Support Care Cancer (1995) 3:210-211 9 Springer-Verlag 1995 David Brooks Day-to-day titration of transdermal fentanyi is unwise Dear Editor, The conclusions of Korte and Mo- rant's paper are unsound [2]. They make no reference to the pharma- cokinetic evidence that analgesic serum concentrations are not achieved until between 1.2 and 31.3 h after application of transder- mal fentanyl (F-TTS) [1]. In one study the mean delay time ranged from 10.7 + 5.7 h for 75 txg/h patches to 18.9 + 10.9 h for 50 p~g/h patches [1]. Similar results have been replicated in several other studies [3-5]. At 24 h after patch application, when they suggest doses should be reviewed and titrated if necessary, most patients will not have had steady state serum concentrations of fentanyl for long enough to make an accurate assessment of analgesic efficacy. This policy of early titration may lead to doses being titrated upwards when, if the patient had been left another 24 h, analgesia would have been achieved at the lower dose. This is supported by the comment by the authors that their initial doses of F-TTS were "too low even though we had used higher F-TTS doses for conversion than those recommended by the manufacturer." Day-to-day titration may not have led to dangerous overdosage in their small series, but in vulnera- ble patients who do not have the intensive monitoring that inclusion in a trial affords, deaths may occur. The policy is illogical and entails unnecessary risks. Patients should be provided with rescue medication and en- couraged to take this, especially in the first 72 h after patch applica- tion. They should be told that "it takes a while for the medication to get into your system" and that un- til it has done so they may need to take frequent rescue medication. Finally, dose titration should be at 48 h after patch application at the earliest, and preferably 72 h after. This policy makes pharmacokinetic sense and leads to good analgesia at lower dosages. References 1. Gourlay GK, Mather LE (1991) Post- operative pain management with TTS fentanyl: pharmacokinetics and phar- macodynamics. In: Lehmann KA, Zech D (eds) Transdermal fentanyl. Springer, Berlin Heidelberg New York, pp 119-140 2. Korte W, Morant R (1994) Transder- real fentanyl in uncontrolled cancer pain: titration on a day-to-day basis as a procedure for safe and effective dose finding - a pilot stndy in 20 patients. Support Care Cancer 2:123-127 3. Plezia PM, Kramer TH, Linford J, Ha- meroff SR (1989) Transdermal fenta- nyl: pharmacokinetics and preliminary clinical evaluation. Pharmacotherapy 9:2-9 4. Portenoy RK, Southam MA, Gupta SK, et al (1993) Transdermal fentanyl for cancer pain. Repeated dose phar- macokinetics. Anesthesiology 78 :36-43 5. Varvel JR, Shafer SL, Hwang SS, Coen PA, Stanski DR (1989) Absorp- tion characteristics of transdermally administered fentanyl. Anesthesiology 70: 928-934 D. Brooks, M.D. Palliative Medicine, Department of Surgical and Anaesthetic Sciences, Royal Haltamshire Hospital, Floor K, Sheffield SI0 2JF, UK Tel./Fax: (114) 2712950 Wolfgang Korte Rudolf Morant Reply Dear Editor, We appreciate Dr. Brook's critical comments and would like to re- spond to them point by point. Dr. Brooks states correctly that mean delay times between applica- tion of the fentanyl transdermal therapeutic system (F-TTS) and analgesic serum concentrations of fentanyl vary between (roughly) 10 h and 20 h [1, 4, 6, 7], indicating a large interindividual variability. He also states that we did not take into account pharmacokinetic evi- dence provided by Gourlay and Mather [1]. We were aware of the data Dr. Brooks refers to, since they originate from a publication that is probably the most compre- hensive review on transdermal fen- tanyl available [3]. The same au- thors Dr. Brooks is citing describe the development of a "pseudo- steady state" of plasma fentanyl concentrations after apprgximately 15 h [4]. This is no contradiction to the data'of Portenoy et al.~[6], de- scribing a "real" steady state after the application of the second F- TTS. In addition, Varvel et al. have shown that the maximal ab- sorption is reached after approxi- mately 8 h, starting to level-out thereafter [7]. These facts are the rationale behind the thought that 24-h intervals for titration should be possible. Dr. Brook believes that, be- cause of the policy of early titra- tion, we probably end up using higher doses of fentanyl than are needed to achieve analgesia. This is not the case. The most sophisti- cated (but also most complicated) approach for dose finding was un- dertaken by Zech et al. [9] using additional i.v. fentanyl patient-con- trolled analgesia during the first 3