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Direct conversion from oral morphine to transdermal fentanyl: a multicenter study in patients with cancer pain
Pain, 64 (1996) 527-534 © 1996 Elsevier Science B.V. All rights reserved 0304-3959/96/$15.00
527
PAIN 2969
Direct conversion from oral morphine to transdermal fentanyl: a multicenter study in patients with cancer pain Barbara Donner, Michael Zenz, Michael Tryba and Michael Strumpf Departments of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Bergmannsheil, 44789 Bochum, Buerkle-de la-Camp Platz I (Germany)
(Received 31 July 1995; accepted 16 August 1995)
Summary Direct conversion from oral morphine to transdermal fentanyl with a ratio of oral morphine/ transdermal fentanyl (100:1 mg) daily was examined in patients with cancer pain. Patients with a 'stable and low level of cancer pain' receiving a constant dosage of sustained release morphine during a pre-study phase of 6 days were included in the study. Initial fentanyl dosage was calculated by a conversion table. The transdermal system was changed every 72 h and the dosage was adjusted to the needs of the patients according to the VAS scores and the requirement of liquid morphine, which was allowed to achieve sufficient pain relief. Regression analysis at the end of the study revealed a mean morphine/transdermal fentanyl ratio of 70:1. Pain relief during treatment with transdermal fentanyl was identical to sustained release morphine. However, significantly more patients took: supplemental medication with liquid morphine during transdermal fentanyl therapy. The number of patients suffering from pain attacks did not increase with transdermal fentanyl. Constipation and medication with laxatives decreased significantly during fentanyl therapy. Other side effects and vital signs were identical. Three patients suffered from a morphine withdrawal syndrom beginning within the first 24 h of transdermal fentanyl therapy. Cutaneous reactions to the patch were rare, mild and transient. Patients and physicians reported satisfaction with the transdermal therapy. 94.7% of the patients chose to continue the transdermal fentanyl therapy at the end of the study due to better performance in comparison to oral morphine. Due to these results an initial conversion from oral morphine to transdermal fentanyl with the ratio of 100:1 is safe and effective. Key words: Morphine, oral; Morphine, sustained release; Fentanyl, transdermal; Cancer pain
Introduction Transdermal fentanyl represents a new administration route for chronic opioid therapy. Fentanyl, an opioid with pure /x-agonist activity, is 75-100 times more potent than morphine on a molar basis (Rowbotham et al. 1989; Enck 1990; Freye 1991; Moser 1992). Parenteral fentanyl is a short-acting analgesic at non-steady-state conditions, when half-life time is primarily determined by redistribution (Mather 1983). Due to low molecular weight and high lipid solubility fen* Corresponding author: B. Donner, MD, Departments of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Bergmannsheil, 44789 Bochum, Buerkle-de la-Camp Platz 1, Germany. SSDI 0304-3959(95)00180-8
tanyl can be administered transdermally (Enck 1990; Roy and Flynn 1990). The cutaneous uptake from a transdermal therapeutic system of fentanyl (fentanyl TFS) is proportional to the application area. After application of a patch, peak serum levels are approached within 8-12 h (Holley and van Stevens 1988; Gourlay et al. 1989; Latasch and Liiders 1989; Plezia et al. 1989; Varvel et al. 1989; Calis et al. 1992; Lehmann and Zech 1992). The transdermal therapeutic system delivers fentanyl continuously for up to 72 h (Caplan and Southam 1991; Southam et al. 1991; Gupta et al. 1992; Sandier 1992). Portenoy et al. (1993) demonstrated that constant serum levels are maintained with the second transdermal system. Fluctuations of serum levels are small after the first 72 h (Portenoy et al. 1993). Due to the dermal depot of fentanyl serum
528
half-life time is 16-21 h (Holley et al. 1988; Larijani et al. 1988; Gourlay et al. 1989; Varvel et al. 1989; Janssen Pharmac. 1990; Gupta et al. 1992; Lehmann and Zech 1992). The management of cancer pain with transdermal fentanyl has been investigated in several clincal studies (Larijani et al. 1988; Levy et al. 1988, 1992; Miser et al. 1989; Payne 1990; Zech et al. 1991a,b,c; Herbst and Strause 1992; Maves and Barcellos 1992; Patt and Hogan 1992; Slover 1992; van Deventer et al. 1993). A ratio of oral morphine/fentanyl TTS of 150:1 has been recommended (Janssen Pharmac. 1990, 1991) but not approved by clinical studies. In most previous studies patients were hospitalized for conversion to transdermal fentanyl (Levy et al. 1988; Miser et al. 1989; Herbst et al. 1992; Slover et al. 1992; Zech et al. 1992) and the switchover to fentanyl TTS was performed by an intermediate step with parenteral administration of fentanyl (Miser et al. 1989; Maves and Barcello 1992; Zech et al. 1992). However, this approach does not meet the needs of the patients who wish to stay at home with an analgesic therapy allowing to live as normal as possible and to be independent from the physician. Present data from chronic dosing surveys are limited and more experience with the transdermal system is needed to confirm the results of previous investigations (Calis et al. 1992; Portenoy et al. 1993). The direct conversion from a 'conventional' therapy with longacting oral opioids to transdermal fentanyl has not yet been studied in patients with constant pain relief under oral opioids. The aim of this study was to examine the feasability of a calculation table for the conversion from oral morphine to transdermal fentanyl with a ratio of 100:1. Sustained release morphine (SRM) was chosen as medication before the switchover to fentanyl, because morphine is the main reference substance for oral use.
Sustained release Jm o r p h i n e
-
Fentanyl TTS
Ii ' -3
0
3
6
9
12
15 day
Liquid morphine for breakthrough pain '
=
Change of fentanyl l"rs and examination of the patient
Fig. 1. Study design: In the pre-study phase SRM-medication was continued, at day 0 switchover to fentanyl TTS with changing of the system and control of analgesia, vital sign and concomitant events every 72 h.
pain intensity above the normal level. Due to the wide variations of the basal pain intensity (VAS 0-4) and the subjective nature we renounced to define the pain attacks more precisely. However, they were recorded separately in intensity (VAS), duration and frequency. Supplemental pain medication and medication with other drugs as well as side effects were documented every day. During the pre-study phase patients were treated to obtain a 'stable syndrom of cancer pain' with an unchanged dosage of morphine. Only 2 of 18 VAS values during the pre-study phase were allowed to be greater than 4. The values for the pain attacks were noted separately. After the pre-study phase the morphine medication was converted to transdermal fentanyl (Fig. 1). Initial doses were chosen with the morphine/fentanyl TTS ratio of 100:1 (Table I). At the time the first patch was applied patients received their last medication of SRM to maintain analgesia until a sufficient fentanyl plasma level could be expected. When dosages of more than 2.4 mg fentanyl per day (100/zg/h) were needed different patches were combined. Every 3 days the patches as well as the application sites were changed. Pain relief, supplemental medication, vital signs (blood pressure, heart frequency, pupil diameter (noted as wide, middle or narrow) and side effects (elicited by questioning and control of the pain diary) were
TABLE I
Methods This multicenter study was performed according to the rules of the declaration of Helsinki and was approved by the local ethics committee. Written informed consent of the patients was obtained prior to the study. Adult patients with cancer pain requiring _<600 mg of SRM per day were included. The study was devided into two parts: a pre-study phase (day - 6 to day - 1) with continuous SRM medication and the study phase (day 0-15) with transdermal fentanyl therapy. Exclusion criteria for the study were allergy to opioids, abuse of opioids, cardiac failure NYHA III and IV, severe hypertension, clinically relevant kidney or liver disease, increased intracranial pressure, active skin disease, allergy to silicone, surgery, chemotherapy or radiation planned during the study phase and patients with impaired consciousness. Analgesic efficacy of the opioid therapy was assessed by visual analogue scales (VAS). Patients noted their pain scores 3 times a day (8:00, 14:00 and 20:00 h) (10 cm VAS; left end = no pain, right end = maximal pain). Pain attacks were defined as an increase of
CALCULATION TABLE FOR THE CONVERSION FROM ORAL MORPHINE TO TRANSDERMAL FENTANYL WITH THE RATIO OF 100:1 Oral morphine (mg/day)
Fentanyl TTS (mg/day)
Fentanyl TTS (~g/h)
30- 90 91-150 151-210 211-270 271-330 331-390 391-450 451-510 511-570 571-630 631-690 690-750 Each further 60
0.6 1.2 1.8 2.4 3.0 3.6 4.2 4.8 5.4 6.0 6.6 7.2 + 0.6
25 50 75 100 125 150 175 200 225 250 275 300 + 25
529 TABLE II
TABLE IV
PATIENTS EXCLUDED FROM THE ANALYSIS
DOSAGE OF SUSTAINED RELEASE TRANSDERMAL FENTANYL
More than 1 criterion was pos,;ible. Reasons for exclusion Tumor progression Additional other opioids > 2 VAS values > 4 Inconstant oral morphine dosage Inconstant dosage of co-analgesics Incorrect use of transdermal fentanyl Other opioids or morphine s.c., i.m.
11 20 13 15 12 11 12
Excluded patients
60
SRM dosage (mg/day) Fentanyl TFs dosage on day 0 (mg/day) Fentanyl TTS dosage on day 15 (mg/day)
MORPHINE
AND
Mean
Range
138.6 1.4 2.4
25 -600 0.6 - 6 0.6 - 12
gut (27.3%), breast (12.1%), and lung (12.1%). 95.9% of the patients required a concomitant therapy with non-opioid analgesics.
Pain relief and opioid dosage registered. The dosage of fent~myl TI'S was adjusted according to the intake of supplemetal morphine and the pain reduction noted in the pain diary. Supplemental medication with liquid morphine was allowed during the whole study period (day - 6 to day 15) to achieve sufficient analgesia. Dosage was adjusted to the opioid needs of the patients, normaly 10-20 mg/dosage. Ca)ncomitant medication and non-opioid analgesics remained unchanged. Patients could be treated as in- or outpatients. At the end of the study period all patients could choose to continue the transdermal therapy or to change back to SRM medication. Patients with unstable cancer pain, protocol violations and progression of tumor disease were excluded from the analysis. For the statistical analysis descriptive statistics and the Wilcoxon-MPSR test were applied. The level of significance was determined with P < 0.05. The oral morphine/transdermal fentanyl ratio was proven by regression analysis.
Results
A total of 98 patients (45 female, 53 male) were included in the study. Si~xtypatients were excluded due to unstable pain, protocol violations and clinically relevant tumor progression. Patients with tumor progression during the study phase were excluded from the analysis of the conversion table, because in this population the increase of the analgesic medication might be due to the changing in the clinical situation and not by the need of a correction in the conversion ratio. Thirty-eight patients were treated according to protocol and were analyzed (Table II). Mean duration of cancer disease was 3.5 years (range: 0.2-17 years) (Table III). The most frequent cancer localisation were
During the pre-study phase (day - 6 to day - 1) the mean SRM dosage was 138.6 m g / d a y (25-600 m g / day). The initial fentanyl doses ranged from 0.6 to 6.0 m g / d a y with a mean dosage of 1.4 mg fentanyl/day. Twenty-two patients required a further increase of the fentanyl dosage. At the end of the study (day 15) the mean fentanyl dosage was 2.4 m g / d a y (0.6-12.0 rag/ day). With the initial fentanyl dosage 42.1% of the patients (n = 16) still experienced sufficient pain relief. In 17 patients (44.7%) a dosage increase of up to 100% was necessary. Two patients required a 200% increase of the initial dose and 3 patients an increase of more than 200% (Tables IVand V). No patient expierenced apparent overdosage. At the start of the transdermal therapy a mean area of 20 cm 2 (range: 10-100 cm 2) was needed, at the end of the study 40 cm 2 (range: 10-200 cm2). The regression analysis comparing fentanyl dosages at the end of the study (day 15) with the morphine dosages at day - 1 demonstrated a mean S R M / fentanyl TTS ratio of 70:1. The coefficient of determination of this relation was 82.7% (Fig. 2). The VAS scores during the morphine phase and the fentanyl TTS phase did not differ. Comparing the median and the 25% and 75% percentile of the VAS values, the analgesic efficacy was good throughout the study. For example at 14:00 h the median of the VAS scores was between 1.1 and 1.8 throughout the study. The 10%, 25%, 75%, and 90% percentiles as well were TABLE V FENTANYL T]?S DOSAGE DURING THE STUDY
TABLE III n
DEMOGRAPHIC DATA OF THE 38 PATIENTS Patients (n = 38) Age (years) Height (cm) Weight (kg)
Mean
Range
57.4 166.3 62.6
33- 77 152-180 48- 98
Reduced Unchanged Increased - 50%
51-100% 101-200% > 200%
%
0 16
0 42.1
7
18.4 26.3 5.3 7.9
10 2 3
530 fentanyl "ITS (mg / day) morphine (mg/day x 100) 12.o
12
/
"O
•
9.6
S
"o
•
8.4 :
9
eT-Zl dosage of morphine
10.8
9
1 0 VAS
VAS
8
fentanyl "l-I'S-dosage
7
7.2
6
6.0 ~
5
4.8 ~
4
3.6 ~
3
2.4-
2
I
1
1.2-
0.0
0
I
i
i
i
~
J
lOI
201
]00
lO0
SO0
600
oral morphine (mg / day)
, . . . . . . . . . . . . . . . -6 -3 0 3 6 9 12
0 15 day
Fig. 5. Pat. 23154:120 mg morphine/day providing a good analgesia, at day 0 switchover to 1.2 mg transdermal fentanyl/day. Pain relief was sufficient following an escalation of the dosage at day 3. But the requirement of supplemental morphine increased every three days before the transdermal system is changed, indicating that pain relief is not maintained for 72 hours.
Fig. 2. Regression analysis ( y = b x + e ) . Dosage of oral morphine during the pre-study phase in correlation to the dosage of transdermal fentanyl at the end of the study phase. lO
VASit I
oral morphine
I
~ T
-6
-3
0
[
transdermal fentanyl
lO - 95 % percentile
b
3
required liquid morphine for breakthrough pain in a dosage of 19.8-30.4 mg/day. More patients (up to 20 patients/day) took breakthrough medication during the fentanyl TTS phase (P < 0.05). The need for liquid morphine after the switchover to transdermal fentanyl was higher as compared to the period of SRM medication (day 0-3:33.1-79.4 mg morphine/day). At the end of the study the mean daily dose of 'oral morphine decreased to the pre-study level (days 12-15; mean: 22.5-31.2 mg morphine/day) (Fig. 4). The number of patients suffering from pain attacks did not differ between the two therapy periods. Twenty-five to 34% of the patients noted pain attacks. On the third day of each patch period the need of liquid morphine was greater than on the first or second day of each period. Calculated for the five 3-day intervals, 29.5% of the patients needed more liquid mot-
median,25 - 75 % percentile
1'2
~s day
Fig. 3. VAS-scores. Median, 25-75% percentiles and 10-90% percentiles at 2 p.m.
similar during morphine and transdermal fentanyl treatment (Fig. 3). During the pre-study phase up to 5 patients per day
701
.400 mg liquid morphine / day / patient
patients l
I
-350
11
I I I
I I
- 300
-250
I
20"
lO-
-6
-4
-2
0
2
4
6
8
10
12
14 day
Fig. 4. Number of patients requiring liquid morphine (IS5]) average dosage of liquid morphine (
(-- -- --),
) maximal dosage of liquid morphine
531
phine on the third day than on the first day of each patch interval. 26.3% of the patients needed more morphine on the third day than at the second day of each application period. In some patients analgesia was not maintained for the whole 72 h period (Fig. 5).
Side effects and vital signs Constipation and medication with laxatives decreased during the therapy with fentanyl TI'S. During the pre-study phase with SRM medication constipation was noted on 58.8% of all days, severe constipation on 18% of the days. With transdermal fentanyl constipation was reduced to 35.1% of the days, severe constipation was noted on 8.3% ,of the days. Concomitantly, the medication with laxatives was reduced from 62% to 38% (P < 0.05). Other side effects (diarrhoea, dizziness, nausea, vomiting, dyspnoea, sweating, pruritus, dry mouth, tireness) were not different. There were no differences in vital signs (respiratory frequency, blood pressure, heart rate) and in pupil diameter. No respiratory depression (respiratory frequency < 8/min) was noted. Three patients experienced a withdrawal symptom within the first 24 h of the fentanyl T r s therapy. The dosages of SRM were 600, 120 and 240 m g / d a y and were converted to 0.6, 1.2 and 2.4 mg transdermal fentanyl/day. Shivering, feeling of coldness, sweating, headache and paraesthesia were the main symptoms. The withdrawal symptoms remitted within the next 3 days. No patient showecl a drug-seeking behavior as a sign for psychological addiction. Transient and mild cutaneous reactions to the patch occurred in 16 patients (42.1%) (Table VI). The incidence of topical reactions did not increase during the observed transdermal therapy interval of 15 days.
Judgement of patients and physicians Medical staff estimated the fentanyl TTS therapy to be good or very good in 73.6%. 78.9% of the patients estimated the fentanyl TTS therapy to be superior to the therapy with oral morphine. At the end of the study 94.7% of the patients wanted to continue the therapy with transdermal fentanyl.
Discussion
Up to now, no valid calculation table for the medication of fentanyl T/'S was studied to allow a safe and effective change from oral morphine to fentanyl TTS. A revision of the guidelines for the use of fentanyl TTS was claimed by MacDonald (1993). Furthermore, this multicenter study adds to the other clinical studies, which showed a good efficacy of fentanyl TTS in the therapy of cancer pain (Larijani et al. 1988; Miser et al. 1989; Payne 1990; Southam et al. 1991; Zech et al. 1991a,b,c; Herbst and Strause 1992; Levy et al. 1992; Maves and Barcellos 1992; Patt and Hogan 1992; van Deventer et al. 1993). However, since our study was open-labeled and non-randomized the data on the analgesic efficacy and other outcomes may be compromised by a placebo effect, but the data resonate with clinical practice.
Dose finding In many studies patients were converted twice: first to parenteral fentanyl, oral or parenteral morphine and then to transdermal fentanyl (Miser et al. 1989; Zech et al. 1991a,c; Maves and Barcellos 1992). In other studies the calculation ratio to fentanyl TTS has not been reported (van Deventer et al. 1993). The product information recommends a morphine/fentanyl TTS conversion ratio of 150:1 (Janssen Pharmac. 1990, 1991). In this multicenter study the final mean S R M / fentanyl TTS ratio was found to be 70:1. This result implicates that a calculation table with a ratio 100:1 is by 30% sub-aequianalgesic. In our study a ratio of 100:1 was sufficient in only 42% of the patients. On the other hand, none of the patients required a dose reduction during the fentanyl phase. Thus, reduction of the opioid dosage in a sub-aeqianalgesic range might avoid overdosage caused by interindividual differences to different opioids (Foley 1985; Jage et al. 1990). Due to the long application interval of fentanyl TTS the phase of dose finding might be prolonged in comparison to the 'conventional' administration routes. The day-to-day change of the fentanyl dosage as performed by Korte and Morant (1994) might lead to overdosage which was demonstrated in a pharamcokinetic study by Gourlay et al. (1989).
TABLE VI C U T A N E O U S R E A C T I O N S IN T H E A R E A O F T H E TRANSD E R M A L SYSTEM
Erythema Pruritus Odema Papula/pustels
Day 3
Day 6
Day 9
Day 12
Day 15
n
n
n
n
n
%
%
%
%
%
4 10.5 3 8 6 15.8 5 13.2 5 13.2 1 2.6 1 2.6 1 2.6 1 2.6 1 2.6 1 2.6 2 5.3 1 2.6 1 2.6 1 2.6
Analgesic efficacy The VAS scores were low with both medications. In several studies pain relief was even better with fentanyl TTS than with alternative treatments. However, in these studies pain was not controlled sufficiently before switching to transdermal fentanyl (Miser et al. 1989; Simmonds et al. 1989; Payne 1990; Southam et al. 1991; Zech et al. 1991a, 1992; Levy et al. 1992; Slover 1992).
532
Many patients on fentanyl TTS required supplemental analgesic medication with other opioids (Simmonds et al. 1989; Herbst and Strause 1992; Levy et al. 1992; Slover 1992; Zech et al. 1992). Our patients were allowed to take liquid morphine as escape medication to achieve immediate pain relief. We have no explanation, why more patients in the fentanyl T-I'S period required an escape medication although pain levels and pain attacks were unchanged in comparison with SRM. One hypothesis might be that the patients were used to an oral medication or, as a second hypothesis, in some cases fentanyl TTS was not effective over the whole 72-h periods in some patients. The latter reason could be assumed for 5 patients. In previous studies some patients required application of the transdermal system every 48 h (Janssen Pharmac. 1990; Calis et al. 1992; Levy et al. 1992).
Side effects Side effects except constipation did not differ between fentanyl TTS and oral morphine (Levy et al. 1988; Maves and Barcellos 1992). The incidence of nausea was high in comparison to the study by Southam et al. (1991) (41.4% vs. 23%), but the incidence of vomiting was similar (20.3%). Constipation and the need for laxatives were reduced with fentanyl TTS. Similar effects were also reported by Slover (1992) and Zech et al. (1992). Constipation due to oral morphine is caused by binding to local opioid receptors in the gastrointesinal tract and the brain. However, the gastrointestinal effect seems to be more important (Jurna and Baldauf 1993). The transdermal route may be the reason for the reduced incidence of constipation with fentanyl TTS. Perhaps fentanyl TTS might become an alternative for patients suffering from severe constipation with 'conventional' opioids. Further studies are needed to prove these preliminary observations. During this multicenter study no patient developed respiratory depression (respiratory rate: < 8/min). In previous studies 6 cancer patients developed respiratory depressions due to fentanyl TI'S (Simmonds and Payne 1989; Southam et al. 1991; Simmonds 1995; Zech and Lehmann 1995). In 3 patients a respiratory rate below 8 / m i n was observed during the titration period (conversion from intravenous to transdermal fentanyl with the ratio of 1:1.5) (Zech and Lehmann 1995). One naloxone reversible respiratory depression occurred in the terminal phase of cancer (Simmonds and Payne 1989; Simmonds 1995). For the other 2 patients no detailed informations were given. Patients developing serious adverse effects must be monitored for a period related to the slow decline of fentanyl serum concentration. Continuous administration of naloxone might be necessary (Holley and van Stevens 1988; Larijani et al. 1988; Gourlay et al. 1989; Varvel et
al. 1989; Janssen Pharmac. 1990; Gupta et al. 1992; Lehmann and Zech 1992; Portenoy et al. 1993). Withdrawal symptoms occurred in 3 of our patients and in 5 patients in a postmarketing surveillance report of the USA (van Gestel and Amery 1992). Furthermore, Skoyles et al. (1993) recently reported a patient with withdrawal symptoms after the switchover from SRM to fentanyl TTS. In general, these withdrawal symptoms occurred during the initial phase after conversion from morphine to fentanyl "ITS. Thus, these withdrawal symptoms seem to be morphine related and may be caused by relatively fast reduction of morphine plasma level. The skin tolerated the transdermal system well although cutaneous symptoms occurred in approximately 13% of the patients. Southam et al. (1991) reported topical reactions in only 4% of the patients. However, in other studies the incidence of cutanaeus reactions was higher too (Donner et al. 1993b). Changing the sites of patch application may minimize chronic local irritation (Calis et al. 1992). Recently Rose et al. (1993) reported on a cancer patient suffering from mental confusion, pinpoint pupils and shallow respiration after she had a heating pad for further pain relief, which also warmed up the area of the fentanyl patch. In the product information it is recommended to monitor patients with fever closely. Fentanyl serum levels might increase by one-third, when temperature is about 40°C (Janssen Pharmac. 1990, 1991).
Judgement of the patient Patients preferred fentanyl TTS over oral morphine. Most of the patients continued with the transdermal therapy after the end of the study period. With transdermal fentanyl patients just have to remember their opioid medication every 48-72 h. Reduced constipation may result in a better quality of life. These two facts account for better compliance of the patient and lead to the feeling of greater independency from pain therapy.
Recommendations for the use of fentanyl TTS Peak plasma levels occur 8-12 h following the application of fentanyl TTS (Holley and van Stevens 1988; Gourlay et al. 1989; Latasch and Liiders 1989; Calis et al. 1992; Lehmann and Zech 1992; van Bestelaere et al. 1993). With the first application the patient should receive the last medication of the long-acting opioid, so that no gap in analgesia should occur with the conversion. We recommend to start the transdermal fentanyl therapy in the morning. This enables good control of the patient's vigilance during the day until peak plasma levels are reached. Very high dosages of opioids are needed in some cancer patients to obtain sufficient pain relief. Lehr
533
and Renaud (1993) reported on a patient requiring 12 mg of fentanyl T-FS per day. Since the fentanyl TTS dosage is limited by the area of application an area 200 cm 2 is needed for 12 mg fentanyl/day. Especially in small and kachectic patients this will be a limiting factor. In any case, the application area shall be changed (Janssen Pharmac. 1990, 1991). Dysphagia and tumor,; of the upper gastrointestinal tract with severe nausea or vomiting may represent special indications for fentanyl TTS. In patients requiring an opioid therapy and suffering from severe constipation an attempt at transdermal fentanyl is advisable. Due to the slow pharmacokinetics of transdermal systems, it is appropriate only for patients with a relatively constant chronic pain sydreme requiring a constant opioid dosage for pain relief. Is pain fluctuating an effective and safe pain control with fentanyl TTS probably is not possible. Conclusion A calculation table for the conversion of morphine to fentanyl T-FS with a ratio of 100:1 is safe and effective. The ratio is slightly too low. The true ratio determined in this study is 70:1. This implies a sufficient margin of safety for the conversion. Constipation was reduced compared to the therapy with oral morphine. No severe side effects, especially no respiratory depression, were observed. Three patients developed withdrawal symptoms immediately after the switch to fentanyl TTS. Transdermal fentanyl is a convenient therapy with avoidance of gastrointestinal absorption and may have special indications, e.g., in patients with nausea and vomiting or bowel ostruction or patients with severe constipation. In our opinion the indication for transdermal fentanyl is limited to patients with a stable pain syndrome as a result of the slow pharmacokinetics. Fentanyl TTS, a strong non-invasive opioid has to be integrated into step III of the analgesic ladder of the WHO. Based on our results patients can be directly converted from oral morphine to transdermal fentanyl on a morphine/fentanyl ratio of 100:1. However, since this conversion ratio is slightly underestimative the true ratio (approximately 70:l) patients should be allowed to supplement their analgesic requirements with liquid morphine during the first days until the effective fentanyl dosage has been adjusted. The development of transdermal systems for opioid therapy may provide a useful alternative route of administration for patients with chronic pain sensitive to opioids. Acknowledgements This study was supported by a grant from Janssen GmbH Neuss and STADA Arzneimittel AG.
Participating investigators are the following: J. Ammon, M.D. (Dept. of Therapeutic Therapeutic Radiology, RWTH, Aachen); B. von Bormann, M.D. (Dept. of Anesthesiology, St. Johannes Hospital, Duisburg); R. Dennhardt, M.D. (Dept. of Anesthesiology, Hospital Nordwest, Frankfurt/Main); W. Dinter, M.D. (Dept. of Anesthesiology, University Diisseldorf); B. Eberhard, M.D. (Pain Ambulance, Frankfurt/Main); I. Gralow, M.D. (Dept. of Anesthesiology and Intensive Care Medicine, University MOnster); G.G. Hanekop, M.D. (Dept. of Anesthesiology, University G6ttingen); U.B. Hankemeier, M.D. (Dept. of Anesthesiology, Ev. Johannes-Hospital, Bielefeld); G. Hege, M.D. (Dept. of Anesthesiology, University Ulm); P. Hoffmann, M.D. (Dept. of Anesthesiology, General Hospital, Hamburg Barmbeck); E. Klaschik, M.D. (Dept. of Anesthesiology and Intensive Care Medicine, Malteser Hospital, Bonn); U.R. Kleeberg, M.D. (Hamburg); D. Loose, M.D. (Dept. of Anesthesiology, Kiel); J. Meyer, M.D., and W. Schr/Sder, M.D. (Dept. of Anesthesiology of the Klinikum Minden); P. Milewski, M.D. (Dept. of Anesthesiology, Klinik am Eichert, G6ppingen); D. Olthoff, M.D. (Dept. of Anesthesiology and Intensive Care Medicine, Leipzig); E. Schick, M.D. (Onkologist, Frankenthal); J. Sorge, M.D. (Dept. of Anesthesiology of the University Hannover); G. Sprotte, M.D. (Dept. of Anesthesiology, University Wiirzburg); M. Strumpf, M.D. (Dept. of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Bergmannsheil, Bochum); D. Zech, M.D. (Dept. of Anesthesiology and Intensive Care Medicine, Pain Therapy, University of Cologne).
References Calls, K.A., Kohler, D.R. and Corso, D.M., Transdermally administered fentanyl for pain management, Clin. Pharmacol., 11 (1992) 22-36. Caplan, R.A. and Southam, M., Transdermal fentanyl: an overview of clinical progress. In: F.G. Estafanous (Ed.), Opioids in Anesthesia, Butterworth-Heinemann, 1991, pp. 267-273. Donner, B., Zenz, M., Tryba, M. and Strumpf, M., Transdermales Fentanyl in der Tumorschmerztherapie, Der Schmerz, 7 (1993a) 18-24. Donner, B., Zenz, M., Tryba, M. and Kurz-Miiller, K., Fentanyl TI~S zur postoperativen Schmerztherapie, Anaesthesist, 42 (1993b) 309-315. Enck, R.E., Transdermal narcotics for pain control, Am. J. Hosp. Pall. Care, 7/8 (1990) 15-17. Foley, K.M., The treatment of cancer pain, New Engl. J. Med., 313 (1985) 84-95. Freye, E., Opioide in der Medizin, Springer, Heidelberg, 1991. Gourlay, G.K., Kowalski, S.R., Plummer, J.L., Cherry, D.A., Gaukroger, P. and Cousins, M.J., The transdermal administration of fentanyl in the treatment of postoperative pain: pharmacokinetics and pharmacodynamic effects, Pain, 37 (1989) 193-202. Gupta, S.K., Southam, M., Gale, R. and Hwang, S.S., System functionality and physicochemical model of fentanyl transdermal system, J. Pain Sympt. Manag., 7 (Suppl.) (1992) 17-26.
534 Herbst, L.H. and Strause, L.G., Transdermal fentanyl use in hospice home-care patients with chronic cancer pain, J. Pain Sympt. Manag., 7 (Suppl.) (1992) 54-57. Holley, F.O. and van Stevens, C., Postoperative analgesia with fentanyl: pharmacokinetics and pharmacodynamics of constant-rate i.v. and transdermal delivery, Br. J. Anaesth., 60 (1988) 608-613. Jage, J., Portenoy, R.K. and Foley, M.K., Die Bestimmung des i.m. Morphin-,~quivalents zur Therapie des Krebsschmerzes mit verschiedenen Opioiden oder bei Wechsel des Verabreichungsweges, Schmerz, 4 (1990) 110-117. Janssen Pharmaceutica Inc., Duragesic, Product Infomation, Piscataway, NJ, 1990. Janssen Phamaceutica Inc., Product Monograph 'Duragesic', fentanyl transdermal system, Mississauga, Ontario, 1991. Jurna, I. and Baldauf, J., Retardiert freigesetztes Naloxon oral: Aufhebung der Obstipation durch orales Morphin ohne Beseitigung der Analgesie, Schmerz, 7 (1993) 314-321. Korte, W. and Morant, R., Transdermal fentanyl in uncontrolled cancer pain: titration on day-to-day basis as a procedure for safe and effective dose finding. A pilot study in 20 patients, Support Care Cancer, 2 (1994) 123-127. Larijani, G.E., Bell, S.D., Goldberg, M.E. and Lessin, J.B., Pharmacokinetics of fentanyl following transdermal application, Anesthesiology, 69 (1988) A363. Latasch, L. and Liiders, S., Transdermal fentanyl against postoperative pain, Acta Anaesth. Belg., 40 (1989) 113-118. Lehmann, K.A. and Zech, D., Transdermal Fentanyl, J. Pain Sympt. Manag., 7 (Suppl.) (1992) 8-16. Lehr, V.T. and Renaud, E.A., High transdermal fentanyl requirements in a patient with chronic cancer pain, Ann. Pharmacother., 27 (1993) 575-578. Levy, S., Jacobs, S., Johnson, J., Schultz, N., Kowal, C., Meisler, A., Lee, J. and Boggiu, K., Transdermal fentanyl: pain and qualityof-life effects, Proc. Am. Soc. Clin. Pharm., 7 (1988) 292. Levy, M.H., Rosen, S.M. and Kedziera, P., Transdermal fentanyl: seeding trial in patients with chronic cancer pain, J. Pain Sympt. Manag., 7 (Suppl.) (1992) 48-50. MacDonald, N., Commentary, J. Pain Sympt. Manag., 8 (1993) 320-321. Mather, L.E., Clinical pharmacokinetics of fentanyl and its newer derivatives, Clin. Pharmacol., 8 (1983) 422-446. Maves, T.J. and Barcellos, W.A., Management of cancer pain with transdermal fentanyl: phase IV trial, University of Iowa, J. Pain Sympt. Manag., 7 (Suppl.) (1992) 58-62. Miser, A.W., Narang, P.K., Dothage, J.A., Young, R.C., Sindelar, S. and Miser, J.S., Transdermal fentanyl for pain control in patients with cancer, Pain, 37 (1989) 15. Moser, K.H., Transdermal fentanyl in cancer pain, Am. Family Physician, 45 (1992) 2289-2294. Patt, R.B. and Hogan, L.A., Transdermal fentanyl for chronic cancer pain: detailed case reports and the influence of confounding factors, J. Pain Sympt. Manag., 7 (Suppl.) (1992) 51-53. Payne, R., Experience with transdermal fentanyl in advanced cancer pain, Eur. J. Pain, 11 (1990) 98-101. Plezia, P.M., Kramer, T.H., Linford, J. and Hameroff, S.R., Transdermal fentanyl: pharmacokinetics and preliminary clinical evaluation, Pharmacotherapy, 9 (1989) 2-9. Portenoy, R.K., Southam, M., Gupta, S.K., Lapin, J., Layman, M., Inturrisi, C.E. and Foley, K.M., Transdermal fentanyl for cancer
pain. Repeated dose pharmocokinetics, Anesthesiology, 78 (1993) 36-43. Rose, P.G., Macfee, M.S. and Boswell, M.V., Fentanyl transdermal system overdose secondary to cutaneous hyperthermia, Anesth. Analg., 77 (1993) 390-391. Rowbotham, D.J., Wyld, R., Peacock, J.E. and Duthie, D.J.R., Transdermal fentanyl for the relief of pain after upper abdominal surgery, Br. J. Anaesth., 63 (1989) 56-59. Roy, S.D. and Flynn., G.L., Transdermal delivery of narcotic analgesics: pH, anatomical and subject influences on cutaneous permeability of fentanyl and sufentanil, Pharmaceut. Res., 7 (1990) 842-847. Sandier, A., Transdermal fentanyl: acute analgesic clinical studies, J. Pain Sympt. Manag., 7 (Suppl.) (1992) 27-35. Simmonds, M.A., Payne, R., Richenbacher, J., Moran, K., Southam, M.A. and Hershe, M.S., TrS (fentanyl) in the management of pain in patients with cancer, Proc. Am. Soc. Clin. Oncol., 8 (1989) 324 Abstract. Simmonds, M.A., Transdermal fentanyl therapy: clinical developement in the United States, Anti-Cancer Drugs, 6 (Suppl. 3) (1995) 35-38. Skoyles, J., Tordoff, S., Rabey, P. and Rowbotham, D., Transdermal fentanyl administered in cancer pain, 7th World Congress on Pain, France (1993) 335 Abstract. Stover, R., Transdermal fentanyl: clinical trial at the University of Colorado Health Science Center, J. Pain Sympt. Manag., 7 (Suppl.) (1992) 45-47. Southam, M., Gupta, S., Knowels, M. and Hwang, S.S., Transdermal fentanyl: an overview of pharmacokinetics, efficacy and safety. In: K.A. Lehmann and D. Zech (Eds.), Transdermal Fentanyl, Springer, Heidelberg, 1991, pp. 107-116. Van Bastelaere, M., Rolly, G. and van Peer, A., Pharmacokinetic behaviour of transdermal fentanyl, Br. J. Anaesth., 70 (Suppl. 1) (1993) 75 Abstract. Van Deventer, P.L., Verbiest, H.B.C., Kansen, P.J., van den Bent, M.J. and Vecht, C.J., Transdermal fentanyl: a feasibility study in patients with chronic cancer pain, 7th World Congress on Pain, Paris, France, 330. Van Gestel, S. and Amery, W., Postmarketing surveillance report of transdermal fentanyl (fentanyl 1~S), Janssen Research Foundation, Berse, Belgium, 1992. Varvel, J.R., Shafer, S.L., Hwang, S.S., Coen, P.A. and Stanski, D.R., Absorption characteristics of transdermally administered fentanyl, Anesthesiology, 70 (1989) 928-934. Zech, D. and Lehmann K.A., Transdermal fentanyl in combination with initial intravenous dose titration by patient controlled analgesia, Anti-Cancer Drugs, 6 (Suppl. 3) (1995) 44-49. Zech, D., Grond, S. and Lynch, J., Clinical Experience. In: K.A. Lehmann and D. Zech (Eds.), Transdermal Fentanyl, Springer, Heidelberg, 1991a, pp. 171-187. Zech, D., Lehmann, K.A. and Rupperth, J., Current development of pain treatment I, Pain Clin., 4 (1991b) 177-181. Zech, D., Grond, S., Lynch, J. and Lehmann, K.A., Transdermales Fentanyl zur Schmerztherapie bei Tumoren im GIT und der Kopf-Hals-Region, Schmerz, 5 (1991c) 181. Zech, D., Grond, S., Dauer, H.G., Stollenwerk, B. and Lehmann, K.A., Transdermal fentanyl and initial dose-finding with patientcontrolled analgesia in cancer pain, A pilot study with 20 terminally ill cancer patients, Pain, 50 (1992) 293-301.
527
PAIN 2969
Direct conversion from oral morphine to transdermal fentanyl: a multicenter study in patients with cancer pain Barbara Donner, Michael Zenz, Michael Tryba and Michael Strumpf Departments of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Bergmannsheil, 44789 Bochum, Buerkle-de la-Camp Platz I (Germany)
(Received 31 July 1995; accepted 16 August 1995)
Summary Direct conversion from oral morphine to transdermal fentanyl with a ratio of oral morphine/ transdermal fentanyl (100:1 mg) daily was examined in patients with cancer pain. Patients with a 'stable and low level of cancer pain' receiving a constant dosage of sustained release morphine during a pre-study phase of 6 days were included in the study. Initial fentanyl dosage was calculated by a conversion table. The transdermal system was changed every 72 h and the dosage was adjusted to the needs of the patients according to the VAS scores and the requirement of liquid morphine, which was allowed to achieve sufficient pain relief. Regression analysis at the end of the study revealed a mean morphine/transdermal fentanyl ratio of 70:1. Pain relief during treatment with transdermal fentanyl was identical to sustained release morphine. However, significantly more patients took: supplemental medication with liquid morphine during transdermal fentanyl therapy. The number of patients suffering from pain attacks did not increase with transdermal fentanyl. Constipation and medication with laxatives decreased significantly during fentanyl therapy. Other side effects and vital signs were identical. Three patients suffered from a morphine withdrawal syndrom beginning within the first 24 h of transdermal fentanyl therapy. Cutaneous reactions to the patch were rare, mild and transient. Patients and physicians reported satisfaction with the transdermal therapy. 94.7% of the patients chose to continue the transdermal fentanyl therapy at the end of the study due to better performance in comparison to oral morphine. Due to these results an initial conversion from oral morphine to transdermal fentanyl with the ratio of 100:1 is safe and effective. Key words: Morphine, oral; Morphine, sustained release; Fentanyl, transdermal; Cancer pain
Introduction Transdermal fentanyl represents a new administration route for chronic opioid therapy. Fentanyl, an opioid with pure /x-agonist activity, is 75-100 times more potent than morphine on a molar basis (Rowbotham et al. 1989; Enck 1990; Freye 1991; Moser 1992). Parenteral fentanyl is a short-acting analgesic at non-steady-state conditions, when half-life time is primarily determined by redistribution (Mather 1983). Due to low molecular weight and high lipid solubility fen* Corresponding author: B. Donner, MD, Departments of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Bergmannsheil, 44789 Bochum, Buerkle-de la-Camp Platz 1, Germany. SSDI 0304-3959(95)00180-8
tanyl can be administered transdermally (Enck 1990; Roy and Flynn 1990). The cutaneous uptake from a transdermal therapeutic system of fentanyl (fentanyl TFS) is proportional to the application area. After application of a patch, peak serum levels are approached within 8-12 h (Holley and van Stevens 1988; Gourlay et al. 1989; Latasch and Liiders 1989; Plezia et al. 1989; Varvel et al. 1989; Calis et al. 1992; Lehmann and Zech 1992). The transdermal therapeutic system delivers fentanyl continuously for up to 72 h (Caplan and Southam 1991; Southam et al. 1991; Gupta et al. 1992; Sandier 1992). Portenoy et al. (1993) demonstrated that constant serum levels are maintained with the second transdermal system. Fluctuations of serum levels are small after the first 72 h (Portenoy et al. 1993). Due to the dermal depot of fentanyl serum
528
half-life time is 16-21 h (Holley et al. 1988; Larijani et al. 1988; Gourlay et al. 1989; Varvel et al. 1989; Janssen Pharmac. 1990; Gupta et al. 1992; Lehmann and Zech 1992). The management of cancer pain with transdermal fentanyl has been investigated in several clincal studies (Larijani et al. 1988; Levy et al. 1988, 1992; Miser et al. 1989; Payne 1990; Zech et al. 1991a,b,c; Herbst and Strause 1992; Maves and Barcellos 1992; Patt and Hogan 1992; Slover 1992; van Deventer et al. 1993). A ratio of oral morphine/fentanyl TTS of 150:1 has been recommended (Janssen Pharmac. 1990, 1991) but not approved by clinical studies. In most previous studies patients were hospitalized for conversion to transdermal fentanyl (Levy et al. 1988; Miser et al. 1989; Herbst et al. 1992; Slover et al. 1992; Zech et al. 1992) and the switchover to fentanyl TTS was performed by an intermediate step with parenteral administration of fentanyl (Miser et al. 1989; Maves and Barcello 1992; Zech et al. 1992). However, this approach does not meet the needs of the patients who wish to stay at home with an analgesic therapy allowing to live as normal as possible and to be independent from the physician. Present data from chronic dosing surveys are limited and more experience with the transdermal system is needed to confirm the results of previous investigations (Calis et al. 1992; Portenoy et al. 1993). The direct conversion from a 'conventional' therapy with longacting oral opioids to transdermal fentanyl has not yet been studied in patients with constant pain relief under oral opioids. The aim of this study was to examine the feasability of a calculation table for the conversion from oral morphine to transdermal fentanyl with a ratio of 100:1. Sustained release morphine (SRM) was chosen as medication before the switchover to fentanyl, because morphine is the main reference substance for oral use.
Sustained release Jm o r p h i n e
-
Fentanyl TTS
Ii ' -3
0
3
6
9
12
15 day
Liquid morphine for breakthrough pain '
=
Change of fentanyl l"rs and examination of the patient
Fig. 1. Study design: In the pre-study phase SRM-medication was continued, at day 0 switchover to fentanyl TTS with changing of the system and control of analgesia, vital sign and concomitant events every 72 h.
pain intensity above the normal level. Due to the wide variations of the basal pain intensity (VAS 0-4) and the subjective nature we renounced to define the pain attacks more precisely. However, they were recorded separately in intensity (VAS), duration and frequency. Supplemental pain medication and medication with other drugs as well as side effects were documented every day. During the pre-study phase patients were treated to obtain a 'stable syndrom of cancer pain' with an unchanged dosage of morphine. Only 2 of 18 VAS values during the pre-study phase were allowed to be greater than 4. The values for the pain attacks were noted separately. After the pre-study phase the morphine medication was converted to transdermal fentanyl (Fig. 1). Initial doses were chosen with the morphine/fentanyl TTS ratio of 100:1 (Table I). At the time the first patch was applied patients received their last medication of SRM to maintain analgesia until a sufficient fentanyl plasma level could be expected. When dosages of more than 2.4 mg fentanyl per day (100/zg/h) were needed different patches were combined. Every 3 days the patches as well as the application sites were changed. Pain relief, supplemental medication, vital signs (blood pressure, heart frequency, pupil diameter (noted as wide, middle or narrow) and side effects (elicited by questioning and control of the pain diary) were
TABLE I
Methods This multicenter study was performed according to the rules of the declaration of Helsinki and was approved by the local ethics committee. Written informed consent of the patients was obtained prior to the study. Adult patients with cancer pain requiring _<600 mg of SRM per day were included. The study was devided into two parts: a pre-study phase (day - 6 to day - 1) with continuous SRM medication and the study phase (day 0-15) with transdermal fentanyl therapy. Exclusion criteria for the study were allergy to opioids, abuse of opioids, cardiac failure NYHA III and IV, severe hypertension, clinically relevant kidney or liver disease, increased intracranial pressure, active skin disease, allergy to silicone, surgery, chemotherapy or radiation planned during the study phase and patients with impaired consciousness. Analgesic efficacy of the opioid therapy was assessed by visual analogue scales (VAS). Patients noted their pain scores 3 times a day (8:00, 14:00 and 20:00 h) (10 cm VAS; left end = no pain, right end = maximal pain). Pain attacks were defined as an increase of
CALCULATION TABLE FOR THE CONVERSION FROM ORAL MORPHINE TO TRANSDERMAL FENTANYL WITH THE RATIO OF 100:1 Oral morphine (mg/day)
Fentanyl TTS (mg/day)
Fentanyl TTS (~g/h)
30- 90 91-150 151-210 211-270 271-330 331-390 391-450 451-510 511-570 571-630 631-690 690-750 Each further 60
0.6 1.2 1.8 2.4 3.0 3.6 4.2 4.8 5.4 6.0 6.6 7.2 + 0.6
25 50 75 100 125 150 175 200 225 250 275 300 + 25
529 TABLE II
TABLE IV
PATIENTS EXCLUDED FROM THE ANALYSIS
DOSAGE OF SUSTAINED RELEASE TRANSDERMAL FENTANYL
More than 1 criterion was pos,;ible. Reasons for exclusion Tumor progression Additional other opioids > 2 VAS values > 4 Inconstant oral morphine dosage Inconstant dosage of co-analgesics Incorrect use of transdermal fentanyl Other opioids or morphine s.c., i.m.
11 20 13 15 12 11 12
Excluded patients
60
SRM dosage (mg/day) Fentanyl TFs dosage on day 0 (mg/day) Fentanyl TTS dosage on day 15 (mg/day)
MORPHINE
AND
Mean
Range
138.6 1.4 2.4
25 -600 0.6 - 6 0.6 - 12
gut (27.3%), breast (12.1%), and lung (12.1%). 95.9% of the patients required a concomitant therapy with non-opioid analgesics.
Pain relief and opioid dosage registered. The dosage of fent~myl TI'S was adjusted according to the intake of supplemetal morphine and the pain reduction noted in the pain diary. Supplemental medication with liquid morphine was allowed during the whole study period (day - 6 to day 15) to achieve sufficient analgesia. Dosage was adjusted to the opioid needs of the patients, normaly 10-20 mg/dosage. Ca)ncomitant medication and non-opioid analgesics remained unchanged. Patients could be treated as in- or outpatients. At the end of the study period all patients could choose to continue the transdermal therapy or to change back to SRM medication. Patients with unstable cancer pain, protocol violations and progression of tumor disease were excluded from the analysis. For the statistical analysis descriptive statistics and the Wilcoxon-MPSR test were applied. The level of significance was determined with P < 0.05. The oral morphine/transdermal fentanyl ratio was proven by regression analysis.
Results
A total of 98 patients (45 female, 53 male) were included in the study. Si~xtypatients were excluded due to unstable pain, protocol violations and clinically relevant tumor progression. Patients with tumor progression during the study phase were excluded from the analysis of the conversion table, because in this population the increase of the analgesic medication might be due to the changing in the clinical situation and not by the need of a correction in the conversion ratio. Thirty-eight patients were treated according to protocol and were analyzed (Table II). Mean duration of cancer disease was 3.5 years (range: 0.2-17 years) (Table III). The most frequent cancer localisation were
During the pre-study phase (day - 6 to day - 1) the mean SRM dosage was 138.6 m g / d a y (25-600 m g / day). The initial fentanyl doses ranged from 0.6 to 6.0 m g / d a y with a mean dosage of 1.4 mg fentanyl/day. Twenty-two patients required a further increase of the fentanyl dosage. At the end of the study (day 15) the mean fentanyl dosage was 2.4 m g / d a y (0.6-12.0 rag/ day). With the initial fentanyl dosage 42.1% of the patients (n = 16) still experienced sufficient pain relief. In 17 patients (44.7%) a dosage increase of up to 100% was necessary. Two patients required a 200% increase of the initial dose and 3 patients an increase of more than 200% (Tables IVand V). No patient expierenced apparent overdosage. At the start of the transdermal therapy a mean area of 20 cm 2 (range: 10-100 cm 2) was needed, at the end of the study 40 cm 2 (range: 10-200 cm2). The regression analysis comparing fentanyl dosages at the end of the study (day 15) with the morphine dosages at day - 1 demonstrated a mean S R M / fentanyl TTS ratio of 70:1. The coefficient of determination of this relation was 82.7% (Fig. 2). The VAS scores during the morphine phase and the fentanyl TTS phase did not differ. Comparing the median and the 25% and 75% percentile of the VAS values, the analgesic efficacy was good throughout the study. For example at 14:00 h the median of the VAS scores was between 1.1 and 1.8 throughout the study. The 10%, 25%, 75%, and 90% percentiles as well were TABLE V FENTANYL T]?S DOSAGE DURING THE STUDY
TABLE III n
DEMOGRAPHIC DATA OF THE 38 PATIENTS Patients (n = 38) Age (years) Height (cm) Weight (kg)
Mean
Range
57.4 166.3 62.6
33- 77 152-180 48- 98
Reduced Unchanged Increased - 50%
51-100% 101-200% > 200%
%
0 16
0 42.1
7
18.4 26.3 5.3 7.9
10 2 3
530 fentanyl "ITS (mg / day) morphine (mg/day x 100) 12.o
12
/
"O
•
9.6
S
"o
•
8.4 :
9
eT-Zl dosage of morphine
10.8
9
1 0 VAS
VAS
8
fentanyl "l-I'S-dosage
7
7.2
6
6.0 ~
5
4.8 ~
4
3.6 ~
3
2.4-
2
I
1
1.2-
0.0
0
I
i
i
i
~
J
lOI
201
]00
lO0
SO0
600
oral morphine (mg / day)
, . . . . . . . . . . . . . . . -6 -3 0 3 6 9 12
0 15 day
Fig. 5. Pat. 23154:120 mg morphine/day providing a good analgesia, at day 0 switchover to 1.2 mg transdermal fentanyl/day. Pain relief was sufficient following an escalation of the dosage at day 3. But the requirement of supplemental morphine increased every three days before the transdermal system is changed, indicating that pain relief is not maintained for 72 hours.
Fig. 2. Regression analysis ( y = b x + e ) . Dosage of oral morphine during the pre-study phase in correlation to the dosage of transdermal fentanyl at the end of the study phase. lO
VASit I
oral morphine
I
~ T
-6
-3
0
[
transdermal fentanyl
lO - 95 % percentile
b
3
required liquid morphine for breakthrough pain in a dosage of 19.8-30.4 mg/day. More patients (up to 20 patients/day) took breakthrough medication during the fentanyl TTS phase (P < 0.05). The need for liquid morphine after the switchover to transdermal fentanyl was higher as compared to the period of SRM medication (day 0-3:33.1-79.4 mg morphine/day). At the end of the study the mean daily dose of 'oral morphine decreased to the pre-study level (days 12-15; mean: 22.5-31.2 mg morphine/day) (Fig. 4). The number of patients suffering from pain attacks did not differ between the two therapy periods. Twenty-five to 34% of the patients noted pain attacks. On the third day of each patch period the need of liquid morphine was greater than on the first or second day of each period. Calculated for the five 3-day intervals, 29.5% of the patients needed more liquid mot-
median,25 - 75 % percentile
1'2
~s day
Fig. 3. VAS-scores. Median, 25-75% percentiles and 10-90% percentiles at 2 p.m.
similar during morphine and transdermal fentanyl treatment (Fig. 3). During the pre-study phase up to 5 patients per day
701
.400 mg liquid morphine / day / patient
patients l
I
-350
11
I I I
I I
- 300
-250
I
20"
lO-
-6
-4
-2
0
2
4
6
8
10
12
14 day
Fig. 4. Number of patients requiring liquid morphine (IS5]) average dosage of liquid morphine (
(-- -- --),
) maximal dosage of liquid morphine
531
phine on the third day than on the first day of each patch interval. 26.3% of the patients needed more morphine on the third day than at the second day of each application period. In some patients analgesia was not maintained for the whole 72 h period (Fig. 5).
Side effects and vital signs Constipation and medication with laxatives decreased during the therapy with fentanyl TI'S. During the pre-study phase with SRM medication constipation was noted on 58.8% of all days, severe constipation on 18% of the days. With transdermal fentanyl constipation was reduced to 35.1% of the days, severe constipation was noted on 8.3% ,of the days. Concomitantly, the medication with laxatives was reduced from 62% to 38% (P < 0.05). Other side effects (diarrhoea, dizziness, nausea, vomiting, dyspnoea, sweating, pruritus, dry mouth, tireness) were not different. There were no differences in vital signs (respiratory frequency, blood pressure, heart rate) and in pupil diameter. No respiratory depression (respiratory frequency < 8/min) was noted. Three patients experienced a withdrawal symptom within the first 24 h of the fentanyl T r s therapy. The dosages of SRM were 600, 120 and 240 m g / d a y and were converted to 0.6, 1.2 and 2.4 mg transdermal fentanyl/day. Shivering, feeling of coldness, sweating, headache and paraesthesia were the main symptoms. The withdrawal symptoms remitted within the next 3 days. No patient showecl a drug-seeking behavior as a sign for psychological addiction. Transient and mild cutaneous reactions to the patch occurred in 16 patients (42.1%) (Table VI). The incidence of topical reactions did not increase during the observed transdermal therapy interval of 15 days.
Judgement of patients and physicians Medical staff estimated the fentanyl TTS therapy to be good or very good in 73.6%. 78.9% of the patients estimated the fentanyl TTS therapy to be superior to the therapy with oral morphine. At the end of the study 94.7% of the patients wanted to continue the therapy with transdermal fentanyl.
Discussion
Up to now, no valid calculation table for the medication of fentanyl T/'S was studied to allow a safe and effective change from oral morphine to fentanyl TTS. A revision of the guidelines for the use of fentanyl TTS was claimed by MacDonald (1993). Furthermore, this multicenter study adds to the other clinical studies, which showed a good efficacy of fentanyl TTS in the therapy of cancer pain (Larijani et al. 1988; Miser et al. 1989; Payne 1990; Southam et al. 1991; Zech et al. 1991a,b,c; Herbst and Strause 1992; Levy et al. 1992; Maves and Barcellos 1992; Patt and Hogan 1992; van Deventer et al. 1993). However, since our study was open-labeled and non-randomized the data on the analgesic efficacy and other outcomes may be compromised by a placebo effect, but the data resonate with clinical practice.
Dose finding In many studies patients were converted twice: first to parenteral fentanyl, oral or parenteral morphine and then to transdermal fentanyl (Miser et al. 1989; Zech et al. 1991a,c; Maves and Barcellos 1992). In other studies the calculation ratio to fentanyl TTS has not been reported (van Deventer et al. 1993). The product information recommends a morphine/fentanyl TTS conversion ratio of 150:1 (Janssen Pharmac. 1990, 1991). In this multicenter study the final mean S R M / fentanyl TTS ratio was found to be 70:1. This result implicates that a calculation table with a ratio 100:1 is by 30% sub-aequianalgesic. In our study a ratio of 100:1 was sufficient in only 42% of the patients. On the other hand, none of the patients required a dose reduction during the fentanyl phase. Thus, reduction of the opioid dosage in a sub-aeqianalgesic range might avoid overdosage caused by interindividual differences to different opioids (Foley 1985; Jage et al. 1990). Due to the long application interval of fentanyl TTS the phase of dose finding might be prolonged in comparison to the 'conventional' administration routes. The day-to-day change of the fentanyl dosage as performed by Korte and Morant (1994) might lead to overdosage which was demonstrated in a pharamcokinetic study by Gourlay et al. (1989).
TABLE VI C U T A N E O U S R E A C T I O N S IN T H E A R E A O F T H E TRANSD E R M A L SYSTEM
Erythema Pruritus Odema Papula/pustels
Day 3
Day 6
Day 9
Day 12
Day 15
n
n
n
n
n
%
%
%
%
%
4 10.5 3 8 6 15.8 5 13.2 5 13.2 1 2.6 1 2.6 1 2.6 1 2.6 1 2.6 1 2.6 2 5.3 1 2.6 1 2.6 1 2.6
Analgesic efficacy The VAS scores were low with both medications. In several studies pain relief was even better with fentanyl TTS than with alternative treatments. However, in these studies pain was not controlled sufficiently before switching to transdermal fentanyl (Miser et al. 1989; Simmonds et al. 1989; Payne 1990; Southam et al. 1991; Zech et al. 1991a, 1992; Levy et al. 1992; Slover 1992).
532
Many patients on fentanyl TTS required supplemental analgesic medication with other opioids (Simmonds et al. 1989; Herbst and Strause 1992; Levy et al. 1992; Slover 1992; Zech et al. 1992). Our patients were allowed to take liquid morphine as escape medication to achieve immediate pain relief. We have no explanation, why more patients in the fentanyl T-I'S period required an escape medication although pain levels and pain attacks were unchanged in comparison with SRM. One hypothesis might be that the patients were used to an oral medication or, as a second hypothesis, in some cases fentanyl TTS was not effective over the whole 72-h periods in some patients. The latter reason could be assumed for 5 patients. In previous studies some patients required application of the transdermal system every 48 h (Janssen Pharmac. 1990; Calis et al. 1992; Levy et al. 1992).
Side effects Side effects except constipation did not differ between fentanyl TTS and oral morphine (Levy et al. 1988; Maves and Barcellos 1992). The incidence of nausea was high in comparison to the study by Southam et al. (1991) (41.4% vs. 23%), but the incidence of vomiting was similar (20.3%). Constipation and the need for laxatives were reduced with fentanyl TTS. Similar effects were also reported by Slover (1992) and Zech et al. (1992). Constipation due to oral morphine is caused by binding to local opioid receptors in the gastrointesinal tract and the brain. However, the gastrointestinal effect seems to be more important (Jurna and Baldauf 1993). The transdermal route may be the reason for the reduced incidence of constipation with fentanyl TTS. Perhaps fentanyl TTS might become an alternative for patients suffering from severe constipation with 'conventional' opioids. Further studies are needed to prove these preliminary observations. During this multicenter study no patient developed respiratory depression (respiratory rate: < 8/min). In previous studies 6 cancer patients developed respiratory depressions due to fentanyl TI'S (Simmonds and Payne 1989; Southam et al. 1991; Simmonds 1995; Zech and Lehmann 1995). In 3 patients a respiratory rate below 8 / m i n was observed during the titration period (conversion from intravenous to transdermal fentanyl with the ratio of 1:1.5) (Zech and Lehmann 1995). One naloxone reversible respiratory depression occurred in the terminal phase of cancer (Simmonds and Payne 1989; Simmonds 1995). For the other 2 patients no detailed informations were given. Patients developing serious adverse effects must be monitored for a period related to the slow decline of fentanyl serum concentration. Continuous administration of naloxone might be necessary (Holley and van Stevens 1988; Larijani et al. 1988; Gourlay et al. 1989; Varvel et
al. 1989; Janssen Pharmac. 1990; Gupta et al. 1992; Lehmann and Zech 1992; Portenoy et al. 1993). Withdrawal symptoms occurred in 3 of our patients and in 5 patients in a postmarketing surveillance report of the USA (van Gestel and Amery 1992). Furthermore, Skoyles et al. (1993) recently reported a patient with withdrawal symptoms after the switchover from SRM to fentanyl TTS. In general, these withdrawal symptoms occurred during the initial phase after conversion from morphine to fentanyl "ITS. Thus, these withdrawal symptoms seem to be morphine related and may be caused by relatively fast reduction of morphine plasma level. The skin tolerated the transdermal system well although cutaneous symptoms occurred in approximately 13% of the patients. Southam et al. (1991) reported topical reactions in only 4% of the patients. However, in other studies the incidence of cutanaeus reactions was higher too (Donner et al. 1993b). Changing the sites of patch application may minimize chronic local irritation (Calis et al. 1992). Recently Rose et al. (1993) reported on a cancer patient suffering from mental confusion, pinpoint pupils and shallow respiration after she had a heating pad for further pain relief, which also warmed up the area of the fentanyl patch. In the product information it is recommended to monitor patients with fever closely. Fentanyl serum levels might increase by one-third, when temperature is about 40°C (Janssen Pharmac. 1990, 1991).
Judgement of the patient Patients preferred fentanyl TTS over oral morphine. Most of the patients continued with the transdermal therapy after the end of the study period. With transdermal fentanyl patients just have to remember their opioid medication every 48-72 h. Reduced constipation may result in a better quality of life. These two facts account for better compliance of the patient and lead to the feeling of greater independency from pain therapy.
Recommendations for the use of fentanyl TTS Peak plasma levels occur 8-12 h following the application of fentanyl TTS (Holley and van Stevens 1988; Gourlay et al. 1989; Latasch and Liiders 1989; Calis et al. 1992; Lehmann and Zech 1992; van Bestelaere et al. 1993). With the first application the patient should receive the last medication of the long-acting opioid, so that no gap in analgesia should occur with the conversion. We recommend to start the transdermal fentanyl therapy in the morning. This enables good control of the patient's vigilance during the day until peak plasma levels are reached. Very high dosages of opioids are needed in some cancer patients to obtain sufficient pain relief. Lehr
533
and Renaud (1993) reported on a patient requiring 12 mg of fentanyl T-FS per day. Since the fentanyl TTS dosage is limited by the area of application an area 200 cm 2 is needed for 12 mg fentanyl/day. Especially in small and kachectic patients this will be a limiting factor. In any case, the application area shall be changed (Janssen Pharmac. 1990, 1991). Dysphagia and tumor,; of the upper gastrointestinal tract with severe nausea or vomiting may represent special indications for fentanyl TTS. In patients requiring an opioid therapy and suffering from severe constipation an attempt at transdermal fentanyl is advisable. Due to the slow pharmacokinetics of transdermal systems, it is appropriate only for patients with a relatively constant chronic pain sydreme requiring a constant opioid dosage for pain relief. Is pain fluctuating an effective and safe pain control with fentanyl TTS probably is not possible. Conclusion A calculation table for the conversion of morphine to fentanyl T-FS with a ratio of 100:1 is safe and effective. The ratio is slightly too low. The true ratio determined in this study is 70:1. This implies a sufficient margin of safety for the conversion. Constipation was reduced compared to the therapy with oral morphine. No severe side effects, especially no respiratory depression, were observed. Three patients developed withdrawal symptoms immediately after the switch to fentanyl TTS. Transdermal fentanyl is a convenient therapy with avoidance of gastrointestinal absorption and may have special indications, e.g., in patients with nausea and vomiting or bowel ostruction or patients with severe constipation. In our opinion the indication for transdermal fentanyl is limited to patients with a stable pain syndrome as a result of the slow pharmacokinetics. Fentanyl TTS, a strong non-invasive opioid has to be integrated into step III of the analgesic ladder of the WHO. Based on our results patients can be directly converted from oral morphine to transdermal fentanyl on a morphine/fentanyl ratio of 100:1. However, since this conversion ratio is slightly underestimative the true ratio (approximately 70:l) patients should be allowed to supplement their analgesic requirements with liquid morphine during the first days until the effective fentanyl dosage has been adjusted. The development of transdermal systems for opioid therapy may provide a useful alternative route of administration for patients with chronic pain sensitive to opioids. Acknowledgements This study was supported by a grant from Janssen GmbH Neuss and STADA Arzneimittel AG.
Participating investigators are the following: J. Ammon, M.D. (Dept. of Therapeutic Therapeutic Radiology, RWTH, Aachen); B. von Bormann, M.D. (Dept. of Anesthesiology, St. Johannes Hospital, Duisburg); R. Dennhardt, M.D. (Dept. of Anesthesiology, Hospital Nordwest, Frankfurt/Main); W. Dinter, M.D. (Dept. of Anesthesiology, University Diisseldorf); B. Eberhard, M.D. (Pain Ambulance, Frankfurt/Main); I. Gralow, M.D. (Dept. of Anesthesiology and Intensive Care Medicine, University MOnster); G.G. Hanekop, M.D. (Dept. of Anesthesiology, University G6ttingen); U.B. Hankemeier, M.D. (Dept. of Anesthesiology, Ev. Johannes-Hospital, Bielefeld); G. Hege, M.D. (Dept. of Anesthesiology, University Ulm); P. Hoffmann, M.D. (Dept. of Anesthesiology, General Hospital, Hamburg Barmbeck); E. Klaschik, M.D. (Dept. of Anesthesiology and Intensive Care Medicine, Malteser Hospital, Bonn); U.R. Kleeberg, M.D. (Hamburg); D. Loose, M.D. (Dept. of Anesthesiology, Kiel); J. Meyer, M.D., and W. Schr/Sder, M.D. (Dept. of Anesthesiology of the Klinikum Minden); P. Milewski, M.D. (Dept. of Anesthesiology, Klinik am Eichert, G6ppingen); D. Olthoff, M.D. (Dept. of Anesthesiology and Intensive Care Medicine, Leipzig); E. Schick, M.D. (Onkologist, Frankenthal); J. Sorge, M.D. (Dept. of Anesthesiology of the University Hannover); G. Sprotte, M.D. (Dept. of Anesthesiology, University Wiirzburg); M. Strumpf, M.D. (Dept. of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Bergmannsheil, Bochum); D. Zech, M.D. (Dept. of Anesthesiology and Intensive Care Medicine, Pain Therapy, University of Cologne).
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