PLASMA FENTANYL CONCENTRATIONS DURING TRANSDERMAL DELIVERY OF FENTANYL TO SURGICAL PATIENTS

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1 Br. J. Anaesth. (988), 6, PLASMA FENTANYL CONCENTRATIONS DURING TRANSDERMAL DELIVERY OF FENTANYL TO SURGICAL PATIENTS D. J. R. DUTHIE, D. J. ROWBOTHAM, R. WYLD, P. D. HENDERSON AND W. S. NIMMO Pain after surgery is treated commonly with intermittent i.m. opioids, but this regimen is often ineffective. Infrequent administration of the drug and variability of drug absorption and patient response are important causes of failure to achieve satisfactory analgesia. Rate-controlled i.v. administration of opioids [-3] may improve analgesia by ensuring drug delivery and minimizing variability of absorption [4, 5]. However, this regimen may require costly electronic apparatus. Transdermal delivery systems are simple to use and permit reproducible and reliable administration of drugs [6, 7]. Glyceryl trinitrate, hyoscine, clonidine and oestrogens can be administered transdermally [8-]. Fentanyl has now been formulated into a transdermal therapeutic system (TTS-fentanyl, Alza Corporation). We have measured plasma fentanyl concentrations in surgical patients given fentanyl by this transdermal system and compared them with data published previously from a matched group of patients receiving fentanyl infusion i.v. []. PATIENTS AND METHODS After Ethics Committee approval and informed written consent, 34 patients aged 8-7 yr, undergoing abdominal surgery were studied. All patients weighed 5- kg and none had clinical evidence of hepatic, psychiatric, renal or respiratory disease. DAVID J. R. DUTHIE, M.B., CH.B., F.F.A.R.C.S.; DAVID J. ROWBOTHAM, M.B., CH.B., M.R.C.P., F.F.A.R.C.S., F.F.A.R.C.S.I. J RONA WYLD, S.R.N.; PETER D.HENDERSON; WALTER S. NIMMO, B.sc, M.D., F.R.C.P., F.F.A.R.C.S.; Department of Anaesthesia, Sheffield University Medical School, Beech Hill Road, Sheffield S RX. Accepted for Publication: December, 987. Correspondence to D.J.R. SUMMARY Plasma fentanyl concentrations were measured during and after transdermal fentanyl delivery in groups of patients undergoing general surgery. At 8 and h, concentrations did not differ from those observed in a matched group of patients receiving fentanyl by i.v. infusion. At 4h, concentrations were significantly lower in one of the transdermal groups. Plasma fentanyl clearance did not differ significantly between the groups. Plasma fentanyl concentrations decreased slowly after removal of the transdermal system. TTS-fentanyl is a rate-controlled adhesive skin patch, which contains fentanyl in a sealed drug reservoir and is applied to a hair-free area of the skin on the upper chest. In this study it was designed to deliver fentanyl at a rate of ug h". TTS-fentanyl was applied h before induction of anaesthesia. Patients were allocated to one of two groups. received fentanyl ug i.v.; group received ug. Anaesthesia was induced with thiopentone 5 mg kg" and maintained with.5-% enflurane and 67 % nitrous oxide in oxygen. Neuromuscular blockade was achieved with vecuronium. mg kg" given at induction of anaesthesia, with repeat bolus doses as required. The lungs were ventilated mechanically and normocapnia maintained. Neuromuscular blockade was antagonized with neostigmine.5 mg and atropine. mg. Fentanyl was given i.v. at induction according to the group allocated. Venous blood samples were taken at.5,,, 4, 8, and 4 h after the start of fentanyl adminis-

2 TRANSDERMAL FENTANYL 65 tration. Further samples were taken after the bolus dose given on induction of anaesthesia (.5,.5 and 3 h). After 4 h, when the TTSfentanyl was removed, samples were taken at 4, 8, and 4 h. Plasma was separated and stored at C until plasma fentanyl concentrations were measured by radioimmunoassay [3, 4]. Immediately after removal of the TTS-fentanyl, the patch was sealed with an impermeable plastic backing. The amount of fentanyl remaining in the system was analysed by high performance liquid chromatography. The total amount of fentanyl delivered to the patient was calculated by subtracting the measured residual fentanyl from the amount inserted at manufacture. Pain relief following surgery was assessed by the nursing and medical staff. Morphine.5- mg i.m. was given if analgesia was unsatisfactory. No formal assessment of pain scores was made. Rate of ventilation was recorded hourly. The study was discontinued if it decreased to less than 8 b.p.m. The anaesthetic regimen used in this study was identical to that used in a control group of patients receiving fentanyl ugh' by i.v. infusion (group 3). The infusion was commenced h before induction of anaesthesia and delivered by a Baxter Travenol Infusor []. All patients in this group received fentanyl ug i.v. at induction of anaesthesia. Blood samples were taken at the same time intervals as the TTS groups during the infusion of fentanyl. Samples were then taken at.5,, and 4 h after cessation of the infusion. Plasma was stored and analysed as described above. Pharmacokinetic calculations Plasma clearance and half-life were calculated for each patient from the plasma fentanyl concentrations. The area under the curve to infinity (AUC ) was calculated by the trapezoid method with extrapolation of the concentration-time curve to infinity. The elimination rate constant was calculated from the slope of the decrease in plasma fentanyl concentrations after removal of the transdermal system or infusion. The following equations were used: 4 ^ () AUC In () where C/ P = plasma clearance; Xd = total dose administered; AUC = area under the concentration time-curve to infinity; k = rate constant; 7 = plasma half-life. Plasma fentanyl concentrations and pharmacokinetic values were compared using one-way analysis of variance and Student's t test. RESULTS There were no significant differences in age, weight, sex, duration of surgery and surgical procedure between the groups (table I). Mean plasma fentanyl concentrations are shown in figure and table II. Comparisons between groups were made from 4 h onwards. At 4 h, plasma fentanyl concentrations were significantly greater in group 3 when compared with group (P<.) and group (P <.5). There was no significant difference between group and. At 8 and h there were no significant differences between the groups. At 4 h, concentrations in group were significantly less than group 3 (P <.) and group (P <.). There were no significant differences between the groups 4 h after fentanyl removal. Plasma fentanyl concentrations decreased significantly 4 h after discontinuation of fentanyl in TABLE I. Details of patients and operations (mean + SD). No significant differences between groups {analysis of variance and chi-square tests) Age (yr) Weight (kg) Sex M/F Duration of surgery (min) Operation (» = (n = (n = ) 9) 3 3) 49± ±4 7 ± 74±3 64±4 6/4 5/4 4/9 5 ±4 ±4 ±3 9 Cholecystectomy Gastric surgery 7 Cholecystectomy Gastric surgery 9 Cholecystectomy 4 Gastric surgery

3 66 BRITISH JOURNAL OF ANAESTHESIA ) 4 t Bolus 8 4 Time (hi FIG.. Mean + SEM plasma fentanyl concentrations in patients in group (A: transdermal fentanyl plus fentanyl ug (Bolus) at induction of anaesthesia), group (: transdermal fentanyl plus fentanyl ng (Bolus) at induction of anaesthesia) and group 3 ( : control; i.v. infusion of fentanyl ug h" (cross-hatched bar) plus -(ig Bolus). TABLE II. Plasma fentanyl concentrations (mean±seaf). s compared by ANOVA from 4 h: *P <.5; ***P <. compared with group 3; ffp <. compared with group Time Plasma fentanyl concentrations (ng ml" ) TTS-fentanyl -ug bolus.3±.. ± *** ±..±.ft Fentanyl ±..8 ±. TTS-fentanyl -ug bolus ±.* ±.*** discontinued at h 3 i.v. infusion -ug bolus.5±..7±..8±..3±.4.8±..8±..8±..8±..8± ±.3. ±.3.7±..6±. group 3 (P <., paired t test). There was a small increase in groups and, but this was not statistically significant. The maximum individual increases in plasma fentanyl concentrations at this time were 6% (from. to.6ngml" ) in group and 9% (from.68 to.3 ng ml" ) in group. Plasma fentanyl concentrations decreased slowly in the TTS-fentanyl groups over 4 h, but exact comparison with the i.v. infusion group was not possible because blood samples were taken only up to 4 h after stopping fentanyl in this group. At h, all patients in group and 6 (66%) in group had plasma fentanyl concentrations greater than ng ml". Twenty-four hour after the removal of TTS-fentanyl, two patients (%) in group and one ( %) in group had plasma fentanyl concentrations greater than ng ml". The mean calculated doses of fentanyl delivered by the TTS-fentanyl systems in 4 h are shown in table III. There were no significant differences between groups and. Pharmacokinetic values are shown in table IV. The mean plasma half-lives in groups and were 5.9 and 5.7 h, respectively. The mean plasma clearance was greater in group, but this was not statistically significant. Pharmacokinetic data for the i.v. group were not compared statistically with the TTS groups, as the final blood sample in the i.v. group was taken only 4 h after stopping the infusion. Two patients from group were withdrawn

4 TRANSDERMAL FENTANYL 67 TABLE III. Total amount of fentanyl (/ng) delivered by TTS other groups at 4 h. There was no significant systems in 4 h (mean + SEAT) difference between the TTS-fentanyl groups in Total fentanyl the total amount of fentanyl administered. Thus, (mg) lower mean plasma fentanyl concentrations at 4 h may be related to the greater plasma clearance in group, although this difference did not.33±.8 achieve statistical significance. Four hours after discontinuation of the i.v. TABLE IV. Calculated plasma fentanyl clearances, half-lives infusion, plasma fentanyl concentrations had and AVC" (mean + SEM). No significant differences between group and. 3 not compared (n = ) (n = 9) 3 Clearance (ml min" ) Plasma half-life (h) AUC" (ng min ml" ) from the trial. In both patients, the ventilatory rate decreased to less than 8 b.p.m. during sleep. Plasma fentanyl concentrations at these times were.8 and.9 ng ml". Both patients had received supplementary morphine mg and mg, respectively. DISCUSSION The range of plasma fentanyl concentrations associated with analgesia and acceptable respiratory function is -3 ng ml" [5-7]. Estimates of the half-life of fentanyl have varied [6], but it is clear that, after constant rate delivery, steady state would be achieved only after many hours. However a bolus of fentanyl ug at induction of anaesthesia, combined with fentanyl ug h" by continuous i.v. infusion, has produced steadystate concentrations rapidly and within the range -3 ng ml" in surgical patients []. In the present study, these data have been compared with two TTS groups in which fentanyl ug and ug boluses were given at induction of anaesthesia. With TTS-fentanyl and ug bolus (group ), concentrations did not differ significantly from the i.v. group between 8 and 4 h. At 4 h, however, only one patient had a plasma concentration greater than Ing ml". With TTS-fentanyl and -ug bolus (group ), five patients had concentrations greater than ng ml" at 4 h. Plasma concentrations did not differ from group 3 at 8 and h. However, concentrations were significantly lower than in the decreased significantly. In both transdermal groups the mean concentrations increased, although not significantly. Two patients in this study showed a marked increase (9 % and 6%) in plasma fentanyl concentrations after removal of the patch. This had no observable clinical effect on these patients. These data, combined with the delay in achieving therapeutic concentrations after application of the system, are compatible with a depot of fentanyl forming in the skin. When the calculated pharmacokinetic values in the TTS-fentanyl groups are compared with those from other studies with i.v. fentanyl [5], the mean half-life of approximately 6 h is much greater than those found in these studies. Direct statistical comparison with group 3 in our study (Ti = 8.5 h) has not been made because of the short sampling time after stopping the infusion. Plasma fentanyl clearance in the transdermal groups did not differ markedly from that reported in other studies. It is likely that the prolonged plasma half-life of fentanyl in these patients is also a result of deposits of the drug remaining in the skin when the patch is removed. This slow decline in plasma fentanyl concentration may be advantageous when the system is used for the relief of postoperative pain, but it should be borne in mind if the patch is removed because of side-effects from fentanyl. Plasma fentanyl concentrations in the two patients withdrawn from the study (.8 and.9 ng ml" ) were both within the therapeutic range. Supplementary morphine had been given to both patients and this probably contributed to the respiratory depression (ventilatory rates < 8 b.p.m.). The delivery of fentanyl by the transdermal route may be useful in the treatment of pain after surgery. If it is applied h before surgery, combined with a bolus dose of ug i.v. at induction of anaesthesia, steady-state fentanyl concentrations occur early in the postoperative period. Concentrations decline slowly after its removal.

5 68 BRITISH JOURNAL OF ANAESTHESIA ACKNOWLEDGEMENT We are grateful to Alza Corporation for supplies of TTSfentanyl and for financial support. REFERENCES. Stapleton JV, Austin KL, Mather LE. A pharmacokinetic approach to postoperative pain: continuous infusion of pethidine. Anaesthesia and Intensive Care 979; 7: Nimmo WS, Todd JG. Fentanyl by constant rate i.v. infusion for postoperative analgesia. British Journal of Anaesthesia 985; 57: Hull CJ, Sibbald A. Control of postoperative pain by interactive demand analgesia. British Journal of Anaesthesia 98; S3: Stanski DR, Greenblatt DJ, Lowenstein E. Kinetics of intravenous and intramuscular morphine. Clinical Pharmacology and Therapeutics 978; 4: Rigg JRA, Browne RA, Davis C, Khandelwal JK, Goldsmith CH. Variation of the disposition of morphine after i.m. administration in surgical patients. British Journal of Anaesthesia 978; SO: Shaw JE, Urquhart J. Programmed, systemic drug delivery by the transdermal route. Trends in Pharmacological Science 98; : Shaw JE, Urquhart J. Transdermal drug administrationa nuisance becomes an opportunity. British Medical Journal 98; 83: Bogaert MG. Clinical pharmacokinetics of glyceryl trinitrate following the use of systemic and topical preparations. Clinical Pharmacokinetics 987; : Uppington J, Dunnet J, Blogg CE. Transdermal hyoscine and postoperative nausea and vomiting. Anaesthesia 986; 4: 6-.. Mroczek WJ, Ulrych M, Yoder S. Weekly transdermal clonidine administration in hypertensive patients. Clinical Pharmacology and Therapeutics 98; 3: 35.. Laufer LR, DeFazio JL, Lu JKH, Meldrum DR, Eggena P, Sambhi MP, Hershman JM, Judd HL. Estrogen replacement therapy by transdermal estradiol administration. American Journal of Obstetrics and Gynecology 983; 46: Duthie DJR, McLaren AD, Nimmo WS. Pharmacokinetics and fentanyl during constant rate i.v. infusion for the relief of pain after surgery. British Journal of Anaesthesia 986; 58: Michiels M, Hendricks R, Heykants J. A sensitive radioimmunoassay for fentanyl. European Journal of Clinical Pharmacology 977; : Schuttler J, White PF. Optimization of the radioimmunoassay for measuring fentanyl and alfentanil in human. serum. Anesthesiology 984; 6: Hug CC. Pharmacokinetics and dynamics of narcotic analgesics. In: Prys-Roberts C, Hug CC, eds. Pharmacokinetics of Anaesthesia. Oxford: Blackwell, 984; Mather LE, Phillips GD. Opioids and adjuvants: principles of use. In: Cousins MJ, Phillips GD, eds. Acute Pain Management. New York: Churchill Livingstone, 986; Andrews CJH, Prys-Roberts C. Fentanyla review. In: Bullingham RES, ed. Opiate Analgesia. Eastbourne: W. B. Saunders, 983; 97-.