BMJ 2001;322:1154 ( 12 May )
Primary care
Randomised crossover trial of transdermal fentanyl and sustained release
oral morphine for treating chronic non-cancer pain
Laurie Allan, director a, Helen Hays, associate clinical professor b,
Niels-Henrik Jensen, head of department c, Bernard Le Polain de Waroux,
staff anaesthesiologist d, Michiel Bolt, anaesthesiologist e, Royden Donald,
specialist anaesthetist f, Eija Kalso, head g.
a Chronic Pain Services, Northwick Park and St Mark's NHS Trust, Harrow,
Middlesex HA1 3UJ, b Department of Family Medicine, University of Alberta,
Edmonton, Alberta, Canada T6G 2C8, c Multidisciplinary Pain Centre,
Department of Anaesthesiology, Herlev University Hospital, DK-2730, Denmark,
d Cliniques Universitaires St-Luc, 1200 Brussels, Belgium, e Alg Ziekenhuis
Eemland De Lichtenberg, 3818 ES Amersfoort, Netherlands, f Strand Private
Hospital, Cape Town 7139, South Africa, g Helsinki University Central
Hospital Pain Clinic, 00290 Helsinki, Finland
Correspondence to: L Allan [log in to unmask]
<mailto:[log in to unmask]>
Abstract
Objectives: To compare patients' preference for transdermal fentanyl or
sustained release oral morphine, their level of pain control, and their
quality of life after treatment.
Design: Randomised, multicentre, international, open label, crossover trial.
Setting: 35 centres in Belgium, Canada, Denmark, Finland, the United
Kingdom, the Netherlands, and South Africa.
Participants: 256 patients (aged 26-82 years) with chronic non-cancer pain
who had been treated with opioids.
Main outcome measures: Patients' preference for transdermal fentanyl or
sustained release oral morphine, pain control, quality of life, and safety
assessments.
Results: Of 212 patients, 138 (65%) preferred transdermal fentanyl, whereas
59 (28%) preferred sustained release oral morphine and 15 (7%) expressed no
preference. Better pain relief was the main reason for preference for
fentanyl given by 35% of patients. More patients considered pain control as
being "good" or "very good" with fentanyl than with morphine (35% v 23%,
P=0.002). These results were reflected in both patients' and investigators'
opinions on the global efficacy of transdermal fentanyl. Patients receiving
fentanyl had on average higher quality of life scores than those receiving
morphine. The incidence of adverse events was similar in both treatment
groups; however, more patients experienced constipation with morphine than
with fentanyl (48% v 29%, P<0.001). Overall, 41% of patients experienced
mild or moderate cutaneous problems associated with wearing the transdermal
fentanyl patch, and more patients withdrew because of adverse events during
treatment with fentanyl than with morphine (10% v 5%). However, within the
subgroup of patients naive to both fentanyl and morphine, similar numbers of
patients withdrew owing to adverse effects (11% v 10%, respectively).
Conclusion: Transdermal fentanyl was preferred to sustained release oral
morphine by patients with chronic non-cancer pain previously treated with
opioids. The main reason for preference was better pain relief, achieved
with less constipation and an enhanced quality of life.
What is already known on this topic
The clinical use of potent opioids in the treatment of chronic non-cancer
pain is supported by retrospective, survey data and small randomised
controlled trials showing efficacy and safety
Studies with transdermal fentanyl have shown efficacy and preference over
sustained release oral morphine in the treatment of cancer pain
What this study adds
This is the first study to provide comparative data supporting treatment
options with potent opioids for chronic non-cancer pain
Both transdermal fentanyl and sustained release oral morphine provided
effective and well tolerated pain relief
During fentanyl treatment patients experienced superior pain relief, higher
quality of life, and less constipation; fentanyl was preferred to morphine
by 65% of patients
Introduction
In 1998 the World Health Organization survey of nearly 26 000 patients from
five continents reported that 22% had had persistent pain sometime over the
previous year. 1 <http://bmj.com/cgi/content/full/322/7295/#B1> Pain is one
of the commonest reasons for visiting a doctor and, when pain is chronic,
the multimillion healthcare costs are only exceeded by the multibillion
costs of work loss, disability, and social welfare benefits. Global
socioeconomic costs at one end of the spectrum are matched by personal
suffering at the other. Pain is often undertreated or mistreated, with
patients going from doctor to doctor for relief and finally moving outside
mainstream medicine in increasing numbers. 2
<http://bmj.com/cgi/content/full/322/7295/#B2>
Opioids are the mainstay of management of cancer pain, providing effective
pain relief. 3 <http://bmj.com/cgi/content/full/322/7295/#B3> 4
<http://bmj.com/cgi/content/full/322/7295/#B4> Opioids are the most
powerful analgesics, but politics, prejudice, and continuing ignorance still
impede optimum prescribing. 5 <http://bmj.com/cgi/content/full/322/7295/#B5>
A review of retrospective and survey data confirms the efficacy of opioids
in the treatment of chronic non-cancer pain and found that fears of
addiction were not justified. 6
<http://bmj.com/cgi/content/full/322/7295/#B6> Randomised controlled trials
of intravenous opioids in chronic non-cancer pain show benefit over placebo
for morphine and fentanyl, whereas oral placebo controlled trials show
efficacy for codeine, morphine, and oxycodone. 7-11
<http://bmj.com/cgi/content/full/322/7295/#B7> Worldwide, the value of
opioids in this role has led to the development of management guidelines,
with recommendations from national organisations. 12-15
<http://bmj.com/cgi/content/full/322/7295/#B12>
Morphine is the standard opioid against which others are judged and is
usually prescribed in a sustained release oral formulation for the treatment
of chronic pain. 5 <http://bmj.com/cgi/content/full/322/7295/#B5> 10
<http://bmj.com/cgi/content/full/322/7295/#B10> Severe constipation, a
persistent complication of oral opioids, may affect some patients' quality
of life more than their pain. 16
<http://bmj.com/cgi/content/full/322/7295/#B16>
Fentanyl, a lipid soluble synthetic opioid, can be delivered in a
transdermal controlled release formulation, providing continuous, controlled
systemic delivery of fentanyl for up to 72 hours. 17
<http://bmj.com/cgi/content/full/322/7295/#B17> Studies with transdermal
fentanyl have shown analgesic efficacy in cancer pain. 18-22
<http://bmj.com/cgi/content/full/322/7295/#B18> Most patients preferred
fentanyl, which was associated with less constipation than morphine. 21
<http://bmj.com/cgi/content/full/322/7295/#B21> 22
<http://bmj.com/cgi/content/full/322/7295/#B22> Also, fentanyl has been
shown to relieve neuropathic pain that is relatively insensitive to opioids.
8 <http://bmj.com/cgi/content/full/322/7295/#B8> 23
<http://bmj.com/cgi/content/full/322/7295/#B23>
Opioids are individually titrated to an effective dose. Therefore little
difference would be expected between opioids in efficacy or improvements in
quality of life, which is confirmed by studies in cancer pain. 5
<http://bmj.com/cgi/content/full/322/7295/#B5> 6
<http://bmj.com/cgi/content/full/322/7295/#B6> 24
<http://bmj.com/cgi/content/full/322/7295/#B24> 25
<http://bmj.com/cgi/content/full/322/7295/#B25> Recognising the increasing
importance of patients' preference and choice, we investigated in a large,
multicentre, two way crossover trial whether patients with chronic
non-cancer pain accustomed to opioids would prefer transdermal fentanyl over
sustained release oral morphine, has been found in patients with cancer
pain. 21 <http://bmj.com/cgi/content/full/322/7295/#B21> We also assessed
pain control, quality of life, and adverse events.
Participants and methods
Protocol
The study was approved by local ethics committees, and patients giving
written, informed consent were recruited from 35 specialist pain clinics in
Belgium (15 patients), Canada (58), Denmark (67), Finland (16), the United
Kingdom (65), the Netherlands (21), and South Africa (14).
Patients were invited to participate if they were aged over 18 years and had
chronic non-cancer pain requiring continuous treatment with potent opioids
for six weeks preceding the trial. They had to have achieved moderate pain
control with a stable dose of oral opioid for seven days before the trial.
Exclusion criteria included pain not responding to opioids, a history of
allergy or hypersensitivity to opioids, life threatening disease, skin
disease precluding the transdermal system, reduced level of consciousness,
social isolation, concomitant psychiatric disorders, history of substance
misuse, clinically relevant cardiac, nervous system, or respiratory disease,
participation in another clinical research project, and possible pregnancy
or lactation.
Treatments
Baseline assessment included recording the patients' characteristics,
medical history, physical abnormalities, and vital signs. Efficacy and
safety data were collected at day 7, 16, and 28 of each treatment period.
Patients' pain was classified according to the International Association for
the Study of Pain as nociceptive (stimulation of intact nociceptors by
noxious stimuli), neuropathic (disease or trauma of the nervous system), or
combined nociceptive and neuropathic (table 1
<http://bmj.com/cgi/content/full/322/7295/#T1> ).
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Table 1. Characteristics at baseline of patients receiving transdermal
fentanyl or sustained release oral morphine. Values are numbers
(percentages) unless stated otherwise
The requirement for opioid was determined individually over the 24 hours
before the first dose of study drug was given. Analgesic doses of fentanyl
equivalent to the patients' previous opioid dose were calculated from the
manufacturer's recommendations. 26
<http://bmj.com/cgi/content/full/322/7295/#B26> Patients were treated with
fentanyl patches (Durogesic, Janssen-Cilag) releasing 25, 50, 75, or 100 µg
fentanyl/hr and sustained release oral morphine as 10, 30, 60, 100, or 200
mg tablets (MS Contin, Napp Laboratories). Patients receiving morphine
received half the equivalent analgesic dose every 12 hours. At crossover,
patients received the same opioid dose as before the study. Patients
randomised to receive fentanyl first were given the first dose of morphine
when the last fentanyl patch was removed. Patients randomised to receive
morphine first had the first fentanyl patch applied when the last dose of
morphine was given.
Patients were prescribed immediate release morphine (initially 5 mg) every
four hours as needed. Patients requiring more than 60 mg of this rescue drug
over two days of a three day period with fentanyl could increase their
fentanyl dose. Patients receiving morphine needing more than two doses of
the rescue drug per day could titrate to a higher dose of morphine.
Subject preferences---The primary efficacy variable was the patient's
preference for transdermal fentanyl or sustained release oral morphine and
their main reason for preference. This evaluation was completed either at
the end of the trial or at the end of treatment in patients who withdrew
before completion.
Pain control and treatment assessment---At each visit patients were assessed
for pain control compared with the previous visit. Both investigator and
patient completed a global treatment assessment at the end of each treatment
period.
Rescue drug---Patients recorded their use of rescue morphine for
breakthrough or incident pain. The use of the drug in the first week of each
study period was excluded from the analysis, which was considered the
"titration period."
Quality of life assessment---Quality of life (SF-36) and pain intensity (0
being low and 100 high) were assessed at baseline and at the end of each
treatment period. 27 <http://bmj.com/cgi/content/full/322/7295/#B27>
Safety observations---The safety evaluation at the first visit, at
crossover, and at the end of the trial included a physical examination,
standardised measurement of vital signs, and overall assessment of disease
progression. Details of all adverse events and presumed relation to the
drugs were noted by the investigator. At each visit bowel function was
assessed by using a questionnaire, and the application site of the fentanyl
patch was evaluated.
Statistical analyses---The primary efficacy variable was analysed with a
binomial test determining whether the proportion of patients who either
"preferred" or "very much preferred" a treatment was larger than 0.5.
Differences in personal variables at baseline between treatment groups were
analysed with the Van Elteren test for continuous variables and the
Cochran-Mantel Haenszel test for categorical variables, both adjusted for
country. The mean daily dose of rescue drug, assessment of global treatment,
assessment of pain control, and quality of life scores were compared with
the Koch non-parametric paired analysis for crossover designs and adjusted
for country. 28 <http://bmj.com/cgi/content/full/322/7295/#B28> Order
effects were assessed by adding an interaction variable for treatment
sequence and were excluded if P>0.10. All other P values less than 0.05 were
considered significant.
Assignment---Patients were assigned to treatment groups by using the central
randomisation minimisation technique. 29
<http://bmj.com/cgi/content/full/322/7295/#B29> One group was randomised to
four weeks of treatment with sustained release oral morphine followed by
transdermal fentanyl for four weeks. The second group received the same
treatments but in reverse order. A washout period was considered unethical.
Results
Participant flow
The figure shows the progress of patients through the study. Sixty patients
withdrew; 37 because of adverse events, five because of insufficient
efficacy, and 18 for other reasons. Five patients without baseline data were
excluded from the efficacy analysis. All patients were included in the
safety analysis.
<http://bmj.com/cgi/content/full/322/7295/1154/Fu2>
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Flow of patients through trial
Baseline characteristics, including type of pain and patients' previous use
of opioids, did not differ between the two groups (tables 1
<http://bmj.com/cgi/content/full/322/7295/#T1> and 2). The mean starting
dose of transdermal fentanyl was 39.7 µg/hr (range 25-200 µg/hr) and of
sustained release oral morphine 123.0 mg/24 hr (range 10-700 mg/24 hr). The
mean dose of fentanyl at the end of the study was 57.3 µg/hr (range 0-325
µg/hr) and of morphine 133.1 mg/24 hrs (range 0-800 mg/24 hrs).
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Table 2. Use of opioids in month before entry to study to receive
transdermal fentanyl and sustained release oral morphine
Analysis
Patient preference
Preference could not be assessed in 39 of 251 patients, leaving a total of
212 patients for analysis. A higher proportion of patients preferred or very
much preferred transdermal fentanyl to oral sustained release morphine (138
(65%) v 59 (28%); P<0.001) (table 3
<http://bmj.com/cgi/content/full/322/7295/#T3> ). Fifteen patients (7%) did
not express a preference. After exclusion of 24 patients with a "bad" or
"very bad" score while taking morphine before the study, 69% of patients
expressed a "strong" or "very strong" preference for fentanyl.
Patient preference for fentanyl was not significantly different in patients
with nociceptive pain (75 of 108, 69%), neuropathic pain (31 of 53, 58%), or
mixed neuropathic and nociceptive pain (32 of 51, 63%). The predominant
reason given for preferring fentanyl was better pain relief, followed by
greater convenience and fewer adverse events (table 3
<http://bmj.com/cgi/content/full/322/7295/#T3> ). In a subgroup of 66
patients who were neither accustomed to fentanyl nor morphine (they had
taken other opioids before the study), 62% preferred fentanyl.
Pain control, treatment assessments, and rescue drug
Patients treated with transdermal fentanyl had on average lower pain
intensity scores than those treated with sustained release oral morphine
(mean 57.8, range 33.1-82.5 v mean 62.9, range 41.2-84.6; P<0.001),
irrespective of the order of treatment. More patients receiving fentanyl
considered their pain control to be good or very good than those receiving
morphine (35% v 23%, P=0.002) (table 4
<http://bmj.com/cgi/content/full/322/7295/#T4> ). Similar satisfaction was
found among patients receiving fentanyl with nociceptive pain (43 of 123,
35%), neuropathic pain (21 of 62, 34%), or combined neuropathic and
nociceptive pain (23 of 63, 37%). The corresponding satisfaction rates with
morphine were 15 or 59 (25%) patients, 27 of 116 (23%), and 12 of 59 (20%),
respectively. Overall, about one quarter of patients considered their pain
control poor or very poor with either treatment (table 4
<http://bmj.com/cgi/content/full/322/7295/#T4> ).
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Table 3. Patients' preferences for transdermal fentanyl or sustained release
oral morphine. Values are numbers (percentages) unless stated otherwise
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Table 4. Assessment of pain control at end point of each four week
intervention period after treatment with transdermal fentanyl or sustained
release oral morphine. Values are numbers (percentages)
In the investigators' opinion, global efficacy of fentanyl was good or very
good in 131 of 225 (58%) patients compared with 75 of 224 (33%) patients
receiving morphine (P<0.001). The corresponding percentages from the patient
assessments were 60% for fentanyl and 36% for morphine (P<0.001).
Analysis of the consumption of rescue drug during the last three weeks of
each treatment period showed that the mean (standard deviation) consumption
was significantly higher with fentanyl (29.4 (33.0) mg) than with morphine
(23.6 (32.0) mg; P<0.001). A significant (P<0.05) period effect was also
observed: the higher consumption during fentanyl treatment was more apparent
in the second trial period (mean 32.4 (SD 38.5) mg) than the first (26.3
(26.0) mg), where the consumption of the rescue drug remained essentially
the same over the two treatment periods in the morphine group (23.7 (35.3)
mg v 23.6 (27.3) mg).
Quality of life---Patients had, on average, quality of life scores below the
median on a scale ranging from 0 to 100 (lowest to highest wellbeing) (table
5 <http://bmj.com/cgi/content/full/322/7295/#T5> ). Patients receiving
transdermal fentanyl had higher overall quality of life scores than patients
receiving sustained release oral morphine in each of eight categories
measured by the SF-36. Differences were significant in the categories for
bodily pain, vitality, social functioning, and mental health. No period
effect was noted.
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Table 5. Quality of life scores* based on SF-36 of both intervention periods
after treatment with transdermal fentanyl or sustained release oral
morphine. Values are means (95% confidence intervals)
Adverse effects---The overall incidence of treatment related adverse events
was similar in both groups (table 6
<http://bmj.com/cgi/content/full/322/7295/#T6> ), as was the proportion of
patients with adverse events (74% v 70%). Transdermal fentanyl was
associated with a higher incidence of nausea (26% v 18%) than was sustained
release oral morphine, whereas constipation was less common with fentanyl
than with morphine (16% v 22%). Reduced constipation was confirmed by the
bowel function questionnaire (29% fentanyl v 48% morphine; P<0.001) (table 6
<http://bmj.com/cgi/content/full/322/7295/#T6> ). Erythema and itching at
application sites commonly occurred in patients receiving fentanyl (101 of
250, 41%) but were of mild to moderate intensity. Few patients had serious
adverse events (2.8% v 3.8% for fentanyl and morphine, respectively), and
only one patient, in the morphine group, hypoventilated. No deaths occurred,
and no clinically important changes of vital signs were observed.
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Table 6. Most common adverse events related to treatment with transdermal
fentanyl or sustained release oral morphine and bowel function, skin
assessments, and disease progression. Values are numbers (percentages) of
patients
Patient withdrawals---Within the total patient population the number of
withdrawals in the fentanyl group was almost double (16%) that in the
morphine group (9%) (table 7
<http://bmj.com/cgi/content/full/322/7295/#T7> ). More patients withdrew
because of adverse events during treatment with transdermal fentanyl (11%)
than with sustained release oral morphine (4%). However, subgroup analysis
of 66 patients who had taken neither fentanyl nor morphine before the study
showed that both the total number of withdrawals and withdrawals for adverse
events were similar between treatment groups (table 7
<http://bmj.com/cgi/content/full/322/7295/#T7> ). Ten patients (16%) in the
fentanyl group and 11 patients (18%) in the morphine group withdrew from the
trial; seven patients receiving fentanyl (11%) and six receiving morphine
(9.8%) withdrew because of an adverse event.
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Table 7. Number of patient withdrawals per treatment group for whole
population and subpopulation of patients who had taken neither morphine nor
fentanyl before study (naive patients). Values are numbers (percentages) of
patients unless stated otherwise
Discussion
Patients with chronic non-cancer pain generally preferred treatment with
transdermal fentanyl (65%) than with sustained release oral morphine (28%).
A similar result was observed in patients with cancer pain. 21
<http://bmj.com/cgi/content/full/322/7295/#B21> 22
<http://bmj.com/cgi/content/full/322/7295/#B22> Furthermore, our findings
confirm that potent opioids can provide satisfactory pain relief for the
difficult clinical problem of chronic non-cancer pain. Although recruitment
bias cannot be excluded, it cannot entirely explain the observed difference
in treatment outcome.
Despite preference and better pain relief, more patients withdrew because of
adverse events in the first fentanyl period than in the first morphine
period. The phenomenon of preference for an opioid despite higher reporting
of adverse events is well recognised in blinded controlled trials. 7
<http://bmj.com/cgi/content/full/322/7295/#B7> 9-11
<http://bmj.com/cgi/content/full/322/7295/#B9> Most patients (76%) had
taken morphine for six weeks before entry to the study and would be
accustomed to its side effects, making it unlikely that they would report
additional adverse events when randomised to sustained release oral
morphine. This may represent "incomplete cross tolerance" leading to a
greater than anticipated potency. 3
<http://bmj.com/cgi/content/full/322/7295/#B3> 30
<http://bmj.com/cgi/content/full/322/7295/#B30> It is supported by analysis
of a subgroup of patients who had taken neither morphine nor fentanyl before
the trial. Here, withdrawals in total and in relation to adverse events were
similar in both groups.
Comparisons of opioid action must be made at equianalgesic doses. It would
be possible to explain the observed improvement in pain control and
constipation with fentanyl if the initial dose ratios were wrong. The dosage
of fentanyl increased consistently during each four week period, and these
patients consumed more rescue drug than those receiving morphine. These
findings confirm that a higher ratio of starting dose may be required
compared with the conservative equianalgesic dose table used in this study.
19 <http://bmj.com/cgi/content/full/322/7295/#B19> However, individual dose
titration is vital and allows for the variability in patients' response to
different opioids and the reported need to reduce the dose during "opioid
rotation" in patients showing toxicity. 3
<http://bmj.com/cgi/content/full/322/7295/#B3> 21
<http://bmj.com/cgi/content/full/322/7295/#B21> 31
<http://bmj.com/cgi/content/full/322/7295/#B31>
The tables for equianalgesic dose derive from studies of single doses in
selected populations and should be regarded as tentative for incomplete
cross tolerance. 3 <http://bmj.com/cgi/content/full/322/7295/#B3> 30
<http://bmj.com/cgi/content/full/322/7295/#B30> Our patients were
conditioned to opioids, mainly morphine, and switching to fentanyl may
partly explain the improved pain control. The switch may have raised
expectation of increased pain relief, partly attributable to a placebo
analgesic effect. 32 <http://bmj.com/cgi/content/full/322/7295/#B32> Most
patients, however, preferred fentanyl regardless of the order of treatment.
Exclusion of patients dissatisfied with morphine did not affect the
percentage of patients preferring fentanyl.
The higher consumption of rescue drug during treatment with fentanyl was
small (5.8 mg/24 hr overall), and probably not clinically important, but may
reflect a less flexible dose titration with fentanyl. Furthermore, the
difference in consumption of rescue drug was not significantly different
between treatments in the first period. Differences in pain relief may also
be explained by selectivity of opioid receptors. Indeed, recent research
indicates a genetic basis for differences in pain sensitivity and response
to analgesics. 33 <http://bmj.com/cgi/content/full/322/7295/#B33>
A significantly lower incidence of constipation was detected in the formal
assessment of bowel function by patients receiving fentanyl (29% fentanyl v
48% morphine; P<0.001), confirming previous reports. 18-22
<http://bmj.com/cgi/content/full/322/7295/#B18> In rats, fentanyl has a
more favourable dose-analgesia to dose-constipation ratio than morphine,
probably because the higher lipid solubility of fentanyl enables it to pass
through the blood-brain barrier more easily than morphine. 34
<http://bmj.com/cgi/content/full/322/7295/#B34> Giving fentanyl
transdermally limits gastrointestinal concentration compared with oral
morphine and consequently has less effect on opioid receptors in the gut.
The fentanyl patch formulation affords a convenient system of delivery over
72 hours. It may prevent "clock watching" and breakthrough pain associated
with shorter acting formulations, thus improving compliance. 4
<http://bmj.com/cgi/content/full/322/7295/#B4> In a "double dummy" design,
preference for one delivery system would have been difficult to assess if
patients were receiving both drugs together, particularly considering the
difficulties and risks associated with simultaneously titrating morphine and
fentanyl, as they have different dose schedules. Placebo effects can explain
analgesia but not poor analgesia. 35
<http://bmj.com/cgi/content/full/322/7295/#B35> Therefore, although a
placebo effect is a possible explanation for our findings, given an overtly
different administration, it is a less plausible explanation for those
receiving fentanyl or morphine who had poor pain control. These findings are
consistent with other reports that opioids do not provide adequate pain
control to all patients with chronic non-cancer pain. 5
<http://bmj.com/cgi/content/full/322/7295/#B5> 9
<http://bmj.com/cgi/content/full/322/7295/#B9> 10
<http://bmj.com/cgi/content/full/322/7295/#B10>
Finally, we believe that using a pragmatic, clinical practice based
approach, particularly in a large sample size, is justified, especially in
the light of recent problems applying quality designs to clinical trials. 36
<http://bmj.com/cgi/content/full/322/7295/#B36> 37
<http://bmj.com/cgi/content/full/322/7295/#B37> The "explanatory" (evidence
based) approach requires a placebo for comparison, whereas the "pragmatic"
approach generally compares a new treatment with the best in clinical use
for the particular clinical circumstances of patients. 38
<http://bmj.com/cgi/content/full/322/7295/#B38> The existence of a gold
standard treatment allows direct comparison rather than a placebo control,
so that transdermal fentanyl can be directly compared with sustained release
oral morphine. 39 <http://bmj.com/cgi/content/full/322/7295/#B39>
Strong treatment preferences can present difficulties but may be avoided by
the crossover design. 40 <http://bmj.com/cgi/content/full/322/7295/#B40> 41
<http://bmj.com/cgi/content/full/322/7295/#B41> Patients' preference,
although important for all clinical decisions, deserves special emphasis
when diseases or treatments affect quality of life, the treatment involves
risks or side effects, or the choice between treatments is a "close call."
42 <http://bmj.com/cgi/content/full/322/7295/#B42> The patient may be the
best judge of the delicate balance between analgesic efficacy, side effects,
and the overall experience of pain. This reflects our choice of patients'
preference as the primary efficacy variable. Furthermore, pragmatic outcome
measures such as quality of life and patients' preference may, ultimately,
form a more accurate evaluation of treatment effects than pain measures
alone.
Acknowledgments
We thank all the investigators who participated in the trial: J Maeyaert, L
Plaghki (Belgium); J Clark, A Mailis, D Moulin, M Ong-Lam, D Reid, P Watson
(Canada); S Andersen, C Christiansen, S Clemensen, K Glahn, T Jonsson, S
Larsen, F Molke Borgbjerg, A Schou Olesen, J Mųlgaard (Denmark); V
Järvimäki, T Heiskanen (Finland); R Atkinson, P Brown, F Campbell, R Gautam,
M Hanna, D Hughes, C Knight, W Notcutt (United Kingdom); G Braak, J Helmers,
G Van Oss, W Zuurmond (Netherlands); D Lines (South Africa).
Contributors: LA was the principal author of the paper. H Noorduin
(international supervisor of the trial), L Bijnens (biostatistics), L
Haazen, M Travers, D Peelmans, N Currie, A Jepsen, M Jarvinen, M Uitendaal,
P Matthysen (local trial coordination and monitoring). MT will act as
guarantor for the paper.
Footnotes
Funding: The study was supported by a grant from Janssen Research
Foundation, Belgium.
Competing interests: LA receives support from both Janssen-Cilag, the
manufacturer of transdermal fentanyl (Durogesic) and Napp Laboratories, the
manufacturer of sustained release morphine. EK has been reimbursed by
Janssen-Cilag for participation at a meeting sponsored by Janssen-Cilag.
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(Accepted 13 December 2000)
Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.
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