signifi-

cant differences in analgesia or side-effects using a

maximum hourly dose (10 mg h21), as used in this study,

and a range of lockout intervals from 5 to 20 min.22 23 In

Table 5 Incidence of overall adverse events that occurred in 2% of patients

in either treatment group*. ITS, iontophoretic transdermal system; PCIA,

patient-controlled intravenous analgesia. *Some patients may have

experienced more than one adverse event.

P-values were calculated using the

CochranMantel Haenszel general association test, controlling for country

Adverse event, n (%) Fentanyl I TS

(n5325)

Morphine PCIA

(n5335)

P-value

Nausea 137 (42.2) 159 (47.5) 0.186

Vomiting 55 (16.9) 50 (14.9) 0.469

Application-site reactions

Erythaema 124 (38.2) 0 ,0.001

Itching 23 (7.1) 0 ,0.001

Vesicles 21 (6.5) 0 ,0.001

Oedema 11 (3.4) 0 ,0.001

Dizziness 13 (4.0) 20 (6.0) 0.344

Pruritus 10 (3.1) 15 (4.5) 0.366

Headache 13 (4.0) 6 (1.8) 0.060

Fever 12 (3.7) 10 (3.0) 0.590

Hypotension 7 (2.2) 12 (3.6) 0.320

Hypoventilation 4 (1.2) 11 (3.3) 0.079

Injection-site reaction 2 (0.6) 10 (3.0) 0.030

Urination impaired 9 (2.8) 7 (2.1) 0.517

Injection-site inflammation 1 (0.3) 9 (2.7) 0.017

Hypocalcaemia 8 (2.5) 4 (1.2) 0.197

Anaemia 4 (1.2) 8 (2.4) 0.276

Immune system disorder 4 (1.2) 8 (2.4) 0.269

Hypoxia 3 (0.9) 8 (2.4) 0.193

Abdominal pain 7 (2.2) 6 (1.8) 0.683

Flatulence 7 (2.2) 4 (1.2) 0.306

Constipation 7 (2.2) 3 (0.9) 0.166


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addition, the variability in the PCIA settings used, along

with the administration of concomitant non-opioid analge-

sics, may allow for wider generalization of our results to

different standard analgesic practices.

A possible limitation of this study is the open-label

design, as patients and investigators knew which method

was being used. The open-label design was necessary to

assess the EOC of the two methods of pain control. It isnevertheless difficult to know whether this may have

favourably or negatively influenced patient judgement of

the fentanyl ITS as the new treatment to be assessed.

Another possible limitation of this study is that morphine

PCIA dosing regimens were not standardized across hospi-

tal sites, as discussed above. Although the specific spinal

anaesthetics (duration of action 4 h) used during surgery

for some patients (fentanyl ITS, 8.0%; morphine PCIA,

9.6%) were not recorded, it is unlikely that the inclusion of

spinal anaesthesia significantly impacted the outcome of

this study. It is also unlikely that between-group differences

in the amount of morphine necessary to titrate patients to

comfort upon study enrolment occurred, because patientswere randomized in a double-blinded fashion to one of the

two treatment groups after comfort had been achieved. That

this trial was carried out at multiple sites in multiple

countries can be seen as a positive characteristic, as it better

represented an average European clinical setting.

Although previous studies have shown that patients

prefer PCIA to conventional routes of administration (i.e.

intramuscular),1 7 several safety concerns exist with PCIA,

such as the risk of medication errors, syringe mix-ups, and

errors in programming. Such errors have resulted in over-

sedation and patient death in some cases.9 Catheter infiltra-

tion and phlebitis may also occur with PCIA use, which

may lead to i.v. line failure and improper dosing.24

Administration of PCIA also requires the patient to be

attached to an i.v. line, a PCA pump, and oftentimes a

pole, which may limit patient mobility. In addition,

blocked cannulae can occur with PCIA, which may result

in analgesic gaps. Administration of PCIA also requires

staff time and resources for analgesic preparation, PCA

set-up, and patient monitoring.8

Fentanyl ITS offers many of the benefits of existing

PCA modalities, in addition to other benefits not provided

by i.v. PCA modalities. The non-invasive nature of fenta-

nyl ITS minimizes potential needle-related complications,

and pre-programming of the system eliminates the risk ofpotentially dangerous adverse effects because of program-

ming errors. Transdermal application with the fentanyl

ITS also eliminates the risk of analgesic gaps related to

catheter infiltration and blocked cannulae. Fentanyl ITS is

self-contained and is discretely attached to the patients

upper, outer arm or chest. The system appears to be easy

for patients to use and for nurses and physiotherapists

to care for. The results of this and previous studies

support the use of the fentanyl ITS as an alternative to

morphine PCIA.

AcknowledgementThis study was funded by the Janssen-Cilag NV, Beerse, Belgium (proto-col FEN-PPA-401).

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