LECTURE
Clinical experience with transdermal fentanyl forthe treatment of cancer pain in Germany
Lukas Radbruch and Frank Elsner
Department of Palliative Medicine, University Hospital Aachen, Aachen, Germany(Received for publication on May 6, 2003)

Abstract. The transdermal therapeutic system with fentanyl was released in Germany in 1995. Before
and after the release several clinical trials were performed in our pain management unit and in other
German pain centers, showing good efﬁcacy after initial dose titration with intravenous patientcontrolled analgesia or switching from pretreatment with oral morphine or other opioids. A sequential
trial showed less use of laxatives with transdermal fentanyl compared to pretreatment with oral morphine. Safety and efﬁcacy of the transdermal system in clinical practice were conﬁrmed in a nationwide
survey with 1005 patients, nearly all of them with cancer pain. Most patients had been treated with
opioids, though 22% had received no opioids or only as required before initiation of transdermal fentanyl. The mean duration of transdermal treatment was 71 G 83 days. Pain relief with transdermal
therapy was swift and efﬁcient. Adverse events with the possibility of a causal relationship to transdermal therapy were documented for 26% of the patients, most frequently nausea, vomiting, constipation and drowsiness. Severe neurotoxic or respiratory complications were reported only rarely.
Problems with transdermal application were reported by 12% of the patients, with patch detachment
and dermatologic symptoms on the site of application being most frequent. Most patients showered
regularly with the patches and only three patients reported that patches became loose under theshower or in the bathtub. In a recent prospective trial driving ability was tested in patients with continuous non-cancer pain, who had received stable doses of transdermal fentanyl. Data were available
from 90 healthy volunteers matched to 30 patients, of whom 9 were excluded from the analysis because
they took additional drugs in violation of the protocol. None of the performance measures for the 21
remaining fentanyl patients was signiﬁcantly inferior to the controls. In conclusion, experience with thetransdermal therapeutic system with fentanyl has been gathered in clinical trials, a large nationwide
survey and clinical practice since the release in 1995. The conversion table based on a conversion ratioof 100 : 1 was safe and efﬁcient in trials and clinical practice. Transdermal fentanyl has become a wellknown and frequently used opioid in the treatment of chronic cancer and non-cancer pain in Germany.
(Keio J Med 53 (1): 23–29, March 2004)
Key words: Transdermal fentanyl, Germany, Cancer pain, Constipation

The application of anaegesics by the oral route is oneof the major recommendations of the World HealthOrganisation in their cancer pain guidelines ﬁrst published in 1986 (World Health Organisation 1986).1
Regular application with ﬁxed intervals and the analgesic ladder using non-opioids for slight pain, codeinetype opioids for moderate pain and morphine-type
opioids for severe pain were the other important rec-ommendations in these guidelines. Following theseguidelines, oral morphine, preferably with slow releasetablets, has become the most important analgesic drugin many countries. The construction of the fentanyl
patch, that allowed the continous transdermal application of a potent opioid, has provided new options, andits beneﬁt for example for patients unable to take oral
medications is evident.

Presented at the 1309th Meeting of the Keio Medical Society in Tokyo, February 26, 2003.
Reprint requests to: Dr. Lukas Radbruch, Department of Palliative Medicine, University of Aachen, Pauwelsstr. 30, 52074 Aachen, Germany,
telephone: þþ49 241 80 80726, facsimile: þþ49 241 80 33 80726, e-mail: lradbruch@ukaachen.de23

24

Clinical Trials with Transdermal Fentanyl in Germany
The fentanyl patch was released in the USA in 1992.
In Germany the patch system with fentanyl was released in 1995, though the release was burdened withsome restrictions initially. The initiation of the transdermal opioid therapy was allowed only for inpatientswith chronic cancer pain and only by pain specialists.
After the initial phase continuation of the therapy was
possible by other non-specialized physicians and in theout-patient setting as well. The reason for these restrictions were concerns of the authorities about the safetyof the transdermal system. Only in 1998 the restrictions were lifted, allowing the initiation of the transdermal therapy also in the out-patient setting and by
non-specialists. Another year later, in 1999, transdermal fentanyl was released for the use in chronic noncancer pain as well.
Even before the release in Germany our unit has
been involved in the research on transdermal fentanyl.
A pilot study with 20 patients (Zech et al. 1992)2 and asubsequent trial with another 50 patients (Grond et al.
1997)3 used intravenous patient-controlled analgesia(PCA) for the initial dose titration of the transdermal
therapy. The pilot study used a conversion ratio of 1 : 1
from the 24-hour dosage of the PCA to transdermal
fentanyl. With this ratio most patients required dose
increases with the transdermal appllication, and so thefollowing study used a conversion ratio of 1 : 1.5. However, with this higher ratio, mild respiratory depression
was seen in 3 of the 50 patients. Other side effects wererare, and patients were treated up to 18 months withoutcomplications.
In the meantime another clinical multicenter trial
in Germany had converted patients pretreated withoral morphine to transdermal fentanyl and had
shown good results with a conversion ratio of 100 : 1 forthe daily dosages (for example 60 mg/day morphine ¼
0.6 mg/day fentanyl ¼ one patch with 2.5 mg). A conversion table using this ratio of 100 : 1 was recommended subsequently and was included in the package
insert.
One of the advantages of the transdermal therapeutic system in these trials were lower incidences of
constipation compared to other oral opioids used for
pretreatment. Signiﬁcantly less constipation with transdermal fentanyl than with oral morphine was found in
an open cross-over study with 202 patients from palliative care centers in the United Kingdom (Ahmedzai
and Brooks 1997).4 One item of the quality of lifequestionnaire of the European Association for theTreatment of Cancer Pain (EORTC) were used to assess constipation. Mean score after 2 weeks of fentanyl
therapy was 20.7 compared to 36.6 after 15 days ofmorphine treatment.

Radbruch L and Elsner F: Transdermal fentanyl in Germany

In a German multicenter study by Donner and colleagues 38 patients were treated with slow releasemorphine for 6 days and then switched to transdermal
fentanyl for 15 days (Donner et al. 1996).5 Patients
reported constipation on 58.8% of days with morphine.
This was reduced to 35.1% of the days with transdermal
fentanyl. Concomitantly, the medication with laxatives
was reduced from 62% to 38% of days. However, assessment of constipation was not standardised. Side
effects such as constipation were elicited by questioning
and control of the pain diary.
In a non-randomized sequential cross-over study additional data were compiled on constipation rates anduse of laxatives (Radbruch et al. 2000).6 In this multicenter trial patients with adequate pain relief fromoral morphine documented bowel movements and useof laxatives for six days. Patients then were switched
to transdermal fentanyl using the conversion ratio of
100 : 1.
The number of patients with bowel movements did
not change after the opioid switch but the number ofpatients taking laxatives was reduced signiﬁcantly from78–87% of the patients per treatment day (morphine)
to 22–48% (fentanyl). Lactulose was used mainly andwas reduced most drastically but other laxatives wereused less frequently, too.
In this trial the equianalgesic ratio was calculated
after dose adjustments to archive the same level of pain
relief after switching to transdermal fentanyl. Comparing the median dose of 2.4 mg/day on day 15 with themedian morphine dosage before conversion, a ratio of
75 : 1 could be calculated from our data. This conﬁrms
the equianalgesic conversion rate of 70 : 1 found by
Donner et al. (Donner et al. 1996),5 providing a goodsafety margin to the conversion ratio of 100 : 1 used inGermany.
Nationwide Survey on Transdermal Fentanyl
Whereas constipation was less with the transdermal
application route than with oral application and otherside effects were comparible, there still was considerable concern about the safety of the transdermal system. Reviewers for the German health authorities
stated their concern that an incidence of two percent of
respiratory depression in cancer pain and up to 6 percent in acute pain (Food and Drug Administration
1990)7 was too high to recommend the use of transdermal fentanyl as an alternative for oral morphine,
and this had led to the restrictions of the release oftransdermal fentanyl in 1995. To ﬁnd additional data on
the safety of the transdermal system a nationwide survey was coordinated in our pain clinic from 1996 to
1998 (Radbruch et al. 2001).8 More than 290 physiciansparticipated in this survey, documenting data from 1005

Keio J Med 2004; 53 (1): 23–29

patients. Most physicians worked in hospital departments and out-patient clinics, though general practitioners participated as well. Pain specialist training was
not predominant among these physicians, as only 27%
were members of the German chapter of the International Association for the Study of Pain.
The survey included 996 patients with cancer pain
and 11 patients with non-cancer pain. Transdermal
therapy was initiated at the time of admission in thesurvey for 824 patients, while 181 patients had beentreated with transdermal fentanyl before admission in
the survey. More than half of the patients had beentreated with step-3 opioids of the WHO analgesic
ladder. However, 23% had only received pretreatment
with step-2 opioids such as tramadol, 8% only nonopioid pretreatment and 14% hat received no analgesics or only as required before initiation of transdermal
fentanyl.
The most important reason for switching to transdermal opioid therapy was insufﬁcient pain relief withthe previous medication followed by a variety of gastrointestinal symptoms impeding oral analgesic therapy.
More than 300 patients were switched from pretreatment with modiﬁed release morphine (median dose 90
mg/d, range 10–950 mg/d), and the median conversion
ratio to transdermal fentanyl used for these patientswas 75 : 1. Normal release morphine and buprenorphine
were given less frequently, whereas oxycodone, levomethadone, piritramid or pentazocine were used only
rarely. Tramadol and to a lesser extent tilidine wereused most frequently as step-2 opioids, while only a few
patients were treated with codeine, dihydrocodeine anddextropropoxyphene. More than 20% of the patients
had received no continuous opioid medication prior toinitiation of transdermal therapy.
Transdermal fentanyl therapy was started with a
median dosage of 1.2 mg/day (50 mg/h) fentanyl initially, with some patients starting on higher doses up to
9.6 mg/day (400 mg/h). In seven cases transdermal
therapy was started with doses of 1.8 or 2.4 mg/day (75or 100 mg/h), though patients had received no continuous opioid medication before. Most patients needed adose increase during the study, and the median dosage
increased to 2.4 mg/day (100 mg/h) after 4 months (Fig.
1). The maximum dose given was 21.6 mg fentanyl per
day or 9 patches with 100 mg/h each. Only three patients reported that they had difﬁculties ﬁnding enoughskin areas for the application due to the high number ofpatches. The mean duration of transdermal treatment
was 71 G 83 days (median 35 days, range 1–478 days,
Fig. 1). Transdermal therapy was documented for morethan one year for 16 patients.
Initially patches were changed every third day in
95% of the patients, only 5% changed patches withother intervals. During the course of transdermal treat-25

Fig. 1

Fentanyl dosage (median and range) for 1005 patients.

ment application intervals were shortened in somepatients. At the end of the study period 14% of thepatients changed patches every second day, and 5%
used other intervals, such as 60-hourly, every fourthday, alternating between every second and third day, or
every day. Most patients (up to 70% on each followup visit) showered regularly with the patches and only
three patients reported that patches became loose under the shower or in the bathtub. Problems with transdermal application were reported by 12% of the patients, with patch detachment (10%) and dermatologic
symptoms on the site of application (4%) being mostfrequent. Seven patients removed a patch themselves,either accidentally while sleeping or during episodes ofconfusion with advanced disease.
Pain relief with transdermal therapy was swift andefﬁcient (Fig. 2). Whereas half of the patients reported
severe or very severe pain on day 0, the percentage
decreased to 14% on day 3. The percentage of patientswith more than moderate pain remained small during
the next months, however, severe pain led to a changeof the analgesic regimen in some cases. Episodic pain
was documented for 60% of the patients on day 0. Although this was reduced considerably during treatment
with transdermal fentanyl, episodic pain was reported
frequently, often in combination with continuous pain,
throughout the study period (Fig. 3).
Adverse events, where the treating physician could
not exclude a causal relationship to transdermal therapy, were documented for 26% of the patients. This
included mainly gastrointestinal symptoms such as
nausea (6% of the patients), vomiting (3%) and constipation (4%) as well as drowsiness (3%), while serious
neurotoxic side effects such as hallucinations (0.2%),
withdrawal (0.1%) or convulsions (0.1%) were reported
only rarely. However, documentation discipline in thisopen survey may have led to underreport of adverse
events. Side effects from the skin were likewise rarewith a few cases of erythema (1%) and pruritus (1%).
Transdermal therapy was continued until the time ofdeath in 424 patients (42%). For another 35 patients(4%) transdermal fentanyl had been discontinued at

26

Radbruch L and Elsner F: Transdermal fentanyl in Germany

Fig. 2 Intensity of continuous pain before and during transdermal therapy with fentanyl for 1005 patients. Rating by the treating physician ona 5-step descriptive scale (very slight, slight, moderate, severe, very severe).

Fig. 3 Prevalence of continuous and episodic pain in 1005 patients treated with transdermal fentanyl. Rating by the treating physician on achecklist (present/not present). For a few patients continuous pain was rated as not present, although intensity of continuous pain (Fig. 2) had
been rated as slight or very slight.

least three days before death. Transdermal therapy was
discontinued in 355 patients (35%) for other reasons
than death, most often for inadequate pain relief(10%), pain relief with other analgesic regimens (10%),adverse events (5%), or rejection of transdermal therapy by the patient (6%). Respiratory depression, one of
the major fears associated with opioid treatment, wasreported by the treating physician for 8 patients in thesurvey. Reviewing these case reports, this may havebeen caused by progressive disease or concomittant
complications such as pleuritis or pnemonia and in mostcases probably represented dyspnoea rather than respiratory depression. Dyspnoea is a common symptom
in cancer patients and was reported by the patients ofthe survey in unchanged intensity throughout the observeration period. Dyspnoea is no typical sign of

Keio J Med 2004; 53 (1): 23–29

opioid-induced respiratory depression, as the opioidrelated decrease of the respiratory drive in the central
nervous system usually does not cause the patient tofeel breathless. In two cases an overdose was suspected,
and both patients needed artiﬁcal ventilation for several hours. Both patients had been on stable doses forlonger time spans, and the overdose was probably due
to progressive renal failure and liver metastases in one
patient and pain relief from chemotherapy in the other.
Fentanyl is metabolized mainly in the liver and only toa lesser extent in the kidneys and therefore renal failure
should not lead to an overdose. However, with decompensation of the renal function and concurrent changes
in the ﬂuid balance a redistribution of fentanyl may
have led to the overdose. Liver function was not assessed at that time and so the share of the liver metastases in the development of the respiratory depression
remained unclear.
Apnoea was reported in a 63 year old patient withchronic lymphatic leucaemia and a history of chronic
obstructive lung disease after 6 weeks of transdermal
therapy with 1.8 mg fentanyl per day. The patch wasremoved, and artiﬁcal respiration was required for several hours. The patient recovered without sequelae. He
had been treated with chemotherapy over the previous
9 weeks, and concurrent pain relief may have led to theobserved opioid toxicity.
Side effects from the skin led to discontinuation inthree patients. One patient suffered from an allergic
reaction to the adhesive and had to stop the application
after 10 days. An erythema with exudations and pruritus on the application site was reported in a patient
after 56 days of transdermal therapy. At this time thepatient was somnolent, and an increase of the fentanyl
absorption rate through the damaged skin area may
have added to that effect. The third patient discontinued transdermal therapy after three days because ofa mild erythema at the site of application.
In the patients of the survey 72 major interventions
involving osteosynthesis, laparatomy or thoracotomy
were performed during treatment with transdermal fentanyl, and minor interventions such as port implantation, cystoskopy or insertion of a central venous line in
74 cases. Only 18 patients discontinued transdermal
therapy in connection with the procedure, in 7 cases
because of pain relief from the surgical therapy, in theremaining 11 because of safety concerns. However,transdermal therapy was continued perioperatively
without a change of dosage in 111 cases (information
not available for 19 patients). This supports our recommendation to leave the transdermal application unchanged perioperatively, if surgical procedures are performed in clinical practice.
In conclusion, in the patients of the survey transdermal therapy with fentanyl was safe and effective,

27

even when analgesic pretreatment and initiation oftransdermal therapy did not follow the WHO recommendations and when patients were treated by general practitioners. Most patients continued transdermal
therapy until death. Complications were rare, evenwhen patients underwent surgical procedures, or received chemo- or radiotherapy.
Driving Ability and Transdermal Fentanyl
The use of opioids for the treatment of acute pain isoften associated with varying degrees of cognitive impairment. This observation has raised concern that
long-term opioid treatment might have a negative impact on cognition and psychomotor function. Clinicalexperience shows that neuropsychological side effects
due to opioid therapy usually decrease in the ﬁrst weeks
under stable medication. However, the effect of longterm treatment with transdermal fentanyl on complex
activities such as driving is not yet clear.
In a prospective trial, patients with continuous noncancer pain, who had received stable doses of transdermal fentanyl for at least 2 weeks, completed a seriesof computerized tests to measure attention, reaction,
visual orientation, motor co-ordination and vigilance(Sabatowski R, et al. 2003).9 Data were available from90 healthy volunteers matched to 30 patients, of whom
9 were excluded from the per-protocol analysis because
they took additional drugs in violation of the protocol.
None of the performance measures for the 21 remaining fentanyl patients was signiﬁcantly inferior to thecontrols.
We conclude that stable doses of transdermal fentanyl for the treatment of chronic non-cancer pain are
not associated with signiﬁcant impairments in psychomotor and cognitive performance. The threshold forﬁtness to drive as deﬁned by German law did not differ
signiﬁcantly between the groups.
Economic Considerations
In comparing fentanyl-TTS with cr-morphine it isnecessary to take into account not only a different
safety proﬁle compared with cr-morphine, but also theimpact of the different mode of administration on costs
and patient functioning. A model was therefore constructed to investigate the cost–utility of transdermal
fentanyl compared with controlled release oral morphine in the treatment of moderate-to-severe chronic
nonmalignant pain (Lehmann et al. 2002).10
The model comprises three phases through which thepatients move sequentially: an initial dose titration,subsequent stabilisation and long-term use. The probability and duration of an event, disutility values and unit
costs are assigned as appropriate for events occurring

28

Radbruch L and Elsner F: Transdermal fentanyl in Germany

within each phase. Outcomes associated with eachphase, such as the level of pain control, toxicity andquality-adjusted life days, are carried forward to subsequent phases. Use of fentanyl-TTS was predicted to incur higher costs than cr-morphine over 1 year of treatment (Euro 3553 vs Euro 3163, respectively), but was
associated with a higher number of quality-adjusted
life-days (234 vs 216, respectively), thus achieving an
incremental cost–utility ratio of Euro 8160 per qualityadjusted life-year gained. Though there certainly are
limitations of using such a model wherein possible inaccuracies are introduced through obtaining estimatesfrom a variety of sources, including assumptions basedon expert opinion, the results of the decision-analytic
model support the use of fentanyl-TTS as a favourable
cost-effective option for the treatment of moderate-tosevere nonmalignant pain.
Opioid Prescriptions in Germany
The options for opioid therapy have expanded considerably with the introduction of new slow release application forms in Germany. Transdermal application
forms of fentanyl (1995) and buprenorphine (2001) as
well as oral slow release oxycodone (1998) and hydromorphone (1999) have been released in the last years(Radbruch et al. 2002).11
Prescription of WHO-step 3 opioids requires special
triplicate prescription forms in Germany. The regulations for these prescription (Betäubungsmittelverschreibungsverordnung BtmVV) have been revised
repeatedly. The 10th revision in February 1998 has
lifted several restrictions, facilitating the prescription of
opioid analgesics. However, physicians still have toorder their own prescription forms at the Bundesopiumstelle, the federal regulatory bureau. More than
80% of the general practitioners reported to have these
forms available (Sabatowski et al. 2001).12 In anothersurvey 85% of the general practitioners who hadtreated cancer patients recently had the prescription
forms available, though the percentage was much lessfor other groups and specialisations of physicians, andonly 37% of the complete sample had opioid prescription forms (Ensink et al. in print).13
In the report of drug presciptions for Germany 1.6
million deﬁned daily doses (DDD) of slow releasemorphine had been prescribed in 1990, and this had
increased to 15.4 million DDD in 2000 (Böger andSchmidt 2001; Schmidt 1991).14–15 In the same period
the amount of other opioids prescribed had increased
even more, including buprenorphine (1.3 mio DDD),
levomethadone (3.9 mio DDD), oxycodone (7.7 mio
DDD) and ﬁrst of all fentanyl (34.0 mio DDD). Transdermal fentanyl has overtaken morphine in Germany inthe number of units and the DDDs sold. These data

do not differentiate between prescriptions for nonmalignant and malignant pain, and most of the increases will be related to non-malignant pain. However,in a recent survey morphine and fentanyl had been used
as frequently for 25.5% of the patients each for pretreatment before admission in 1304 patients in German
palliative care units. The use of fentanyl was increased
even further during inpatient treatment (28.2% of thepatients, although the use of morphine increased more
(42.3% of the patients) (Nauck et al. in print).16
Conclusions
Experience with the transdermal therapeutic systemwith fentanyl has been gathered in clinical trials, a large
nationwide survey and clinical practice since the releasein 1995. The conversion table based on a conversion
ratio of 100 : 1 was safe and efﬁcient in trials and clinicalpractice. Side effects typical for opioids were documented with transdermal application with fentanyl, although constipation was less than with oral morphine.
Patients reported ease of administration and high satisfaction with the transdermal therapeutic system. Most
patients reported adequate pain relief with one patch
system over long periods of time, though some patients
have been treated with high dosages up to 1200 mg perhour. In some patients, longterm treatment for morethan one year with stable dosages has been reported.
Transdermal fentanyl has become a well-known andfrequently used opioid in the treatment of chronic cancer and non-cancer pain in Germany.
Acknowledgements: The lecture was supported by a travel grant from
Janssen Pharmaceutical K.K., Japan. The chair for palliative medicineof the University Hospital of Aachen (Lukas Radbruch) is funded byan unrestricted grant of the Grünenthal Foundation for Palliative
Care.

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