PAIN MEDICINE
Volume 10 • Number 8 • 2009
PALLIATIVE CARE SECTION
Original Research Article
Danish Pain Specialists’ Rationales behind the Choice of
Fentanyl Transdermal Patches and Oral Transmucosal
Systems—A Delphi Study
pme_724
1442..1451
Ramune Jacobsen, MSc, MPH, Claus Møldrup, PhD, and Lona Christrup, PhD
University of Copenhagen, Faculty of Pharmaceutical Sciences, Department of Pharmacology and Pharmacotherapy,
Copenhagen, Denmark
ABSTRACT
Objective. The aim of this study was to describe the rationale behind the choice of fentanyl
administration forms among Danish pain specialists.
Methods. Sixty Danish physicians specializing in pain management were contacted via an Internet
survey system to perform a two-phase Delphi survey. Response rates were 45% in the brainstorming
and 88% in the rating phases, respectively. Statistical analysis with SPSS for Windows 15.00
included descriptive statistics and factor analysis.
Results. The most important rationale to choose fentanyl patches was that patients’ clinical condition did not allow them to take analgesia orally, while the main explanations for not choosing a
fentanyl patch was a specific chronic pain condition such as nonmalignant or neuropathic pain
origin, and price. The foremost rationale behind the choice of oral transmucosal fentanyl citrate
(OTFC) were cancer patients’ need for the alternative to oral, intravenous or subcutaneous rescue
medication, followed by patients’ wish and ability to administer pain medication independently. The
main reasons for not choosing OTFC were price and the argument that OTFC administration
requires much energy and healthy patients’ mouth and therefore is inapplicable for terminal pain
patients.
Conclusion. The study had shown that the rationales behind the choice of administration form with
fentanyl reported by a panel of Danish pain specialists partly differed from those overviewed in the
literature and those thought to be important while developing fentanyl patches and OTFC.
Key Words. Fentanyl; Administration Form; Pain Specialists; Rationale; Delphi Survey; Denmark
Introduction
F
entanyl is a synthetic opioid, m-receptor
agonist with short-acting analgesic activity
Reprint requests to: Ramune Jacobsen, MSc, MPH, Section
for Social Pharmacy, Department of Pharmacology and
Pharmacotherapy, Faculty of Pharmaceutical Sciences,
University of Copenhagen, Universitetsparken 2,
DK-2100 Copenhagen, Denmark. Tel: +45 30 69 16 92;
Fax: +45 35 33 60 50; E-mail: [email protected].
and potency 80 times that of morphine [1]. The
low molecular weight, high potency, and lipid
solubility of fentanyl make it suitable for delivery
via a transdermal therapeutic system for the management of chronic pain in patients who require
continuous opioid analgesia [2]. On the other
hand, these chemical properties of fentanyl also
make it suitable for the management of breakthrough pain if transmucosal delivery and needed
dosing are applied [3].
© American Academy of Pain Medicine 1526-2375/09/$15.00/1442 1442–1451
doi:10.1111/j.1526-4637.2009.00724.x
Fentanyl Transdermal Patches and Oral Transmucosal Systems
Fentanyl is registered in Denmark in different
dosage forms: injectables, transdermal patches,
and oral transmucosal fentanyl citrate (OTFC)
systems [4]. The transdermal systems provide
continuous systemic delivery of fentanyl for 72
hours where the amount of fentanyl released per
hour from a reservoir is proportional to the system’s surface area. Five different size systems are
available today, which respectively release fentanyl in doses from 12 to 100 mg per hour [5]. The
OTFC systems are a solid form of oral transmucosal fentanyl citrate formulation on a plastic
stick that dissolves in the mouth for absorption
across the buccal mucosa. Normally, 25% of the
drug is absorbed via the buccal mucosa directly
into the bloodstream. Six OTFC dosages containing 200, 400, 600, 800, 1,200, and 1,600 mg
of fentanyl citrate are available [6].
The reviews of literature on transdermal fentanyl emphasize that among the considerations for
developing a transdermal patch was the potential
of improving the therapeutic efficacy and safety
[7,8]. Transdermal fentanyl was presented as a
potent medication for intensive pain; however, as
with oral administration of opioids, its application
requires effective breakthrough medicine as well
[9]. With regard to safety, transdermal fentanyl
was reported to cause fewer side effects (e.g., constipation, nausea, vomiting, drowsiness) than oral
opiods [10,11]. Other factors taken into account
while developing the transdermal route were
patients’ characteristics and preferences [7].
Transdermal patches were aimed at patients who
require continuous opioid administration for
severe cancer pain not manageable by other
opioids, and who cannot swallow, have gastrointestinal problems (e.g., bowel obstruction,
severe dysphasia, or severe emesis) [11,12] or who
are active and find regular dosing inconvenient
[13]. Furthermore, it was expected that the userfriendly characteristics of the patches, such as
convenience, comfort, and simple and easy administration, might improve patients’ medication
compliance [7,8,12,14].
The considerations for developing OTFC
systems were in line with those for fentanyl
patches: efficacy, safety, and user-friendly properties [15]. Regarding efficacy, OTFC systems were
introduced as the perfect administration form for
breakthrough analgesia for patients tolerant to
other opioids [16,17]. A meta-analysis including
four studies with 393 participants had shown that
OTFC assured lower pain intensity and higher
pain relief if compared with oral immediate-
1443
release morphine [18]. Besides that, OTFC
systems, which are noninvasive and considered to
be easy to administer, were thought to be accepted
by patients [15,19].
Despite quite intensive pharmacological and
clinical investigations regarding the two presented administration forms with fentanyl [2,18],
the rationales behind the choice of fentanyl
patches or OTFC from health care professionals’
or patients’ perspectives have not yet been
studied.
The objective of this study was to elucidate the
rationale behind the use of fentanyl patches and
OTFC among the Danish physicians specializing
in pain management.
Methods
Delphi Technique
The Delphi method was used for gathering the data
for this study. A two-phase Delphi study was conducted via an Internet e-mail survey system (http://
www.defgo.net). The Delphi technique is
a validated type of survey research that aims to
structure group opinion and discussion. Its purposes are: 1) to generate discussion and 2) to enable
a judgment on a specified topic so that it represents
a given group’s views [20]. The Rand Corporation
in California first made an attempt to make the
Delphi method match scientific standards [21].
The Delphi technique is characterized by
anonymous expert input, questionnaires with controlled feedback and statistical analysis of the
group responses. Data are collected through
repetitive surveys and the results of preceding
rounds are fed back by the researcher to the
respondents. The number of rounds used in the
Delphi process varies, although two rounds are
frequently sufficient [20,22]. The panel usually
consists of a group of experts who reflect current
knowledge and perceptions on the subject under
consideration. The Delphi technique has been
successfully used as a means to obtain information
on topics about which little is known [20].
In the field of health care, the Delphi method
has been used in planning policies and programs,
in biomedical research, behavioral research,
mental health, reproductive health, pharmacology,
nursing, and many other fields by examining
health professionals’ and service users’ views [23].
Panel Members
The Delphi technique is particularly useful in
achieving validity when the sample population is a
1444
representative group rather than a random sample.
This is because participants are selected according
to their expertise in a given area, increasing the
likelihood of content validity. For that reason, purposive sampling is often used [20]. For this study, a
purposive sampling of physicians specializing in
pain management was therefore chosen. Members
of the Danish Special Interest Group (SIG) of
specialists working within the pain area were
contacted for recruitment to the study. There was
no exclusion criterion beyond being a member of
this group. The target population consisted of 60
Danish pain specialists. The study was performed
from November 2007 to February 2008.
Delphi Rounds’ Questionnaires
Following the normal Delphi procedure, the
Delphi study was carried out in two parts—a
brainstorming phase to generate a list of reasons
and a rating phase to identify the importance of
each reason [24].
The purpose of the initial (brainstorming) questionnaire was to identify the main reasons to
administer and not administer fentanyl patches
and OTFC. Based on the literature regarding the
clinical use of different administration forms with
fentanyl, it was hypothesized that the main categories of reasons to choose or not to choose fentanyl
patches and OTFC will be: 1) efficacy and safety of
the medication; 2) convenience of the administration form; and 3) clinical condition of the patient
[13,15]. Thus, during the first round, panel
members were asked the questions about 1) the
most important advantages/disadvantages of
fentanyl patches/OTFC, and 2) the situations
in which the respondents would consider
administering/not administering fentanyl patches/
OTFC. The first question was meant to cover
all the reasons under efficacy/safety and convenience
categories, whereas responses to the second
question were supposed to cover the rationale
behind the category of patients’ clinical condition
(if they had been omitted while answering the first
part of the questionnaire). The questionnaire was
pilot-tested within a small group of professionals.
After 6 weeks and two recalls, all responses were
sorted, aggregating items into reasons to administer and not administer fentanyl patches and
OTFC.
The second (rating) questionnaire provided a
comprehensive list of the reasons to administer
and not administer fentanyl patches and OTFC
(altogether 125 items). It was e-mailed to those
doctors who had responded in the brainstorming
Jacobsen et al.
phase, asking them to rate each statement on an
11-point numerical scale ranging from 0 (not
important at all) to 10 (very important). In addition, each panel member was encouraged to
comment on the provided items and/or add other
items that were not included in the list. After
another 6 weeks and two more recalls, the received
data were analyzed.
Statistical Analysis
Statistical analyses were performed with SPSS for
Windows 15.00. Analyses were conducted separately on the scores of items related to: 1) reasons
to administer fentanyl patches; 2) reasons not to
administer fentanyl patches; 3) reasons to administer OTFC; and, finally, 4) reasons not to administer OTFC.
First of all, descriptive statistics of the items
was calculated. This included calculation of
items’ importance means and standards deviations (SD). Items with average importance of less
than 4 on a scale of 0–10 were excluded from the
further analysis and final results. The exclusion of
the items with low importance or considering
items with low importance ratings as the ones
without sufficient face validity is an acceptable
approach in surveys based on Delphi methods
[25,26].
Second, a principal components factor analysis
with varimax rotation was performed in order to
evaluate whether some of the items could be
merged into more general ones. Factor analysis is
a series of statistical tests used to reduce or simplify data by examining the correlation matrix
between variables, and attempts to identify
groups of variables such that there are strong
correlations amongst all the variables within the
group, but weak correlations between variables
within the group and those outside the group
[27]. In other words, factor analysis takes a large
set of variables and looks for a way that the data
may be reduced or summarized using a smaller
set of factors or components. Items loading 0.6
and higher are regarded as being highly correlated with the factors, and the correlation being
moderately high is above 0.3 [28]. In this study,
a covariance structure model was used for the
analysis of correlation matrices [29]. The
number of factors was extracted from the scree
plot [30].
Third, a Cronbach’s alpha internal consistency
of each of the constructed factors’ scales was
assessed [28]. Cronbach’s alpha is a useful coefficient for assessing internal consistency reliability,
1445
Fentanyl Transdermal Patches and Oral Transmucosal Systems
or the level to which several items correlate and
therefore measure the same thing [31]. Internal
consistency reliabilities theoretically vary from a
low of 0 to a high of 1.0 with the values of 0.6 and
below being unacceptable [30].
Finally, descriptive statistics—means and standards deviations—of formed factors’ scales was
computed.
Results
Response Rates and Description of the Panel
The responses from each round are shown in
Table 1.
From the target population of 60 specialists, five
did not get e-mails with the link to the questionnaire because of invalid e-mail addresses or other
delivery problems. Response rates in different
phases varied considerably: from 45% in the brainstorming to 88% in the rating phases, respectively.
The majority of respondents (61.5%) were men.
The duration of years respondents practiced as pain
specialists varied form 3 to 20 with the mean (SD)
of 11.6 (6.05) years. Experience with fentanyl
patches between the respondents varied from
seeing 1 to 40 patients with patches, i.e., new or
continuous users, per month. The majority of the
respondents (40%) saw 10 patients with fentanyl
patches per month. On the other hand, the majority
of the responding physicians (80%) did not see any
patient being prescribed OTFC. Four doctors
reported seeing one patient being prescribed
OTFC, and only one respondent saw four patients
being prescribed OTFC during the last month.
Rationales behind the Choice of Fentanyl Patches
Thirty-nine items presenting reasons why patches
might be chosen as an administration form with
fentanyl were generated. Three items were
excluded from further analysis due to low average
rates. A scree plot suggested a three-factor solution explaining 64.08% of total variance (Table 2).
The results on mean importance (SD) of these
factors are presented in Table 3.
The main reasons to administer fentanyl
patches suggested by pain specialists were: 1)
Table 1
chronic pain patients with difficult or impossible
oral intake; 2) continuous pain relief beneficial
against sustained release oral administration
including possible decrease in opioid-related side
effects, e.g., constipation; and 3) convenient and
reliable administration applicable to terminal and
ambulatory pain patients.
Rationales for Not Choosing Fentanyl Patches
Thirty-three items presenting the reasons not to
administer fentanyl patches were generated and
presented in the importance evaluation round.
Due to low average rates, nine items were
excluded from further analysis. A scree plot suggested a six-factor solution explaining 84.35% of
total variance (Table 4). The results on average
(SD) importance of all the reasons are presented in
Table 5.
The main reasons to not administer fentanyl
patches suggested by pain specialists were: 1) specific chronic pain and patient-related conditions
(e.g., nonmalignant, neuropathic pain, patients’
ability to peroral intake); 2) high price; 3) acute
pain conditions; 4) risk of local irritation; 5) problems with sticking patches on the skin; 6) imprecise dosing; 7) opioid-naive patients; and 8)
difficult to control effect.
Rationales behind the Choice of OTFC
Thirty items presenting reasons why OTFC
might be chosen as an administration form with
fentanyl were generated. One item was excluded
from further analysis due to low averaged rate. A
scree plot suggested a two-factor solution explaining 65.16% of total variance (Table 6). The results
on average (SD) importance of all the reasons are
presented in Table 7.
The most important reasons to administer
OTFC suggested by pain specialists were: 1) alternative administration form for cancer-related
breakthrough pain; 2) convenient, selfadministrative, and individualized pain relief; and
3) children with pain.
Rationales for Not Choosing OTFC
Twenty-three items presenting reasons why
OTFC might be not chosen as an administration
Response rates
Delphi Phases
Delivered
Questionnaires (N)
Nonresponse—
Attrition Rate N (%)
Responded but
Declined N (%)
Participants in the
Survey N (%)
Brainstorming
Rating
55
25
16 (29.10)
3 (12.00)
14 (25.45)
0 (0.00)
25 (45.45)
22 (88.00)
1446
Table 2
Jacobsen et al.
Factors relating to the reasons to administer fentanyl patches
Factor Loading
Factor and its Label
Items
1. Continuous pain relief
beneficial against sustained
release oral administration
Chronbach alpha = 0.938
Less side effects
Less constipation
Potential opioid misuse
Patients’ dislike to take medicine
Independence from the function of kidneys
Gradual absorption
Effective pain relief
Good compliance
Patients’ acceptance
Morphine hyperalgesia
Pain relief for several days*
Opioidrotation
Continuous pain relief
Patients with intensive opioid sensitive pain
Patients with stable continuous pain condition*
Easy titration
Easy conversation from other opioids
Patients at home
Start with 12 mg/h
Less risk for breakthrough pain comparing with oral
administration
Terminal patients
Less risk for infection comparing with subcutaneous
administration
Patients having experience with fentanyl
Depot administration
Reliable absorption
Administration every third day
Easy administration
Convenient administration timetable*
Forgetful patients*
Patients with swallowing difficulties
Patients having difficulties with oral intake
Patients without eating ability
Patients with damage gastro-intestinal tract
Patients with nausea and/or vomiting
Chronic cancer pain
Ineffective oral administration
2. Convenient and reliable
administration applicable to
palliative and ambulatory patients
Chronbach alpha = 0.936
3. Chronic pain patients with
difficult or impossible oral intake
Cronbach alpha = 0.897
1
2
3
0.868
0.858
0.799
0.735
0.684
0.661
0.650
0.630
0.610
0.573
0.553
0.539
0.524
0.415
0.395
0.315
0.236
0.175
0.178
0.258
0.230
0.150
-0.184
0.112
0.072
0.482
0.381
0.412
0.308
0.221
0.427
0.427
0.309
0.297
0.254
0.837
0.836
0.809
0.795
0.751
0.004
0.230
0.273
0.434
0.228
0.301
0.369
0.033
0.588
0.067
0.571
-0.046
0.393
0.356
0.434
0.377
0.299
0.081
0.285
0.078
0.171
0.075
0.657
0.645
0.572
0.320
-0.057
0.292
0.365
0.441
0.244
0.568
0.472
0.217
0.241
0.021
0.254
0.089
0.532
0.175
0.625
0.616
0.609
0.592
0.584
0.349
0.214
0.076
0.199
-0.045
0.234
0.279
0.200
0.328
0.158
0.248
0.584
0.297
-0.133
0.552
0.488
0.873
0.873
0.863
0.814
0.768
0.633
0.572
* The items assigned to a factor based on their practical meanings.
form with fentanyl were generated. One item was
excluded from further analysis due to low average
rate. A scree plot suggested a four-factor solution
explaining 68.29% of total variance (Table 8). The
results on importance means (SD) of all the
reasons are presented in Table 9.
Table 3 Mean importance of the reasons to administer
fentanyl patches
Final Reasons to Administer Fentanyl
Patches
Importance Mean
(SD), Scale 0–10
Chronic pain patients with difficult or
impossible oral intake
Continuous pain relief beneficial against
sustained release oral administration
Convenient and reliable administration
applicable to terminal and ambulatory
patients
7.37 (0.842)
6.18 (1.724)
5.74 (1.021)
The most important reasons to not administer
OTFC suggested by pain specialists were: 1) high
price; 2) energy and healthy mouth requiring
administration usually inappropriate for terminal
patients; 3) possibility for alternative rescue medicine; 4) risk of inappropriate administration and
therefore inadequate pain relief; 5) psychological
patient-related barriers to rescue medicine; 6)
industry and medicine provider-related inconveniences; and 7) too childish administration inappropriate for grown-up patients.
Discussion
The purpose of this study was to describe the
rationale behind the prescription of two different
administration forms containing fentanyl—
patches and OTFC—among a panel of Danish
physicians specializing in pain management.
1447
Fentanyl Transdermal Patches and Oral Transmucosal Systems
Table 4
Factors relating to the reasons to not administer fentanyl patches
Factor Loadings
Factor and Its Labels
Items
1
2
3
4
5
6
1. Imprecise dosing
Cronbach alpha = 0.861
Patients with fever
Cachexic patients
Broad leap in doses between different patches
Imprecise dosing
High price*
Sweating patients
Ineffective dose increase
Tolerance
Problems with dose reduce
Side effects
Fall of effectiveness after 2 days
Unpredictable absorption
Opioidnaive patients
Young patients
Overdosing risk
Development of allergy
Development of skin rush
Difficulties with sticking patches on the skin*
Patients with psoriasis
Short duration of the treatment with opioids
Nonmalignant pain origin
Neuropathic pain
Patients with ability to take opioids orally
Unstable pain condition*
0.862
0.853
0.778
0.757
0.694
0.564
0.288
-0.096
0.304
-0.454
0.386
0.352
0.061
0.076
0.180
0.130
0.274
0.174
0.352
-0.076
-0.094
0.074
0.300
0.002
0.216
-0.124
0.157
0.415
0.213
0.319
0.858
0.851
0.785
0.743
0.637
0.636
0.291
0.212
0.369
-0.016
0.130
0.412
0.115
0.035
-0.244
-0.199
0.066
0.173
-0.042
-0.058
0.464
0.175
0.399
0.095
0.069
0.237
0.360
0.194
0.398
0.235
0.890
0.837
0.836
-0.006
-0.067
0.127
0.176
-0.091
0.151
0.158
-0.138
0.109
0.169
0.247
0.122
0.211
0.290
0.152
0.237
0.037
-0.166
0.133
0.155
0.349
-0.095
-0.071
0.290
0.952
0.864
0.637
0.600
-0.058
-0.037
0.147
0.177
0.222
0.119
0.025
0.177
0.074
-0.201
0.438
-0.166
-0.008
-0.075
-0.180
-0.108
0.059
-0.019
0.195
0.018
0.082
0.003
0.111
0.413
0.819
0.803
0.740
0.720
0.149
-0.074
0.306
-0.208
-0.188
0.135
0.447
0.164
0.256
0.288
-0.113
-0.098
-0.399
0.014
0.362
-0.164
-0.035
0.080
0.216
0.339
0.483
-0.277
0.107
0.080
0.750
2. Difficult to control effect
Cronbach alpha = 0.826
3. Opioidnaive patients
Cronbach alpha = 0.875
4. Risk of local irritation
Cronbach alpha = 0.832
5. Specific chronic pain and
patient-related conditions
Cronbach alpha = 0.797
6. Acute pain conditions
* The items regarded as separate reasons.
The results of the study had shown that the
most important reasons to use fentanyl patches for
pain patients were patients’ inability to take analgesia orally, fentanyl patch-related benefits if compared with oral sustained formulations, e.g., less
opioid-related side effects and better patients’
compliance, and convenience of patch application.
Thus, most important rationale for choosing fentanyl patches reported by Danish pain specialists
were in line with the rationales being considered
while developing the transdermal fentanyl application route [7,8,11,12,14]. The member of the
panel did not consider a fentanyl patch as an effective medication for neuropathic pain. Probably,
Table 5 Mean importance of the reasons to not
administer fentanyl patches
Final Reasons to not Administer Fentanyl
Patches
Specific chronic pain and patient-related
conditions (e.g., nonmalignant, neuropathic
pain, patients’ ability to peroral intake)
High price
Acute pain conditions
Risk of local irritation
Problems with sticking patches on the skin
Imprecise dosing
Opioidnaive patients
Difficult to control effect
Importance
Mean (SD),
Scale 0–10
7.06 (2.493)
6.82
6.48
5.82
5.62
5.15
4.83
4.42
(2.648)
(2.657)
(2.623)
(2.598)
(2.392)
(2.931)
(2.204)
the essential problem here is the difficulties treating neuropathic pain generally: only up to 60% of
neuropathic pain is relieved [32,33]. Moreover,
arguments not mentioned in the reviewing literature, such as risk of local irritation, problems with
patch sticking, imprecise dosing and difficult to
control effect were seen as the reasons why fentanyl patches were not prescribed to pain patients.
Nevertheless, despite some disagreement between
the rationales reported by the panel and those
found in the literature, it seems that the expectations for fentanyl patches were generally met. This
was also confirmed by the number of patients with
fentanyl patches being seen by pain specialist per
month: this number ranged up to 40.
On the contrary to the situation with the
patches, the number of patients with OTFC being
seen by pain specialist per month was very low: the
majority of the respondents did not see any patient
with OTFC. Respectively, differences in rationales
for the use of OTFC reported in the study, and
those elucidated from the literature, were more
substantial. The panel of pain specialists confirmed that OTFC with such properties as fast
onset and short duration of effect are recommendable for cancer-related breakthrough pain as an
alternative rescue medication in the situations
where other administration routes are not efficient
or impossible [34,35]. However, expectations
1448
Table 6
Jacobsen et al.
Factors relating to the reasons to administer oral transmucosal fentanyl citrate
Factor Loading
Factor and its Label
Items
1
2
1. An alternative administration
form for cancer-related
breakthrough pain
Cronbach alpha = 0.950
Cancer-related breakthrough pain in case of insufficient treatment with tablets
Cancer-related breakthrough pain without specific reason
Severe cancer-related breakthrough pain
Cancer-related breakthrough pain
Cancer-related breakthrough pain for patients with fentanyl patches
Short duration of the pain relieving effect
Good pain-relieving properties
Independence from nausea and/or vomiting
Activity-related breakthrough pain
Fast pain-relieving effect
Cancer-related breakthrough pain if other rescue medications do not work
Cancer-related breakthrough pain if patients request an alternative to injections
Cancer-related breakthrough for patients with healthy mouth
Cancer-related breakthrough pain if tablets work too slow*
Cancer-related breakthrough pain in case of low intake of rescue medicine
Patients with damaged intestinal absorption*
Easier administration if compared with i.v. or s.c. routes
Cancer-related breakthrough pain in case of difficult peroral intake
Acute pain condition*
Patients with swallowing difficulties*
Short lasting pain conditions*
Absorption via oral mucosa*
Patents’ ability to self-administrate their medicines
Individualized dosing
Patients’ wish for independence
Possibility to repeat the administration after 10–20 minutes
Easy storage
Children with pain†
Cancer-related breakthrough pain in case patients do not wish s.c.
administration provided by the nurse
0.875
0.835
0.826
0.811
0.797
0.744
0.708
0.696
0.695
0.692
0.667
0.587
0.576
0.528
0.526
0.517
0.503
0.482
0.381
0.374
0.349
0.324
0.080
0.329
0.298
0.340
0.395
-0.473
0.475
0.243
0.190
0.408
0.447
0.387
0.302
0.414
0.218
0.406
0.562
0.370
0.202
0.476
0.730
-0.416
0.775
0.207
0.137
0.840
0.789
0.573
0.362
0.922
0.861
0.852
0.845
0.725
0.539
0.529
2. Convenient, self-administrative
and individualized pain relief
Cronbach alpha = 0.927
* Items assigned to a factor based on their practical meanings.
† The item regarded as a separate reason.
i.v. = intravenous; s.c. = subcutaneous.
regarding the ease of OTFC application and their
acceptance among pain patients [15,19] were not
met. Pain specialists reported that patients’ selfcontrol over OTFC administration, even though
seen as a OTFC-related advantage, was relevant
only for patients having an intact oral mucosa and
who were in a relatively good condition. On the
other hand, exhausting and complicated administration was seen among the most important
reasons why lollipops were not recommended for
palliative patients with breakthrough pain. Moreover, among the reasons not to choose OTFC, a
bad taste and childishness of OTFC application—
factors, which were rarely seen while reviewing the
Table 7 Mean importance of the reasons to administer
oral transmucosal fentanyl citrate (OTFC)
Final Reasons to Administer OTFC
Alternative administration form for
cancer-related breakthrough pain
Convenient, self-administrative, and
individualized pain relief
Children with pain
Importance Mean
(SD), Scale 0–10
6.73 (1.196)
6.29 (0.993)
5.13 (2.900)
characteristics of OTFC in the literature—were
mentioned. Thus, in the future, while trying to
develop new drugs for breakthrough pain analgesia, more attention should be paid to the specificity
of the patients’ population as well as the details of
medicine application. In this respect, fentanyl
nasal sprays, currently at the development stage,
seem to be a more promising option [35–37].
Validity of the Study
The Delphi approach is recognized as being a
valid way to address the appropriateness of medication prescribing [38,39]. This technique with
open-ended questioning and attitudinal measurement, combines concepts embedded both in the
quantitative and the qualitative paradigms, which
is probably the most important advantage of this
technique [20]. A questionnaire survey, requiring
not only critical analyses of the literature, but also
construction and validation of a questionnaire and
pilot group discussions, would have taken much
more time to achieve the same aims. Alternatively,
focus groups could have been formed to generate
ideas and share views about the subject of interest,
1449
Fentanyl Transdermal Patches and Oral Transmucosal Systems
Table 8
Factors relating to the reasons to not administer oral transmucosal fentanyl citrate
Factor Loading
Factor and its Label
Items
1. Risk of inappropriate administration
and therefore inadequate pain relief
Cronbach alpha = 0.890
Problems with proper administration
Unsure absorption
Difficult administration if compared with tablets
Unsure dosing
Too childish administration*
The need for active patient’s effort
A tendency to damage oral mucosa
Difficult administration in case of dry mouth†
Patients’ ability to take alternative form of
rescue medication
Cancer pain without severe breakthroughs
Too short duration of effect
Too high price*
Patients’ ability to take medication orally
Preventable cancer-related breakthrough pain
Bad taste
Delivery to health care facilities problems
Psychological patient-related barriers to
rescue medicine*
Bad compliance
Exhausted patients
Patients with cognitive problems
Patients with fungus in the mouth
Patients with damaged oral mucosa
2. Possibility for alternative
rescue medicine
Cronbach alpha = 0.723
3. Industry and medicine
provider-related inconveniences
Cronbach alpha = 0.872
4. Energy and healthy mouth requiring
administration usually inappropriate
for terminal patients
Cronbach alpha = 0.822
1
2
3
4
0.911
0.836
0.738
0.705
0.674
0.660
0.584
0.240
0.031
0.108
0.231
-0.029
0.031
-0.126
-0.442
0.225
0.164
0.824
0.266
0.320
-0.067
0.483
0.462
0.039
-0.316
0.777
-0.145
0.007
-0.156
0.529
-0.098
0.048
0.548
0.262
-0.173
0.130
-0.376
0.266
0.121
0.011
-0.560
0.202
0.103
0.012
0.791
0.769
0.748
0.641
0.455
-0.302
-0.248
-0.108
-0.144
0.134
-0.139
-0.290
0.126
0.846
0.699
0.445
0.277
-0.147
0.263
-0.154
0.211
0.240
0.273
0.189
-0.334
0.183
0.302
-0.101
0.001
-0.284
0.304
0.120
0.410
0.100
0.074
0.405
0.198
0.299
0.002
0.814
0.661
0.659
0.516
0.467
* The items regarded as separate reasons.
†
The item assigned to a factor based on its practical meaning.
but these views could have had limited validity in
the case of possible pressure or domination by
influential panel members [40]. Thus, such characteristics of Delphi technique as time- and costeffectiveness, the possibility for participants to
respond at their convenience, and the anonymity
of participants providing them with the opportunity to express opinions freely [23] were the
reasons why Delphi was chosen in our case.
However, to enhance the quality of the study, the
disadvantages of the Delphi technique should also
be discussed [41].
Table 9 Mean importance of the reasons to not
administer oral transmucosal fentanyl citrate (OTFC)
Final Reasons to not Administer OTFC
High price
Energy and healthy mouth requiring
administration usually inappropriate for
terminal patients
Possibility for alternative rescue medicine
Risk of inappropriate administration and
therefore inadequate pain relief
Psychological patient-related barriers to
rescue medicine
Industry and medicine provider-related
inconveniences
Too childish administration inappropriate for
grownups patients
Importance Mean
(SD), Scale 0–10
8.10 (0.538)
8.01 (1.796)
6.80 (1.139)
6.02 (2.485)
5.42 (2.673)
5.25 (3.011)
4.50 (3.606)
First of all, the weakness of the Delphi
method is that there is no agreement on the
panel size for Delphi studies, and there is only
very little empirical evidence on the effect of the
quantity and quality of the panel on the reliability and validity of the survey process [23,41].
Regarding the quantity, it has been stated that a
panel of 10 people is sufficient for performing a
good validity survey [42]. Despite that, the
majority of Delphi studies uses about 100 participants [41]. Regarding the quality, it has been
argued that heterogeneous groups, characterized
by panel members with different perspectives on
a problem, produce higher quality solutions than
homogenous samples [41]. On the other hand, it
has been proven that experts who have similar
training and general understanding in the field of
interest provide effective and reliable utilization
of a small sample from a limited number of
experts [23]. This survey was started with a
sample of 60 pain specialists, but a quite low
response rate (which is acceptable for Internetbased surveys [43]) in the brainstorming phase
allowed the construction of a panel of 25 doctors.
Despite that, the small size of the panel probably
did not affect validity much, as it was a homogenous sample: all the respondents were the
members of the SIG of physicians specializing in
pain management.
1450
Second, the Delphi method has been criticized
for its simplicity while presenting quantitative
findings. In this respect, factor analysis was suggested as a valuable statistical procedure for
pruning out redundant items that elicit the same
response from subjects [44]. In this survey, as in
many other contemporary studies [45–50], more
advanced statistical procedures, including factor
analysis, were applied for the analysis of quantitative Delphi survey outcome.
The limitations of the study, however, are associated with difficulties in generalizing the findings
to other populations of health care professionals.
The findings reflect the opinion of a relatively small
population of Danish pain specialists. The results
probably would not be the same when conducting a
similar study with other specialists (e.g., oncologists palliative care specialists) prescribing fentanyl
for pain management. Thus, administration of the
similar survey to a wider population of clinicians
could help validate the trends seen within this
study. Furthermore, the panel of Danish pain
specialists did not have enough experience with
OTFC. Therefore, it would be also interesting to
investigate whether the reasons for and against
prescribing OTFC differ significantly among
experts in other countries that prescribe it more
frequently, e.g., clinicians in the United States.
Conclusion
The results from the study have shown that the
importance of clinical rationales behind the use
of fentanyl patches and OTFC reported by the
panel of Danish pain specialists partly differed
from those overviewed in the literature and
those initially thought to be important while
developing fentanyl patches and OTFC. More
similar studies in other care setting and other
countries are required to understand better the
actual reasons why one or another administration
form of analgesia is recommended to pain patients.
Acknowledgments
This study is a part of the PhD project at the Faculty
of Pharmaceutical Sciences, University of Copenhagen,
partly supported by Nycomed A/S, Denmark.
References
1 Zacny JP, Lichtor JL, Zaragoza JG, de Wit H. Subjective and behavioral responses to intravenous fentanyl in healthy volunteers. Psychopharmacology
(Berl) 1992;107:319–26.
Jacobsen et al.
2 Jeal W, Benfield P. Transdermal fentanyl. A review
of its pharmacological properties and therapeutic
efficacy in pain control. Drugs 1997;53:109–38.
3 Fine PG, Streisand JB. A review of oral transmucosal fentanyl citrate: Potent, rapid and noninvasive
opioid analgesia. J Palliat Med 1998;1:55–63.
4 Danish Medicine Agency (Laegemiddelstyrelsen).
The list of approved medicines. 2007. Available
at: http://www.laegemiddelstyrelsen.dk (accessed
December 2007).
5 U.S. Food and Drug Administration. Duragesic
label. 2007. Available at: http://www.fda.gov/cder/
foi/label/2005/19813s039lbl.pdf (accessed December 2007).
6 U.S. Food and Drug Administration. Medication
guide actiq. 2007. Available at: http://www.fda.gov/
cder/Offices/ODS/MG/fentanyl_citrateMG.pdf
(accessed December 2007).
7 Mosser KH. Transdermal fentanyl in cancer pain.
Am Fam Physician 1992;45:2289–94.
8 Southam MA. Transdermal fentanyl therapy:
System design, pharmacokinetics and efficacy. Anticancer Drugs 1995;6:29–34.
9 Mystakidou K, Katsouda E, Tsilika E, Parpa E,
Vlahos L. Transdermal therapeutic fentanyl-system
(TTS-F). In Vivo 2004;18:633–42.
10 Gourlay GK. Treatment of cancer pain with transdermal fentanyl. Lancet Oncol 2001;2:165–72.
11 Kornick CA, Santiago-Palma J, Moryl N, Payne R,
Obbens EA. Benefit-risk assessment of transdermal
fentanyl for the treatment of chronic pain. Drug Saf
2003;26:951–73.
12 Mercadante S, Fulfaro F. Alternatives to oral
opioids for cancer pain. Oncology (Williston Park)
1999;13:215–25.
13 Radovanovic D, Pjevic M, Malbasa Z, Stokic A. The
use of transdermal fentanyl in the treatment of
cancer pain. Arch Oncol 2002;10:263–6.
14 Simmonds MA, Richenbacher J. Transdermal fentanyl: Long-term analgesic studies. J Pain Symptom
Manage 1992;7:S36–9.
15 Gordon DB. Oral transmucosal fentanyl citrate for
cancer breakthrough pain: A review. Oncol Nurs
Forum 2006;33:257–64.
16 Mystakidou K, Katsouda E, Parpa E, Vlahos L,
Tsiatas ML. Oral transmucosal fentanyl citrate:
Overview of pharmacological and clinical characteristics. Drug Deliv 2006;13:269–76.
17 Rees E. The role of oral transmucosal fetanyl citrate
in the management of breakthrough cancer pain. Int
J Palliat Nurs 2002;8:304–8.
18 Zeppetella G, Ribeiro MD. Opioids for the management of breakthrough (episodic) pain in cancer
patients. Cochrane Database Syst Rev 2006;25:
CD004311.
19 Reddy SK, Nguyen P. Breakthrough pain in cancer
patients: New therapeutic approaches to an old
challenge. Curr Rev Pain 2000;4:242–7.
Fentanyl Transdermal Patches and Oral Transmucosal Systems
20 Efstathiou N, Ameen J, Coll AM. Healthcare providers’ priorities for cancer care: A Delphi study in
Greece. Eur J Oncol Nurs 2007;11:141–50.
21 Møldrup C, Morgall JM. Risks of future drugs: A
Danish expert Delphi. Technol Forecast Soc
Change 2001;67:273–89.
22 Stevens B, McGrath P, Yamada J, et al. Identification of pain indicators for infants at risk for neurological impairment: A Delphi consensus study.
BMC Pediatr 2006;6:1.
23 Akins RB, Tolson H, Cole BR. Stability of response
characteristics of a Delphi panel: Application of
bootstrap data expansion. BMC Med Res Methodol
2005;5:37.
24 Nevo D, Chan YEA. Delphi study of knowledge
management systems: Scope and requirements. Inf
Manage 2007;44:538–97.
25 Campbell SM, Cantrill JA, Roberts D. Prescribing
indicators for UK general practice: Delphi consultation study. Br Med J 2000;321:425–8.
26 Rasmussen HM, Sondergaard J, Kampmann JP,
Andersen M. General practitioners prefer prescribing indicators based on detailed information on
individual patients: A Delphi study. Eur J Clin Pharmacol 2005;61:237–41.
27 Fayers PM, Machin D. Quality of Life. Assessment,
Analysis and Interpretation, Chichester, England:
John Wiley & Sons Ltd; 2007.
28 Kilner T. Educating the ambulance technician,
paramedic, and clinical supervisor: Using factor
analysis to inform the curriculum. Emerg Med J
2004;21:379–85.
29 Cudeck R. Analysis of correlation matrices using
covariance structure models. Psychol Bull
1989;105:317–27.
30 Stevens JP. Applied Multivariate Statistics for the
Social Sciences, 4th edition. Mahwah, New Jersey:
Lawrence Erlbaum Associates, Publishers; 2002.
31 Bland JM, Altman DG. Cronbach’s alpha. Br Med J
1997;314:572.
32 Dworkin RH, O’Connor AB, Backonja M, et al.
Pharmacologic management of neuropathic pain:
Evidence-based recommendations. Pain 2007;132:
237–51.
33 Jensen TS. Management of neuropathic pain. In:
Castro-Lopes J, Raja S, Schmelz M, eds. Pain 2008.
An Updated Review. Refresher Course Syllabus.
Seattle: IASP Press; 2008:287–95.
34 Mystakidou K, Katsouda E, Parpa E, Tsiatas ML,
Vlahos L. Oral transmucosal fentanyl citrate for the
treatment of breakthrough pain in cancer patients:
An overview of its pharmacological and clinical characteristics. Am J Hosp Palliat Care 2005;22:228–32.
35 Christrup LL, Foster D, Popper LD, Troen T,
Upton R. Pharmacokinetics, efficacy, and tolerability of fentanyl following intranasal versus intravenous administration in adults undergoing
third-molar extraction: A randomized, double-
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
1451
blind, double-dummy, two-way, crossover study.
Clin Ther 2008;30:469–81.
Dale O, Hjortkjaer R, Kharasch ED. Nasal administration of opioids for pain management in adults.
Acta Anaesthesiol Scand 2002;46:759–70.
Zeppetella G. An assessment of the safety, efficacy,
and acceptability of intranasal fentanyl citrate in the
management of cancer-related breakthrough pain: A
pilot study. J Pain Symptom Manage 2000;20:
253–8.
Baker JA, Lovell K, Harris N, Campbell M. Multidisciplinary consensus of best practice for pro re
nata (PRN) psychotropic medications within acute
mental health settings: A Delphi study. J Psychiatr
Ment Health Nurs 2007;14:478–84.
Richter A, Ostrowski C, Dombeck MP, Gondek K,
Hutchinson JL. Delphi panel study of current
hypertension treatment patterns. Clin Ther 2001;
23:160–7.
Schopper D, Ammon C, Ronchi A, Rougemont A.
When providers and community leaders define
health priorities: The results of a Delphi survey in
the canton of Geneva. Soc Sci Med 2000;51:335–42.
Powell C. The Delphi technique: Myths and realities. J Adv Nurs 2003;41:376–82.
Delbecq AL, Van de Ven AH, Gustafson D. Group
Techniques for Program Planning. A Guide to
Nominal Group and Delphi Processes. Glenview,
IL: Scot, Foresman and Company; 1975.
Crawford CD, Couper MP, Lamias MJ. Web
surveys: Perceptions of burden. Soc Sci Comput
Rev 2001;19:146–62.
Sackman H. Delphi Critique. Expert Opinion,
Forecasting, and Group Process. Lexington: Lexington Books; 1975.
Cook C, Brismee JM, Sizer PS. Factors associated
with physiotherapists’ confidence during assessment
of clinical cervical and lumbar spine instability.
Physiother Res Int 2005;10:59–71.
Facione NC, Facione PA, Sanchez CA. Critical
thinking disposition as a measure of competent
clinical judgment: The development of the California Critical Thinking Disposition Inventory. J Nurs
Educ 1994;33:345–50.
Fasser CE, Smith QW, Luchi RJ. Geriatrics fellows’
perceptions of the quality of their research training.
Acad Med 1992;67:696–8.
Hamilton PA, Keyser PK. The relationship of ideology to developing community health nursing
theory. Public Health Nurs 1992;9:142–8.
Misener TR, Alexander JW, Blaha AJ, et al.
National Delphi study to determine competencies
for nursing leadership in public health. Image J
Nurs Sch 1997;29:47–51.
Shore BE, Franks P. Physician satisfaction with
patient encounters. Reliability and validity of an
encounter-specific questionnaire. Med Care
1986;24:580–9.