TRANSDERMAL DELIVERY OF FENTANYL TO SURGICAL. PATIENTS. D. J. R. DUTHIE, D. J. ROWBOTHAM, R. WYLD, P. D. HENDERSON. AND W. S. ...
Br. J. Anaesth. (1988), 60, 614-618
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 [1-3] 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 [8-11]. 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. [12]. PATIENTS AND METHODS
After Ethics Committee approval and informed written consent, 34 patients aged 18-70 yr, undergoing abdominal surgery were studied. All patients weighed 50-100 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 S10 2RX. Accepted for Publication: December 20, 1987. 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 12 h, concentrations did not differ from those observed in a matched group of patients receiving fentanyl by i.v. infusion. At 24h, 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 100 ug h"1. TTS-fentanyl was applied 2 h before induction of anaesthesia. Patients were allocated to one of two groups. Group 1 received fentanyl 100 ug i.v.; group 2 received 200 ug. Anaesthesia was induced with thiopentone 5 mg kg"1 and maintained with 0.5-2% enflurane and 67 % nitrous oxide in oxygen. Neuromuscular blockade was achieved with vecuronium 0.01 mg kg"1 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 2.5 mg and atropine 1.2 mg. Fentanyl was given i.v. at induction according to the group allocated. Venous blood samples were taken at 0.5, 1,2, 4, 8, 12 and 24 h after the start of fentanyl adminis-
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TRANSDERMAL FENTANYL tration. Further samples were taken after the bolus dose given on induction of anaesthesia (2.25, 2.5 and 3 h). After 24 h, when the TTSfentanyl was removed, samples were taken at 4, 8, 12 and 24 h. Plasma was separated and stored at — 20 °C until plasma fentanyl concentrations were measured by radioimmunoassay [13, 14]. 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 2.5-10 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 100 ugh' 1 by i.v. infusion (group 3). The infusion was commenced 2 h before induction of anaesthesia and delivered by a Baxter Travenol Infusor [2]. All patients in this group received fentanyl 100 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 0.5, 1, 2 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
(AUC10) 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:
(1)
4AUC^00 In 2
(2) 101
where C/P = plasma clearance; Xd = total dose administered; AUC00 = area under the concentration time-curve to infinity; k = rate constant; 71 = 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 1 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 1 ( P < 0.001) and group 2 (P < 0.05). There was no significant difference between group 1 and 2. At 8 and 12 h there were no significant differences between the groups. At 24 h, concentrations in group 2 were significantly less than group 3 (P < 0.001) and group 1 (P < 0.01). 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)
Duration of
(yr)
Weight (kg)
Sex M/F
surgery (min)
49±12
70 ±10
6/4
105 ±40
49+11
74±13
5/4
111 ±40
49 ±14
64±14
4/9
100±30
Age
Group 1 (» = 10) Group 2 (n = 9) Group 3 (n = 13)
Operation 9 Cholecystectomy 1 Gastric surgery 7 Cholecystectomy 2 Gastric surgery 9 Cholecystectomy 4 Gastric surgery
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1
2
) 2 4
8
12
24
t Bolus
28
32
36
48
Time (hi
100
FIG. 1. Mean + SEM plasma fentanyl concentrations in patients in group 1 (A: transdermal fentanyl plus fentanyl 100 ug (Bolus) at induction of anaesthesia), group 2 ( 0 : transdermal fentanyl plus fentanyl 200 ng (Bolus) at induction of anaesthesia) and group 3 ( • : control; i.v. infusion of fentanyl 100 ug h"1 (cross-hatched bar) plus 100-(ig Bolus).
time were 116% (from 1.2 to 2.6ngml" 1 ) in group 1 and 92% (from 0.68 to 1.31 ng ml"1) in group 2. Plasma fentanyl concentrations decreased Plasma fentanyl concentrations (ng ml"1) slowly in the TTS-fentanyl groups over 24 h, but exact comparison with the i.v. infusion group was Group 1 Group 2 Group 3 not possible because blood samples were taken Time TTS-fentanyl TTS-fentanyl i.v. infusion only up to 4 h after stopping fentanyl in this 100-ug bolus 200-ug bolus 100-ug bolus 00 group. At 12 h, all patients in group 1 and 6 0.5±0.1 0.5 0 0 (66%) in group 2 had plasma fentanyl concen1 0 0 0.7±0.1 trations greater than 1 ng ml"1. Twenty-four hour 2 0.3±0.1 0.3 + 0.1 0.8±0.1 after the removal of TTS-fentanyl, two patients 2.25 1.0 ±0.2 1.6 + 0.1 2.3±0.4 (20%) in group 1 and one (11 %) in group 2 had 2.5 0.9 + 0.2 1.2 + 0.1 1.8±0.1 3 1.0 + 0.3 1.3 + 0.2 1.8±0.2 plasma fentanyl concentrations greater than 1 ng 4 0.7 + 0.2*** 1.1 ±0.2* 1.8±0.2 ml"1. 8 1.3 + 0.2 1.2 + 0.3 1.8±0.2 The mean calculated doses of fentanyl delivered 12 1.6 ±0.2 1.5 + 0.2 1.8±0.2 by the TTS-fentanyl systems in 24 h are shown in 24 1.3±0.1*** 2.3 + 0.2 2.0±0.2ft table III. There were no significant differences Fentanyl discontinued at 24 h between groups 1 and 2. 0.5 — — 2.2±0.3 Pharmacokinetic values are shown in table IV. 1 — — 2.1 ±0.3 2 — — 1.7±0.1 The mean plasma half-lives in groups 1 and 2 4 2.1+0.2 1.5 + 0.2 1.6±0.2 were 15.9 and 15.7 h, respectively. The mean 8 1.7 + 0.2 1.3 + 0.2 plasma clearance was greater in group 2, but this 12 — 1.7±0.2 1.2 + 0.2 was not statistically significant. Pharmacokinetic 24 — 0.8 ±0.2 0.7 + 0.1 data for the i.v. group were not compared group 3 (P < 0.01, paired t test). There was a statistically with the TTS groups, as the final small increase in groups 1 and 2, but this was not blood sample in the i.v. group was taken only 4 h statistically significant. The maximum individual after stopping the infusion. increases in plasma fentanyl concentrations at this Two patients from group 2 were withdrawn TABLE II. Plasma fentanyl concentrations (mean±SEAf). Groups compared by ANOVA from 4 h: *P < 0.05; ***P < 0.001 compared with group 3; ffP < 0.01 compared with group 2
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other groups at 24 h. There was no significant difference between the TTS-fentanyl groups in the total amount of fentanyl administered. Thus, Total fentanyl lower mean plasma fentanyl concentrations at (mg) 24 h may be related to the greater plasma clearance 2.25 + 0.28 Group 1 in group 2, although this difference did not 2.33±0.18 Group 2 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 decreased significantly. In both transdermal group 1 and 2. Group 3 not compared groups the mean concentrations increased, alPlasma though not significantly. Two patients in this Clearance half-life AUC" study showed a marked increase (92 % and 116%) 1 1 (ml min" ) (h) (ng min ml" ) in plasma fentanyl concentrations after removal of the patch. This had no observable clinical effect Group 1 450 + 59 15.9 + 2.3 5715 + 791 (n = 10) on these patients. These data, combined with the Group 2 650 + 70 15.7 + 2.3 4379 + 628 delay in achieving therapeutic concentrations (n = 9) after application of the system, are compatible Group 3 720 + 70 8.5 + 2.0 5412 + 511 with a depot of fentanyl forming in the skin. When the calculated pharmacokinetic values in the TTS-fentanyl groups are compared with from the trial. In both patients, the ventilatory those from other studies with i.v. fentanyl [15], rate decreased to less than 8 b.p.m. during sleep. the mean half-life of approximately 16 h is much Plasma fentanyl concentrations at these times greater than those found in these studies. Direct were 2.8 and 2.9 ng ml"1. Both patients had statistical comparison with group 3 in our study received supplementary morphine 20 mg and 10 (Ti = 8.5 h) has not been made because of the mg, respectively. short sampling time after stopping the infusion. Plasma fentanyl clearance in the transdermal DISCUSSION groups did not differ markedly from that reported The range of plasma fentanyl concentrations in other studies. It is likely that the prolonged associated with analgesia and acceptable respira- plasma half-life of fentanyl in these patients is also tory function is 1-3 ng ml"1 [15-17]. Estimates of a result of deposits of the drug remaining in the the half-life of fentanyl have varied [16], but it is skin when the patch is removed. This slow decline in plasma fentanyl concenclear that, after constant rate delivery, steady state would be achieved only after many hours. How- tration may be advantageous when the system is ever a bolus of fentanyl 100 ug at induction of used for the relief of postoperative pain, but it anaesthesia, combined with fentanyl 100 ug h"1 should be borne in mind if the patch is removed by continuous i.v. infusion, has produced steady- because of side-effects from fentanyl. state concentrations rapidly and within the range Plasma fentanyl concentrations in the two 1-3 ng ml"1 in surgical patients [12]. patients withdrawn from the study (2.8 and 2.9 ng 1 In the present study, these data have been ml" ) were both within the therapeutic range. compared with two TTS groups in which fentanyl Supplementary morphine had been given to both 100 ug and 200 ug boluses were given at induction patients and this probably contributed to the of anaesthesia. With TTS-fentanyl and 100 ug respiratory depression (ventilatory rates < 8 bolus (group 1), concentrations did not differ b.p.m.). significantly from the i.v. group between 8 and The delivery of fentanyl by the transdermal 24 h. At 4 h, however, only one patient had a route may be useful in the treatment of pain after plasma concentration greater than Ing ml"1. surgery. If it is applied 2 h before surgery, With TTS-fentanyl and 200-ug bolus (group 2), combined with a bolus dose of 200 ug i.v. at five patients had concentrations greater than 1 ng induction of anaesthesia, steady-state fentanyl ml"1 at 4 h. Plasma concentrations did not differ concentrations occur early in the postoperative from group 3 at 8 and 12 h. However, con- period. Concentrations decline slowly after its centrations were significantly lower than in the removal. TABLE III. Total amount of fentanyl (/ng) delivered by TTS systems in 24 h (mean + SEAT)
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We are grateful to Alza Corporation for supplies of TTSfentanyl and for financial support.
