2847

Transdermal Fentanyl in the Management of Children

with Chronic Severe Pain
Results from an International Study

Julia C. Finkel, M.D.1–3 BACKGROUND. The current study was conducted to assess the safety and tolerabil-
Allen Finley, M.D.4 – 6 ity of a transdermal fentanyl delivery system for the relief of chronic pain in a
Christine Greco, M.D.7 pediatric population, and also to validate titration recommendations and conver-
Steve J. Weisman, M.D.8 –10 sion to transdermal fentanyl from oral opioid therapy.
Lonnie Zeltzer, M.D.11–15 METHODS. This 15-day (with 3-month extension), single-arm, open-label trial was
conducted at 66 sites in 10 countries. A total of 199 pediatric patients (ages 2–16
1
Department of Anesthesiology, George Washing- years) with both malignant and nonmalignant conditions who were receiving oral
ton University, Washington, DC. or parenteral opioids for moderate to severe chronic pain were enrolled. Trans-
2
Department of Pediatrics, George Washington dermal fentanyl doses were titrated upward according to the rescue medication
University, Washington, DC. consumed during the previous application period. Degree of pain was assessed by
3
Anesthesia Pain Management Service, Children’s patients and parents/guardians using visual and numeric scales. Level of play and
National Medical Center, Washington, DC.
4
quality of life were assessed using the Play Performance Scale (PPS) and the Child
Department of Pediatrics, George Washington
Health Questionnaire (CHQ). Adverse events were monitored on Days 1–15. Hy-
University, Washington, DC.
5 poventilation and sedation were monitored every 4 hours during the first 72 hours
Department of Anesthesia, Dalhousie University,
Halifax, Nova Scotia, Canada. of the study.
6
Department of Psychology, Dalhousie University, RESULTS. A total of 173 patients completed the primary treatment period and 130
Halifax, Nova Scotia, Canada. entered the extension phase. The average daily pain intensity scores were reported
7
Pediatric Pain Management, IWK Health Centre, to have decreased by Day 16 and improvements in the mean PPS scores were
Halifax, Nova Scotia, Canada. observed to the end of the extension period. The CHQ scores demonstrated
8
Pain Treatment Services, Children’s Hospital, improvements in 11 of 12 domains after Month 1 of the extension period.
Boston, Massachusetts. CONCLUSIONS. Transdermal fentanyl was found to be a safe and well tolerated
9
Pain Management, Children’s Hospital of Wis- alternative to oral opioid treatment for children ages 2–16 years who were previ-
consin, Milwaukee, Wisconsin.
ously exposed to opioid therapy. Cancer 2005;104:2847–57.
10
Department of Anesthesiology, Medical College © 2005 American Cancer Society.
of Wisconsin, Milwaukee, Wisconsin.
11
Department of Pediatrics, Medical College of KEYWORDS: chronic pain, transdermal, opioid, tolerability.
Wisconsin, Milwaukee, Wisconsin.
12
Department of Pediatrics, David Geffen School
of Medicine, University of California–Los Angeles,
Los Angeles, California.
I n both malignant and nonmalignant conditions, persistent pain
and fear of pain is a recognized source of anxiety to children and
their families. Nevertheless, severe pain in children frequently goes
13
Department of Anesthesiology, David Geffen untreated.1
School of Medicine, University of California–Los Pure ␮-opioid agonists have demonstrated unquestioned analge-
Angeles, Los Angeles, California.
14
Department of Psychiatry, David Geffen School
of Medicine, University of California–Los Angeles,
Los Angeles, California.
Supported by Johnson and Johnson. Dr. Greco acts as a consultant for Janssen Phar-
15
Department of Biobehavioral Sciences, David maceuticals.
Geffen School of Medicine, University of Califor-
Address for reprints: Julia C. Finkel, M.D., An- Dr. Zeltzer has acted in the past as a consultant for
nia–Los Angeles, Los Angeles, California.
esthesia Pain Management Service, Children’s Janssen Pharmaceuticals.
16
Pediatric Pain Program, David Geffen School of National Medical Center, 111 Michigan Avenue,
Medicine, University of California–Los Angeles, Los NW, Washington, DC 20010; Fax: (202) 884- Received March 24, 2005; revision received June
Angeles, California. 5999; E-mail: jfinkel@cnmc.org 20, 2005; accepted July 8, 2005.

© 2005 American Cancer Society

DOI 10.1002/cncr.21497
Published online 14 November 2005 in Wiley InterScience (www.interscience.wiley.com).
2848 CANCER December 15, 2005 / Volume 104 / Number 12
sic efficacy in adults and are often the only effective
method with which to relieve a patient’s chronic
pain2; however, to our knowledge, few studies have
been conducted to date to provide evidence of their
safety and efficacy in children.3,4 In addition, routes of
drug administration that are acceptable for acute pain
or for use in adults may be distressing to children with
chronic pain.1
Past use of analgesia in pediatric patients suggests
that young children were believed to feel pain less
severely than adults,5 and also that they would be
predisposed to addiction.6,7 Young children are often
more sensitive to pain than adults.8 Chronic pain in
children is now known to be a direct cause of cognitive
and emotional disturbance, as a result of anxiety,
sleep disturbances, physical disability, restriction of
daily activities, and social withdrawal.1,9 –11 Further-
more, it is now recognized that children are not more
easily addicted to opioids than adults.12 In addition,
children are perhaps more vulnerable than adults to
the negative effects of pain. There is evidence that
pediatric stress can influence the behavior and phys-
iologic function of individuals for life8,13,14 and that
sensitization of nociceptive pathways early in life can
lead to increased pain perception in the future.1,15–17
The subcutaneous, intravenous, and even oral ad-
ministration of opioids can be a source of suffering
and distress in some children, particularly those re-
quiring chronic opioid use for severe illnesses.18 In
this patient group, transdermal delivery might be pref-
erable, and once titrated and at steady state should
demonstrate efficacy equal to more conventional
routes of administration. In adults, the transdermal
delivery of fentanyl has shown significant advantages
over the oral and parenteral routes in the treatment of
chronic pain, in terms of ease of delivery, duration of
symptom relief, incidence and severity of side effects,
and quality of life benefits.19 –21
The objectives of the current study were to deter-
mine the safety and tolerability of transdermal fenta-
nyl in children with chronic severe pain, and to vali-
date titration recommendations and initial dose
conversion from oral opioid therapy.
MATERIALS AND METHODS
Study Design
The current study was a single-arm, nonrandomized,
open-label, multicenter trial conducted in accordance
with the principles of Good Clinical Practice and the
Declaration of Helsinki at 66 sites in 10 countries
(Australia, Austria, Brazil, Canada, Costa Rica, Israel,
Mexico, Poland, Slovakia, and the U.S.). The primary
study was conducted over 15 days and was followed by
a 3-month extension period.
Patients
The trial enrolled a total of 199 pediatric patients with
moderate to severe chronic pain because of malignant
(n ⫽ 132 patients) or nonmalignant (n ⫽ 67 patients)
disease. In patients with malignancy, 45.8% had met-
astatic disease, 32.1% had localized disease, 17.6% had
regional involvement, and 4.6% had an unclassified
extent of disease. The most common diagnoses of
malignancy were leukemia (27.3%), “other” malignan-
cies (18.2%), sympathetic nervous system malignan-
cies (14.4%), and bone malignancies (12.9%).
Male and female patients were included if they
were at least age 2 years and age younger than 16
years. Patients must have received opioids continu-
ously for a minimum of 7 days prior to enrollment,
with a projected need for continuous opioid treatment
for at least the length of the primary treatment period.
Patients also must have received the equivalent of
at least 30 mg of oral morphine on the day before
enrollment. The main exclusion criteria were a known
sensitivity to fentanyl, other opioids, or adhesives; skin
disease that affected the application or local tolerance
of or absorption from the fentanyl patch; or a life
expectancy of fewer than 15 days. In all cases, the
child’s parent, guardian, or legal representative was
required to sign an informed consent form. In those
cases in which a child was able to understand the
purpose and implications of the trial, his or her con-
sent also was sought.
Methods
Patients were converted from oral or parenteral opi-
oids to transdermal fentanyl on Day 1. The opioid
analgesic requirement was calculated from opioid use
during the previous 24-hour period. The equivalent
analgesic oral morphine dose was calculated using the
equianalgesic potency conversion table (Table 1). The
equivalent transdermal fentanyl dose was calculated
using a second conversion table (Table 2).22
Dose application
Transdermal fentanyl patches (at doses of 12.5␮g/hr,
25␮g/hr, 50␮g/hr, 75␮g/hr, or 100 ␮g/hr) were applied
to nonirritated and nonirradiated skin on a flat sur-
face, such as the chest, back, flank, or upper arm.
Dose titration
After the initiation of transdermal fentanyl treatment,
doses were titrated upward (with a frequency of no
less than every 3 days) using the dose calculated from
the conversion table, until steady-state analgesic ef-
fectiveness with transdermal fentanyl alone was ob-
tained. Titration was based on the requirement for
 Transdermal Fentanyl: Pediatric Pain/Finkel et al. 2849

TABLE 1 TABLE 2
Equianalgesic Potency Conversion Table Recommended Initial Dose of Transdermal Fentanyl Based
on the Daily Oral Morphine Dose
Equianalgesic dose (mg)
Oral 24-hour morphine Transdermal fentanyl
Name Intramusculara Oral dose (mg/day) dose

Morphine 10b 30 (60) 30–44 12.5

Hydromorphone 1.5 7.5 45–134 25.0
Oxycodone 15 30 135–180 37.5
Levorphanol 2 4 181–224 50.0
Oxymorphone 1 10 (p.r.) 225–270 62.5
Meperidine 75 — 271–314 75.0
Codeine 130 200 315–360 87.5
Methadonec 10 20 361–404 100.0
Tramadold 100 120 405–450 112.5
451–494 125.0
p.r.: per rectum. 495–540 137.5
a
Based on single-dose studies in which an intramuscular dose of each drug was compared with 541–584 150.0
morphine to establish the relative potency. Oral doses are recommended when changing from a 585–630 162.5
parenteral to an oral route.36 631–674 175.0
b
The conversion ratio of 10 mg of parenteral morphine equaling 30 mg of oral morphine is based on 675–720 187.5
clinical experience in patients with chronic pain. The conversion ratio of 10 mg of parenteral morphine 721–764 200.0
equaling 60 mg of oral morphine is based on potency in patients with acute pain.37 765–810 212.5
c
Methadone should be withdrawn the day prior to patch application. 811–854 225.0
d
It is advisable to apply the transdermal fentanyl patch at the time of the next scheduled dose of 855–900 237.5
tramadol. 901–944 250.0
945–990 262.5
991–1034 275.0
1035–1080 287.5
immediate-release morphine to counter any residual 1081–1124 300.0
or breakthrough pain experienced by the patient. The
dose of transdermal fentanyl was increased by 12.5
␮g/hour for every 45 mg of morphine equivalents Scale for Global Functional Status of Adults.23,24 Level
(ME) of rescue medication consumed on Day 2 or Day of activity was described in terms of active play, quiet
3 of the previous patch application period, up to a play, degree of physical limitations, and degree of
maximum increase of 25 ␮g/hour at any 1 time. independence. Ratings ranged from 80 –100 (“fully ac-
tive, normal”) through 50 –70 (“mild to moderately
Evaluations restricted”) to 0 – 40 (“moderate to severe restriction”)
Clinical effectiveness and were measured in terms of the individual child’s
A global assessment of pain treatment was made using baseline rating.
a four-point scale on Days 1 and 16 of the primary The overall quality of life of the patients, including
treatment period. Treatment was rated as poor, fair, their ability to function physically and socially, was
good, or very good by the patient’s parent or guardian. monitored using the Child Health Questionnaire
The degree of pain was measured by patients age 6 (CHQ).25 The CHQ is designed for self-completion by
years and older using a colored, vertical Visual Ana- the patient, if age 10 years or older, and their parent/
logue Scale (VAS) ranging from 0 (no pain) to 10 (most guardian. Questionnaires were completed at baseline
pain). Assessments were made by the parent/guardian and at the end of Months 1 and 3 of the extension
of each patient using a Numeric Pain Intensity Scale, period.
ranging from 0 (no pain) to 10 (worst possible pain). The parent portion of the CHQ (CHQ-PF50) con-
Scores were recorded twice each day (morning and tains 50 items in 12 domains and was completed by all
evening) in a diary. Pain levels also were recorded at parents/guardians of patients ages 5–16 years. The 12
the time rescue medication was given and 1 hour later domains are: physical function, role/social emotional
by the parent/guardian only. behavior, role physical, bodily pain, general behavior,
The level of play and activity of the patient was mental health, self-esteem, general health, parent-
monitored every 3 days of the primary treatment pe- time impact, parent-emotional impact, family activi-
riod from Day 1 to the endpoint (coinciding with the ties, and family cohesion. The child portion of the
patch change) by the parent/guardian using the Play CHQ (CHQ-CF87) contains 87 items in 10 domains:
Performance Scale (PPS) modified from the Karnofsky physical function; role/social functioning because of
2850 CANCER December 15, 2005 / Volume 104 / Number 12
emotional, behavior, and physical problems scales;
bodily pain; general behavior; mental health; self-es-
teem; general health; and family activities. The ques-
tionnaire was completed by patients ages 10 –16 years.
Scores for both questionnaires ranged from 0 –100,
with a high score reflecting better functioning and
well-being.
Safety
Adverse events were monitored in all patients who
had received the trial medication and were reported
between the first and last dose of the trial medication.
The incidence of adverse events and serious adverse
events determined to be related to the study medica-
tion were defined by investigators with an assessment
of “doubtful,” “possible, ” “probable, ” or “very likely.”
Vital signs (including systolic and diastolic blood pres-
sure, heart rate, respiratory rate, and temperature)
were obtained and recorded at baseline and each
morning on Days 2, 3, 4, 7, and 16. Assessments then
were made monthly during the extension period. A
physical examination was performed at baseline, if
possible on Day 16, and monthly during the extension
period.
The patients’ respiratory rates and sedation levels
were monitored every 4 hours during the first 72 hours
after application of the first transdermal fentanyl
patch. Any occurrence of bradypnea was reported as a
serious adverse event. The Observer’s Assessment of
Alertness/Sedation Scale26 was used to grade the level
of alertness.
Statistical Methods
The current study was an open-label and single-arm
trial, so therefore no formal inferential statistical tests
were performed. Sample size determination was
based on clinical judgment rather than statistical con-
sideration.
An intent-to-treat (ITT) analysis was performed
whereby all enrolled patients, regardless of their compli-
ance with the protocol, were included in the analysis
unless they received no medication at all. The ITT in-
cluded all patient data for the primary treatment period
and any extension data obtained by the data cutoff date.
Calculations were performed using the SAS威 software
(Version 6.12; SAS Institute, Inc., Cary, NC).27,28
All effectiveness parameters (i.e., global assess-
ment, pain level, play performance, CHQ, dosing and
titration information, and rescue medication) were
summarized descriptively by timepoint for the pri-
mary treatment period only, overall, and by gender
and age category. CHQ, dosing and titration informa-
tion, and rescue medications were also summarized
for the extension period.
Play performance
The Pearson correlation between play performance,
pain score, and average daily dose at each timepoint
of the primary treatment period (i.e. baseline, Day 4,
Day 7, Day 10, Day 13, Day 19, and endpoint) was
calculated. In addition, correlation also was examined
using change scores at each timepoint from baseline.
CHQ
The 12 domain scores from the CHQ-PF50 were stan-
dardized using the mean and standard deviation (SD)
from the U.S. general population and clinical sample
data. The scores then were aggregated using factor
score coefficients from the U.S. general population
and clinical sample data. The association between
CHQ changes from baseline and other effectiveness
parameters (pain as reported by parent and child,
global satisfaction as reported by the parent, and play
performance as reported by parent or guardian) was
explored using Pearson correlation coefficients.
Dosing and titration
The following information was collected from patient
diaries: average ME opioid taken within the last 24 hours
before the initiation of transdermal fentanyl treatment,
the duration of treatment with transdermal fentanyl, the
average daily dose of transdermal fentanyl, the number
of days until the first dose titration was required, the
number of days until subsequent titrations were re-
quired, and the average titration dose.
RESULTS
Patient Status
A total of 199 patients were enrolled into the study and
entered into the ITT population. Of these, 173 patients
(86.9%) completed the primary treatment period and
130 patients (65.3%) entered the extension period. At
the time of the database cutoff, 26 patients remained
in the extension period.
Patient Demographics
Of the 199 ITT patients, 118 (59.3%) were male and 81
(40.7%) were female. The majority of patients were
white (54.8%). The mean age of the patients was 10.7
⫾ 0.28 years and the median age was 12 years (range,
1–16 yrs). Three patients fell outside of the desired age
range (1 patient was age 1 year and 2 patients were
each age 16 years) and were not included in age cat-
egory data analyses.
Specification of pain type included nociceptive
(70.9%), neuropathic (14.6%), and multiple pain
(14.1%) etiologies. An underlying malignancy was

TABLE 3
Use of Rescue Medication during the Primary Treatment Period, by Body Weight, Expressed in Morphine Eequivalents
No. assessed
Overall mean daily dose in mg/kg (SE) of opioid (fentanyl ⫹ rescue medication)
No. of patients requiring rescue medication during the primary treatment period
Mean daily dose of rescue medication in mg/kg (SE)
SE: standard error.
present in 132 patients and was found to be related to
the cause of pain for 96 patients.
Patient Withdrawal
A total of 26 patients (13.1%) were withdrawn from the
study during the primary treatment period: 6 (3.0%) as
a result of death, 6 (3.0%) because of adverse events,
and an additional 14 patients (7.0%) for various other
reasons including a decrease in pain; the patient with-
drew; and the patient was ineligible, noncompliant, or
demonstrated an insufficient response. Of the 130 pa-
tients who entered the extension treatment period,
104 (80.0%) discontinued treatment. The most fre-
quent cause for treatment discontinuation (n ⫽ 43
patients [33.1%]) was “other,” mostly comprising pa-
tients whose pain had improved or resolved, or who
were being weaned off opioids. Additional “other” rea-
sons included increased pain (two patients) and the
patient requiring an increase in the frequency the
patch was changed (two patients). The next most fre-
quent causes for discontinuation were death (n ⫽ 21
patients [16.2%]) and adverse events (n ⫽ 11 patients
[8.5%]).
A total of 48 patients (24.1%) had death as an
adverse event during the combined primary and ex-
tension treatment periods. The most common diag-
noses leading to death were neuroblastoma (eight pa-
tients), malignant neoplasm (six patients), and
sarcoma (eight patients). None of these events were
considered by investigators to be related to treatment
with transdermal fentanyl, apart from one case of
neuroblastoma for which the association with the trial
medication was considered “doubtful.”
Treatment Initiation
Examination of the medical histories revealed that all
patients had previously received at least one opioid
analgesic. Morphine, including morphine sulfate, was
the opioid previously used by most patients (70.4%).
Transdermal Fentanyl: Pediatric Pain/Finkel et al. 2851
Body weight category (quartiles)
Total 1st 2nd–3rd 4th
n ⴝ 199 n ⴝ 54 n ⴝ 97 n ⴝ 47
198 (99.5%) 54 (100%) 97 (100%) 47 (100%)
4.72 (0.306) 6.45 (0.750) 4.26 (0.378) 3.67 (0.470)
169 (84.9%) 45 (83.3%) 82 (84.5%) 41 (87.2%)
1.35 (0.163) 1.88 (0.501) 1.17 (0.167) 1.15 (0.174)
Fentanyl was the second most frequently used opioid
(16.1%).
The most common starting dose of transdermal
fentanyl was 25 ␮g/hour, which was required by 90
patients (45.2%). The lowest starting dose, 12.5 ␮g/
hour, was considered appropriate for 59 patients
(29.6%). The median recorded initial dose was 25 ␮g/
hour (range, 12.5–175.0 ␮g/hour). The location of the
fentanyl patch varied between applications, although
the upper back was used most often (in 63.3% of
patients). Tape was used at least once to adhere the
patch to the application site in 81 patients (40.7%).
Dose Titration
The average duration of treatment with transdermal
fentanyl in the primary treatment period was 14.8
⫾ 0.25 days in the ITT patient group. Seventy-seven
patients (38.7%) required an upward dose titration, at
an average time to first dose titration of 5.6 ⫾ 0.30
days. The mean initial daily dose of transdermal fen-
tanyl per kilogram (kg) of body weight was 0.98
⫾ 0.057 ␮g/kg/hour, which rose to an average final
dose of 1.20 ⫾ 0.091 ␮g/kg/hour at the end of the
primary treatment period.
A total of 84.9% of patients received at least 1
rescue medication, with a mean oral ME of 1.35 ⫾ 0.16
mg/kg during the primary treatment period. Overall,
the mean average daily dose of opioid (i.e., transder-
mal fentanyl plus rescue medication) was 4.72 ⫾ 0.31
mg/kg, expressed as MEs. The average ratio of the
total daily transdermal fentanyl dose versus the total
daily dose of opioid increased over the primary treat-
ment period from 0.88 ⫾ 0.01 mg/kg to 0.91 ⫾ 0.01
mg/kg. The trend was for the reduced rescue medica-
tion to level off after 5 days, suggesting the rapid
optimization of the transdermal fentanyl dose. The
overall mean dosage of total opioids and rescue med-
ication by body weight during the primary treatment
period are summarized in Table 3.
2852 CANCER December 15, 2005 / Volume 104 / Number 12
TABLE 4
Summary of Global Assessment of Pain Treatment at the Baseline
and Endpoint
Parameter
Baselinea
No. assessed
Very good
Good
Fair
Poor
Endpointa
No. assessed
Very good
Good
Fair
Poor
Percentages are based on the number of patients assessed at a given timepoint.
a
Baseline: Day 1. The endpoint is defined as the last nonmissing, postbaseline observation through the
last day of administration of the trial medication during the primary treatment period.
Evaluations
Clinical effectiveness
Global assessment of pain treatment. The global as-
sessment of pain treatment at the baseline and end-
point is summarized in Table 4. A global assessment
was performed at both baseline and Day 16 in a total
of 145 patients. Of this group, 54 patients (37.2%) who
had prebaseline pain treatment rated as poor or fair
had their treatment with transdermal fentanyl rated as
good or very good. For 73 patients (50.3%) whose
original treatment was rated as good or very good, no
reduction in satisfaction with therapy at the end of the
primary treatment period was reported. The prebase-
line and transdermal fentanyl treatment of 14 patients
(9.7%) was rated as poor or fair, and 4 patients (2.7%)
had their pain relief rated as worse by Day 16. There
appeared to be no age-related or gender-related dif-
ferences with regard to response to treatment.
Pain level. The average daily pain intensity levels re-
ported by parents/guardians using the numeric pain
scale for the ITT population decreased steadily
throughout the study period from 3.5 ⫾ 0.23 at base-
line to 2.6 ⫾ 0.21 by Day 16, a change of 0.9 points
from baseline. The trend was similar for both morning
and evening intensity levels, although some conver-
gence of the pain intensity scores was apparent be-
tween the two assessment time points (Fig. 1). Com-
parable changes in daily pain intensity levels were
reported by patients using the VAS, with a reduction
from 3.7 ⫾ 0.26 at baseline to 3.1 ⫾ 0.26 by the end of
the primary treatment period, a change of 0.6 points
from baseline.
Total (n ⴝ 199) No. (%)
189
34 (18.0)
66 (34.9)
58 (30.7)
31 (16.4)
149
78 (52.3)
52 (34.9)
15 (10.1)
4 (2.7) FIGURE 1. Mean (standard error) morning and evening pain intensity levels
at baseline (Day 1) and Day 16 as reported by parents/guardians.
PPS. Parent/guardian-rated improvements in mean
PPS scores were observed from baseline (41.22 ⫾ 1.68)
to the data collection endpoint (53.80 ⫾ 1.91), repre-
senting a mean change of 11.5%. This represents a
change from “mostly in bed and participating only in
quiet activities” to “gets dressed but lies around much
of the day, no active play but is able to participate in
quiet play.”
Correlation analysis revealed a positive associa-
tion between pain (as reported by the patient or par-
ent/guardian) and functional status, such that func-
tional status improved as pain decreased. A positive
correlation between PPS scores and the global assess-
ment of pain treatment also was apparent. (However,
it should be noted that the correlation analysis was not
powered and therefore there is a possibility that these
correlations could reflect chance occurrence). At the
endpoint, the mean PPS scores of the patients whose
parents/guardians rated their transdermal fentanyl
patch treatment as “very good” was 61.5 ⫾ 2.84 (n
⫽ 75 patients; baseline, 47.7 ⫾ 3.61 [n ⫽ 31 patients]),
whereas the PPS scores of those patients whose par-
ents/guardians had rated their pain treatment as
“poor” at the endpoint was 12.5 ⫾ 2.50 (n ⫽ 4 patients;
baseline, 34.0 ⫾ 3.56 [n ⫽ 25 patients]).
CHQ. The baseline results of the CHQ parent form
were compared with those of a normative population
sample (n ⫽ 391 participants) of children in the U.S.29
Patients demonstrated significant impairment in their
functioning at baseline compared with the accepted
norm for children in this age group. At baseline, 78%
of patients were rated by their parents/guardians as
“limited a lot” in activities requiring “a lot” of energy
and 74% were reportedly “limited a lot” in activities
requiring “some” energy. Approximately 43% of the

FIGURE 2. Child Health Questionnaire.
Parent report domain change from base-
line at the end of Month 1 and Month 3.
PF: physical functioning; RP: role phys-
ical; REB: role emotional behavior; BP:
bodily pain; BE: general behavior; MH:
mental health; SE: self esteem; GH: gen-
eral health; PI: parent impact–time
health; PE: parent impact– emotional;
FA: family activities; FC: family cohesion;
PSS: physical summary score; PHS: psy-
chosocial summary score (a higher
score indicates better physical or psy-
chosocial functioning and well-being).
parents/guardians reported that their child had “se-
vere pain” during the 4-week period before the base-
line assessment, and 63% reported that their child had
pain “almost every day.” The results from the CHQ
child form were comparable to those of the parent/
guardian-completed form, and both forms demon-
strated excellent correlation with the PPS scores.
At the end of Month 1 of the extension phase, the
parents of the participating patients (n ⫽ 36 patients)
reported improvement in 11 of the 12 domains as-
sessed. The largest improvement was noted in bodily
pain (29.52 ⫾ 4.52; baseline, 18.14). Five other do-
mains demonstrated an improvement of greater than
5 points from baseline: mental health (8.28 ⫾ 2.76;
baseline, 54.33), family activities (6.96 ⫾ 3.19; base-
line, 43.04), role emotional behavior (12.36 ⫾ 6.08;
baseline, 34.72), physical function (7.15 ⫾ 2.71; base-
line, 23.65), and role physical (13.82 ⫾ 5.76; baseline,
17.07). The mean change for other domains ranged
from 0.28 –3.57. At the end of Month 3, participating
patients continued to demonstrate sustained im-
provements in 11 of the 12 domains, with the greatest
improvements from baseline being reported in bodily
pain (27.14 ⫾ 7.53), role physical (23.53 ⫾ 8.09), phys-
ical functioning (13.89 ⫾ 5.74), and role/social behav-
ior (16.01 ⫾ 9.29). Mean score changes from baseline
to the end of Months 1 and 3 are shown in Figure 2.
Results from the child form demonstrated improve-
ments at Month 1 in the majority of the physical
domains, with large improvements noted in bodily
pain (26.45 ⫾ 4.74), role physical (10.68 ⫾ 8.33), and
physical functioning (8.77 ⫾ 3.41). Such improve-
ments were maintained at the end of Month 3 and
confirmed the findings from the parent form and PPS
scores.
Transdermal Fentanyl: Pediatric Pain/Finkel et al. 2853
Safety (combined primary and extension periods)
Transdermal fentanyl was found to be safe and well
tolerated in this population. Age, body weight, and
initial dose by body weight had no apparent clinically
relevant effects on the overall safety profile of trans-
dermal fentanyl. Evaluation of vital signs and physical
examination did not suggest any safety concerns.
One hundred eighty patients (90.5%) reported at
least 1 adverse event during treatment. The most fre-
quent adverse events were fever (n ⫽ 71 patients),
emesis (n ⫽ 66 patients), nausea (n ⫽ 42 patients),
headache (n ⫽ 37 patients), and abdominal pain (n
⫽ 34 patients). One hundred patients (50.3%) had
adverse events with “doubtful” (15.1%), “possible”
(16.6%), “probable” (5.5%), or “likely” (13.1%) correla-
tions with the study medication. The most frequent
adverse events found to be related to the trial medi-
cation were emesis (16.1%), nausea (10.6%), pruritus
(7.5%), application site reaction (7.5%), headache
(7.0%), constipation (6.0%), and somnolence (5.5%).
The overall incidence of serious adverse events
was 43.2% (n ⫽ 86 patients). The most common seri-
ous adverse events were severe fever (n ⫽ 21 patients
[10.6%]), neuroblastoma (n ⫽ 8 patients [4%]), emesis
(n ⫽ 8 patients [4%]), malignant neoplasm (n ⫽ 7
patients [3.5%]), and pain (n ⫽ 7 patients [3.5%]).
Serious adverse events considered by the investigator
to be related to the study treatment were reported to
occur in 19 patients (9.5%) and included emesis (n ⫽ 5
patients [2.5%]), pain (n ⫽ 4 patients [2%]), dyspnea (n
⫽ 3 patients [1.5%]), somnolence (n ⫽ 2 patients
[1%]), and neuroblastoma (n ⫽ 1 patient [0.5%]).
No patient had a respiratory rate that indicated
bradypnea occurred within the initial 72 hours of
2854 CANCER December 15, 2005 / Volume 104 / Number 12

TABLE 5
Incidence of Adverse Events within the Respiratory System and Correlation with the Study Medication (in the ITT Population)

Overall None Doubtful Possible Probable Likely

Correlation No. (%) No. (%) No. (%) No. (%) No. (%) No. (%)

Respiratory system disorders 61 (30.7) 48 (24.1) 10 (5.0) 2 (1.0) 1 (0.5) 0

Dyspnea 11 (5.5) 7 (3.5) 4 (2.0) 0 0 0
Rhinitis 8 (4.0) 5 (2.5) 3 (1.5) 0 0 0
Pharyngitis 7 (3.5) 6 (3.0) 1 (0.5) 0 0 0
Respiratory depression 5 (2.5) 4 (2.0) 0 0 1 (0.5) 0
Bradypnea 2 (1.0) 1 (0.5) 0 1 (0.5) 0 0
Bronchospasm 2 (1.0) 1 (0.5) 0 1 (0.5) 0 0
Respiratory disorder 2 (1.0) 1 (0.5) 1 (0.5) 0 0 0
Asthma 1 (0.5) 0 1 (0.5) 0 0 0

ITT: intent to treat. Includes all adverse events that occurred during the combined primary and extension treatment periods. Adverse events were summarized using the World Health Organization Adverse Reaction
Terminology (WHOART) dictionary by body system and preferred term. Percentages are based on the total number of subjects in the intent-to-treat population.

treatment. Bradypnea was defined as fewer than 12 ration of 10 –12 breaths per minute while awake) was
breaths per minute for patients ages 2– 6 years, fewer reported for a 12-year-old female on Day 6 of treat-
than 10 breaths per minute for patients ages 7–10 ment with transdermal fentanyl. The patient was re-
years, and fewer than 8 breaths per minute for chil- ceiving a dose of 100 ␮g/hour (4.35 ␮g/hr/kg) at the
dren ages 11–16 years. A total of 61 patients reported time of the onset of the adverse event. The bradypnea
at least 1 adverse event associated with the respiratory was not considered serious but was considered by the
system (Table 5). With the exception of four patients, investigator to be possibly related to the trial medica-
the adverse events experienced were evaluated by the tion. The patient recovered from the adverse event
investigator as not being related to treatment. within 1 day of onset. There was no interruption of the
One of the 4 patients was an 11-year-old male who trial medication.
began experiencing respiratory depression of moder- A 15-year-old male experienced a mild bronchos-
ate severity on Day 1 of treatment. He was receiving pasm (verbatim term: wheezing) on Day 2 of treat-
12.5 ␮g/hour (0.28 ␮g/hr/kg) of transdermal fentanyl ment with transdermal fentanyl. At the onset of the
at the time of onset of the adverse event. The event event, the patient was receiving a dose of 25 ␮g/hour
was considered serious and most likely related to the (0.34 ␮g/hr/kg) of transdermal fentanyl. The broncho-
trial medication. The respiratory depression resulted spasm was not considered serious but was considered
in a temporary withdrawal of the trial medication but by the investigator to be possibly related to the trial
did not require any other therapy. Vital signs on Day 2 medication. The patient recovered from the adverse
of treatment were a heart rate of 76 beats per minute, event within 1 day of onset. There was no interruption
a respiratory rate of 18 breaths per minute, systolic/ of the trial medication.
diastolic blood pressure of 132/78 mm Hg, and a tem- Analysis of other adverse events commonly asso-
perature of 38.2 °C. The patient recovered from the ciated with opioid use, including gastrointestinal
serious adverse event within 2 days of its onset. The symptoms, raised no unexpected safety concerns (Ta-
trial medication was resumed on Day 2 of the study at ble 6). One patient whose somnolence was “very
a dose of 12.5 ␮g/hour (0.28 ␮g/hr/kg). likely” related to the study medication withdrew from
A case of moderate respiratory disorder (verbatim the study, whereupon she recovered from this adverse
term: increased tachypnea) was experienced by a event. One patient with pruritus and an abrasion that
4-year-old male, beginning on Day 1 of treatment. The had a “likely” correlation with the study medication
patient was receiving a dose of 37.5 ␮g/hour (2.5 ␮g/ recovered from the pruritus but not the abrasion after
hr/kg) of transdermal fentanyl at the time of onset of study withdrawal. One patient with nausea and one
the adverse event. The event was not considered seri- with emesis believed to be “possibly” related to the
ous and the correlation between the event and the study treatment withdrew from the study and both
trial medication was considered doubtful. The patient patients recovered. One patient with severe nausea
recovered from the adverse event within 1 day of and emesis, both of which were considered to “possi-
onset. bly” be related to treatment, withdrew but the adverse
Mild bradypnea (verbatim term: decreased respi- events continued.

TABLE 6
Incidence of Adverse Events Commonly Associated with Opioids
(Somnolence, Pruritus, and Emesis and Nausea) and Correlation with
the Study Medication (in an ITT Population)
Overall None Doubtful Possible
Correlation No. (%) No. (%) No. (%) No. (%)
Somnolence 14 (7.0) 3 (1.5) 3 (1.5) 4 (2.0)
Pruritus 24 (12.1) 9 (4.5) 2 (1.0) 5 (2.5)
Vomiting 66 (33.2) 34 (17.1) 19 (9.5) 10 (5.0)
Nausea 42 (21.1) 21 (10.6) 9 (4.5) 11 (5.5)
ITT: intent to treat. Includes all adverse events that occurred during the combined primary and
extension treatment periods. Adverse events were summarized using the World Health Organzation
Adverse Reaction Terminology (WHOART) dictionary by body system and preferred term. Percentages
are based on the total number of subjects in the intent-to-treat population.
There were 18 patients who required a change in
the dosage of the trial medication because of an ad-
verse event: 6 patients required a dose reduction (for
somnolence, pruritus, or nausea), 11 patients required
a dose increase (9 of which were because of pain
reported as an adverse event), and 1 patient required
both a dose increase and a decrease (because of dif-
ferent adverse events).
The mean daily sedation scores were found to
decrease over time, but remained above those scores
that would indicate a state of moderate alertness. The
mean daily sedation scores at Day 1, Day 2, and at the
endpoint were 2.65, 2.27, and 2.13, respectively.
Fifty-three patients died during the study. Apart
from one patient, none of the deaths were considered
to be related to treatment with transdermal fentanyl,
but instead were the result of the patient’s underlying
disease. One patient with metastatic neuroblastoma
developed severe progression of the neuroblastoma
on Day 12 of the study and died the same day. The
correlation between the progression of neuroblastoma
and the trial medication was assessed by the investi-
gator as “doubtful. ”
DISCUSSION
Chronic pain in children may be undertreated, leading
to unnecessary suffering by the patient.1,30,31 The use
of opioids in children has been limited by caution over
other possible ill effects. The ethical dilemmas in-
volved in properly testing opioid formulations in chil-
dren have resulted in a lack of defined dosing proce-
dures for this patient group.
In the current study, a combination of direct con-
version from current treatments and upward titration
depending on rescue medication requirements has
produced favorable efficacy, safety, and tolerability
profiles in patients who have been switched to trans-
Transdermal Fentanyl: Pediatric Pain/Finkel et al. 2855
dermal fentanyl from oral or parenteral opioids. The
data presented herein suggest that transdermal fent-
anyl is a well tolerated treatment for chronic pain
experienced by children previously exposed to opioid
Probable Likely therapy. The conclusions regarding dose titration
No. (%) No. (%) should be restricted to the duration used in this study.
Furthermore, the observations made in the current
3 (1.5) 1 (0.5) study were of a heterogeneous population and there-
3 (1.5) 5 (2.5) fore only a generalized recommendation can be made
1 (0.5) 2 (1.0)
because no specific patient population was examined.
0 1 (0.5)
The use of transdermal fentanyl was associated
with improved scores on the patients’ PPS and CHQ,
compared with baseline. On the CHQ, 11 of 12 do-
mains demonstrated some improvement at the end of
Month 1 or Month 3. The greatest change was ob-
served in the bodily pain and physical domains. Sub-
stantial improvements also were noted in the emo-
tional behavior and mental health domains. Although
such comprehensive improvements might be attribut-
able to the confounding factors of an open-label, sin-
gle-arm trial and, for some measures, small sample
size, these positive results nevertheless indicate a sat-
isfactory quality of life for these pediatric patients
receiving transdermal fentanyl. This finding is espe-
cially important for those patients in the study who
were in palliative care and nearing end of their life.
Many children near the end of life have difficulty
swallowing and therefore oral medication as the sole
means of analgesia can limit good pain control. Sim-
ilarly, good standards for palliative care suggest limit-
ing invasive procedures that provide analgesia
through intravenous, intramuscular, or subcutaneous
routes of delivery.32 For these reasons, a transdermal
delivery system is ideal for this seriously ill pediatric
population.
Approximately 60% of the patients in the current
study did not require upward titration during the pri-
mary treatment period, suggesting the conversion ta-
ble used in the current study was appropriate and that
the converted doses would allow a relevant evaluation
of safety.
Greater than 80% of the total daily opioid require-
ment was delivered by transdermal fentanyl, immedi-
ately after conversion to the patch. The use of rescue
medication reached a stable daily total within two
patch applications, indicating that the proposed titra-
tion algorithm can be used successfully. The majority
of patients requiring dose adjustments achieved ade-
quate analgesia within 6 days. By the end of the pri-
mary treatment period, 90% of the total daily opioid
dose was being provided by transdermal fentanyl.
The adverse events observed in the current study
are consistent with those of a potent opioid and a
study population with serious and often progressive
2856 CANCER December 15, 2005 / Volume 104 / Number 12
and life-threatening disease. There were no adverse
events associated with transdermal fentanyl that indi-
cated a specific risk in this pediatric population. The
pattern of medication-related adverse events was sim-
ilar to that observed in adult patients and is the ex-
pected profile of an opioid analgesic. Because the
protocol had a minimum requirement for baseline
opioid treatment of 30 mg/day ME, young children
qualifying for the study on this basis received a high
dose of opioid per kg of body weight compared with
some older children in the study (body weight catego-
ries ranged from 6.45 mg/kg3 in the 1st quartile to 3.67
mg/kg3 in the 4th quartile). However, conversion to
transdermal fentanyl at correspondingly high doses
appeared to produce no adverse consequences in
younger patients who had demonstrated tolerance to
equivalent opioid doses.
There was an overall improvement in pain relief
and treatment satisfaction associated with the admin-
istration of transdermal fentanyl over the primary
treatment period. The convergence of pain intensity
scores between morning and evening may suggest
that blood levels of fentanyl remained fairly constant
during the treatment period. This possibility would
have to be examined specifically. Continuous pain
relief may reduce the need for additional analgesics
and also reduce sleep disturbances caused by the re-
currence of pain.33
The transdermal delivery of fentanyl has the po-
tential advantages of being a noninvasive approach
and being able to be administered in cases in which
oral administration is difficult because of advancing
disease or poor compliance. Use of the transdermal
route also has resulted in a decreased incidence of
constipation and nausea in adult patients being
treated for cancer pain.21 A previous study of trans-
dermal fentanyl in 13 pediatric patients with opioid-
dependent and stable chronic cancer pain demon-
strated a decrease in gastrointestinal disturbance, with
some patients able to stop taking laxatives or anti-
emetics.18
Results from global assessments of pain treat-
ment, safety, and quality of life indicate that transder-
mal fentanyl is an acceptable alternative to oral opioid
therapy in children. Transdermal fentanyl is especially
useful for good pain management in children with
life-limiting conditions in whom oral or injectable
routes of drug delivery are difficult to administer or
would add further distress. The results also suggest
that the dose conversion and titration guidelines pro-
posed are appropriate for use in this population. The
data produced by this study also may be applicable to
adult patients in clinical practice, particularly when
there is a requirement for a low starting dose of trans-
dermal fentanyl. The sustained duration of pain relief
and the low frequency of dosing with transdermal
fentanyl both serve to improve patient compliance
and increase acceptability of the treatment.34,35
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