Vol.7 No. 3 [Sup$)A/.& 1992

Alan Sadler,

Journal of Pain and symptomManagemtnt S27

FRCPC

Departmentofrinesthesiology,Unix&y of Ti~onto,Toronto,Ontario,Canada

Eie transaknnal therapeuticsystem (?TS)

is a novel techniqueof drug administrationthat can mimic

long-&nn continuousintravenousi@sions in maintainingstubk drugplasma concentrations.FmmyI,

a

potent @id-sohdde ynthetic opioid_,hzs beeninco@oratedintoswh a .&em and has undergoneprelimina~ chkical trials in postoperativepatient ~of~t&&nzsto a.mss ana&.& ejicay and inciakxe of undesirable side &kts @z&us, nausea and vomtia

urinary retention,respiratoy akpression),In genera4 when

applied 2 hrprwperatbeb, a TTS ($ntanYr, patch (;Z di@rent doses)prom& moderate-to-good analgesia for Q uarie& of surgicnlprocedurprfor periodsof up to 3 days. Mostpatientswill requiresmall amounts of fustemica~yadmink’ered opioidsfvr sup$ment&y ana&sia, especiallyin thejirst 24 postopmalivehr. Eie iruiu&e of side effectssuch as nausea and vomitingvariesbe&m s&d&sbut can be as h&h as 70%. C&iml& s&$cant respiratorydepressionis rare but was reportedin severalof thestudks. TTS @ntany~ in a simple and UT&Ltechniquefor the controlof postoperatiaepain. J

Pain Symptom Manage

1992;7:;s27-s35.

Amzig&

The

narcotics,administration(cutunwus),fatany

trcsdermal

route

is

the

respiratorypattern

most recent

technicpte of opioid administration to be developed, and it holds significant potential for acute pain control. The interest in this route is related primarily to the advances in the use of prolongedaction medication,’ which have resulted in the development of the transdermal therapeutic system (‘ITS). TX3 has been successfi.d in providing effective, stable serum levels in the long-term use of glyceryl trinitrate for the treatment of angina,2 hyoscine for motion sickness,3clonidine for hypertension,4 and estrogen-replacement therapy.5 The A&frees reprintrequeststo: Nan Sandler, ERCPC, Toronto General Hospital, 200 Elizabeth Street, GW 2-502, Toronto, Ontario, Canada M5G 264. Q U.S. Cancer Pain Relief Committee, 1992 Published by Elsevicr, New York, New York

potential advantages of an uncomplicated prolonged-action delivery system that could provide stable serum levels have prompted investigation into the delivery of opioids (primarily the lipidsoluble synthetic opioids fentanyl and sufentanil) transdermally for postoperative analge~ia.~ Pentanyl, in particular, may have the advantage of few cardiovascular and sedation-related side effects, and these features, coupled with lipid-soluble properties that allow percutaneous absorption, make it an attractive candidate for a transdennal system. The major obstacle to transdermal drug absorption is the stratum comeum, where diffusionoccurs primarily via the intercellular lipid medium6 TTS (fentanyl) can accommodate this obstacle and provide effective drug delivery. Advantages of TTS

0885-3924/92/s5.00

S28

(fentanyl) include decreased gastrointestinal @I) degradation and fmt-pass hepatic metabolism; stable plasma concentrations; improved patient compliance through extreme ease of administration; m&i&y dosage; and decreased risk, due to lack of needle usage, of any infective process.7 The major disadvantage of ‘P’lS (fentanyl) is the inability of the system to respond rapidly to increasing or decreasing analgesic requirements or to the approximately fivefold degree of variability in analgesic requirements among patients. In addition, the potential for abuse with this system may be great. There are four systems that have been developed that provide effective transdermal drug delivery.8 The ‘ITS (fentanyl) patch utilizes the membranepermeation model. In this system a drug reservoir is formed from a shallow compartment molded from a drug-impermeable laminate and the open surface of the compartment is covered by a microporous rate-controlling membrane. The outer surface of this membrane is coated with an adhesive polymer that is in contact with the skin. Large amounts of fentanyl (up to 10 mg) are present in the reservoir in a gel matrix to provide a driving force for di&sion. Increiiyed systemic rcqu~enicr~is are accommodated by increasing the size of the TIS (fentanyl) patch (25, 50, 75, or 100 cm*). These different patch sizes provide sustained (fentanyl) infusion rates of approximately 25, 50, 75, and 100 ug/hr over periods of up to 72 hr. A substantial amount of fentanyl remains within the system and the skin depot upon removal of the patch. In one study using a 100~pg/hr TTS (fentanyl) system, 1.07 f 0.43 mg of fentanyl was calculated to be present in the skin depot after 24 hr of useP An important feature of the TTS (fentanyl) patch is that the skin layers, especially the dermis, act as a secondary reservoir that must be filled before sustained systemic absorption occurs. Continued absorption occurs from the skin reservoir after the patch is removed. Analgesic effectiveness of TTS (fentanyl) patches for acute pain has been measured exclusively in postoperative pain studies. Pain control has been quantified by visual analogue scale (VAS) systems and by postoperative parenteral opioid requirements. In general, the clinical studies fall into either an open-label designrO-I3 (Table 1) or a formal, double-blind, randomized, placebo-controlled chnical trial of TTS (fentanyl) versus standard postoperative analgesic regimens (Table 2).rJJ--19

Sandlef

RI. 7 No. 3 (SupPr.)A@ 1992

In the open-label studies, the TTS (fentanyl) patches were usually applied 2 hr preoperatively, although one study applied the patch intraoperatively.12 The duration of patch application ranged from 24 to 72 br with two studies changing the applied patch for a fresh TTS (fentanyl) patch every 24 hr (Table 1). In all the open-label rtudies, small amounts of intraoperative opioids were used. Plezia and colleagues,r” in an early open-label study in 8 patients undergoing orthopedic procedures, applied TTS (fentanyl) 75-ug/hr patches for 24 hr postoperatively. Satisfactory analgesia was achieved in 7 of the patients (mean VAS 4.3,O = no pain, 9 = maximum pain), with miniial sedation, nausea, or respiratory depression. Supplemental morphine requirements ranged from 0 to 49 mg, with 4 patients requesting no supplemental morphine. Holley and van Steentill used a huger lOO+g/hr TTS (fentanyl) patch, w&h was applied 2 hr preoperatively to 8 patients (7 thoracotomy, 1 lumbar fusion). Intraoperatively, 100 ug (fentanyl) was given. There were no differences in pain scores compared with those of patients receiving IV infusions of fentanyl, although no details were reported. Mean morphine requirement over the 24&r study was 14.6 f 6 mg, similar to that of patients who received an IV fentanyl infusion of 100 ug/hr. In the study, 60% percent of the postoperative morphine supplementation was required in the Post-Anesthetic Care Unit (PACU), a recurring observation in many of these studies.6 Respiratory depression and side effects were not reported. Gourlay and colleagues,t2 in 13 patients undergoing abdominal surgery, applied a variety of TTS (fentanyl) patches (most were 75 ug/hr) just before surgery and then changed them at 24 hr postoperatively. The second patches were removed after 24 hr. In addition 100-200 ug of fentanyl were given intraoperatively. Pain scores were not reported formally, hut all patients required supplementary meperidine postoperativeiy, particularly in the first 12 hr. The following side effects were noted: 11 (85’/0) of 13 patients were nauseated and, most importantly, 3 patients demonstrated respiratory depression as bradypneic episodes (Table 3). Finally, Bell and Goldbergi assessed the 75-pg/ hr TTS (fentanyl) patch in two small groups of patients. One group had the patch changed every 24 hr for 3 days, whereas the other group had the same patch applied for 72 hr. Patches were applied

s.29

Study

jv

Surgery

Anesthesia TiW

Plezia et al.*O (1986)

8

Orthopedic

General

l-I-SF-75

2124

0.1-0.5

Holley and van Steenis” (1988)

8

Lumbar fusion (1) Thoracotomy (7)

General

TTSF-100

2124

300 Kg F

13

Abdominal

General

TI’SF-75 (50-125)

0/24/48a

100-203

11 9

AbdOd

General

TTSF-75

AbdOIllid

General

2/244/48”/72 Z/f2

3OO!JgF

Gourlcy

et al.12 (1989)

Bell and Goldberg’s (1989)

(pg/hr)

Appl/Durn

(hr/Rr)

P/P Opioid rng/kg M

pg F

300 pg F

TTSF, TTS (fcnkyl) pa:+ AppI, time of ITS (fentanyl)patch application preoperatively; bum, dluatima of TTS (fentanyl) use; I/P Opioid, intraoperative opioid dose; F = fkntanyl; M, morphix. aFresb TTSF, parchreapplied at 24148 hr

2 hr before surgery, and all patients were given 300 pg of fentanyl intraoperatively. Fain scores were highest during the first 24 hr postoperatively for both groups, as were supplemental morphine requirements. 8n the basis of respiratory rate, there was no evidence of respiratory depression. The incidence of nausea (36%) and vomiting (18%) was much higher in the group that had the TTS (fentanyl) patches replaced every 24 hr compared to the group in which the patch was left in place for 72 hr (nausea and vomiting, O’/O).

In addition to these open-label studies, there have been several well-designed clinical trials evaluating TTS (fentanyl}. These studies are sum~?;i;r%cd ;ii iables 2-5. Plezia and colleagues,14 using a 75-ug/hr patch, were unable to demonstrate a significant difference in pain scores between

‘I’ransdermal Therapeutic Stem

the active and placebo groups in their study. Caplan qd coIlleagues, l6 Rowbotham and colleagues,t7 and k&hskey’ did observe sign&ant between-WUp diaerences in pain scores, with the TTS (fenhnyl) groups having lower pain scores than the placeb soups (Table 3), Similarly, although &oat all patients required supplemental opioid ana&esics, Chphn and colleagues,16 Rowbotham and col!eagues, ’ 7 and McIeskey’ all found sign&&~ lo-$+ L, azi!gesic ic+rcments iii the TTS (fentanyl) patients; other studies’4J5J~1ghave found decreased, but not significantly different, analgesic myirements (Table 4). A common finding, however, is phat supplementary analgesic requiremesu are relatively high in both the open-label studies sad the controlled studies in the &~f 24 hr postoperatively, reflecting the prolonged T_ (14-24 hr) of the TTS (fentanyl)system.6 Side effects were variable in the controlled studies. Plezia alad coHeagues’4 described an ap-

T&l!92 (I’%) Fentanyl4omp~kive

Stwlies: Demographic Data Appl/Durn

w

SfJ@ Plezia et aLL4(1988)

43

SWly

Anesthesia

orthopedic

General

S)

W

hr)

I/P Opioid 2OOpgF

WSF-75

2136

TQF-7s

0.5124

WSF-75

O/24

100 pg F

AbdOtid von

Ebrmallll

et aLI (1988)

40

Hip replacement

Epidural

Caplan et aLI (1989)

42

Shoulder repair

Rowbotham

30

Upper abdominal

General

T=TSF-100

2124

200 pg F

General

‘ITSF-50

2124

IOOpgF

McL&ey7

et aLI (1989) (1990)

54

Lower abdominal

block

0

Interscalene

TqF-50 T-.fSF-75 lTSF, TIX (fentanyl) patch; Appl, time ofTi3 (fentanyl) patch application preoperatively; IX@, &Won imraoperative opioid doose;F = fentanyl; S = sukntanti. Sandier et alI.‘8Jg (1991)

20

lower

abdominal

General

2172

5pgS

of ‘ITS (fenlanyl) use; I/P Woid,

Sandkr

230

Tmsdmal

Vol.7No. 3 (Su~pl.)A&d i992

Table3 Therapeutic System (‘ITS) Fentanyl-Comparative

Studies:

Pain Control

Study

Postoperative pain control

Plezia ct aLI (1988) Sandier et al.1sJg (1991) Von Bomxxnn et aLI (1988) Caplan et al.t6 (1989) Rowbotham ct al.” (1989) Mchkcy’ (1990)

No between-group diflierences No between-group diffircnces TTSF group: Decreased pain TTSF group: Significantly less pain TTSF group: Significartdy less pain TTSF group: Significantly lesspain

l-rw,

ITS (huanyl).

proximate 30% incidence of nausea and vomiting in both the ‘ITS (fentanyl) and placebo groups in their study. Caplan and colleagues,‘6 in a detailed analysis of side effects, recorded a higher incidence of nausea and vomiting (30-70°0) and other side effects in both TTS (fentanyl) and placebo groups (Table 6). Von Bormann and colleagues,15 however, found little or no nausea or vomiting. Respiratory depression, potentially the most serious problem, was also reported in several of the comparative studies (Table 5).14-16~‘8~20 In a study by Duthie and colleagues,2o which primarily assessed the pharmacokinetics of 100 pg/hr TTS (fentanyl), 2 of 19 patients had to bc withdrawn from the study due to respiratory rates lower than 8 per min during sleep. Although the patches were in place for 24 hr, the exact times of the bradypneic episodes were not specified. Plezia and colleaguesI noted that 2 of 22 patients in the ‘ITS (fentanyl) group required naloxone immediately postoperatively due to prolonged apnea in the PACU. In addition, 1 patient from the lTS (fentanyl) group and 1 from the placebo group developed respiratory depression (undefined) while on the ward (times not specified), which resolved without treatment. Caplan and colleagues,16 in a very well designed and comprehensive 24&r trial, observed 3 patients in the ‘ITS (fentanyl) group (Jf= 22) who had transient episodes of bradypnea during sleep

(5-7 breaths per min). Arousal of these patients resulted in correction of the bradypnea to more than 8 breaths per min. Von Bormann and colleagues I5 also reported 1 of 20 patients in their 24-hr study who suffered from severe respiratory depression, requiring naloxone reversal while on the ward. Dermatologic reactions have been reported in a minority of patients in most studies, These have consisted of mild irritation, itching, erythema, or occasional papules, all of which have resolved within 24 hr of patch removal. We have performed a pilot clinical trial of two TTS (fentanyl) patches to assess the analgesic effectiveness and safety of the system in posthysterectomy patients. 18~lgIn this study 20 patients (ASA l-2) undergoing abdominal hysterectomy were entered into a randomized, double-blind, placebo-controlled trial comparing two dosage Ievels of TTS (fentanyl). Group I (placebo, .M = 8) was treated with nonopioid TTS patches. Group II (N= 6) was treated with a TTS (fentanyl)50 patch and Group III (N = 6) with a TTS (fentanyl)-75 patch. Blinding was achieved by applying the two different-sized patches (active or placebo) to all patients, producing the required fentanyl-placebo combinations. TTS patches were applied 2 hr preoperatively after diazepam premeditation. Patients were given a standard general anesthetic including sufentanil 0.5 clp/kg, thiopentone 3-5

Table 4 Transdermal Therapeutic System (lTS) Fentanyl Comparative Studies: Postoperative Opioid Requirements _-. I_-..-.Study Postoperative opioid required --. Plczia et aLI (1988) Von Bormarm et a1.15(1988) Sandlcr ct aL’*Jg (1991) Caplan et aLI (1989) Rowbotham et al.‘? (1988) Mchkey’ (1990) TTSF, T-l-s (fcntanyi).

TTSF TTSF TTSF lTSF TTSF TTSF

group: Decreased morphine use group: Decreased meperidine use group: Decreased morphine use group: Significantly decreased morphine use group: Sigoiticantly decreased morphine use group: Significantly decreased morphine use --

Vol. 7Jvb. 3 @g@.) A@‘1 1992

Tramhal

Fenhmyk Acute Anakesic Studies

Incidence Study

A&C

Gourlay et al.‘2 (1989)

Placebo

Description

3/13

-

SRR

*/9

-

(ward)

Treatment 1 patient-naloxone 2 patients---O, mask Dose reduced

SRR (ward)

TSS (fentanyl) removed

Plezia et al.” (1988)

3/22

'/Zl

AP (PAev) SRR (ward)

2 patients-naloxone TSS (fentanyl) removed

Caplan et al. I6 (1989)

3122

O/20

SRR

VonBormannet al.‘5(1988)

l/20

O/20

Sandier et al.‘8~1g(1991)

E/12

Oh

Duthie et aI?0 (19S8)

(ward)

Patientsaroused 1 patient-naloxone TSS (fentanyl) removed

Ap(ward)

0, mask

SRR (ward) DESAT (ward) Active, TI’S (fenranyl) group; Placebo, placebo Tl?? group; SRR, slow respiratory rate ( < lO/min); AP, apneic episodes; DESAT, hemoglobin desaturation; ward, SRR or AP occurring when patient returned to the ward; F’ACU, SRR or AP oecuning in Post Anesthetic Care Unit_

mg/kg, pancuronium 0.1 mgjkg, N,O, and isoflurane. Postoperatively, on the ward, aL!patients used a morphine-loaded patient-controlled analgesia @‘CA) device as required for supplementary analgesia. In the PAW, patients were prompted at 5to IO-min intervals for IV morphine supplementation (1-2 mg) if in pain. Patients were monitored continuously by trained nursing personnel for 72 hr after patch application and for 12 hr after patch removal. Analgesia was assessed by VAS (0 = no pain, 10 = maximum pain) and hourly morphine requirement. Respiratory effects were monitored continuously with respiratory inductive plethysmography and pulse oximetry for 8 hr during the night before surgery and 84 hr postoperatively. The use and calibration of the respiratory inductive have been described elseplethysmograph Table6 Percent of Patients with oP;oid-Related Side meets During Application of Transdezmal Therapeutic System Pentanyl Patch Side effects Nausea vomiting Urinary retention PllBihlS Dizziness Headache

Patients (“/a) Placebo

ACtiVC

77 73 27 14 4 4

Adapted f?om RA CapIan et al., JAii permission).

60 30 10 20 10 5 1989;261:1036-1039

(with

where.21T2’Slow respiratory rate @RR) was defined a~ less than 10 breaths/min for 5 min and apnea (AP) as tidal volume less than 100 mL for 15 set or longer. Arterial blood gases (ABG) were drawn (under local anesthesia) if repeated episodes of hemoglobin desaturation of less than 90% or respiratory rate of less than 8/min occurred. On analysis of the data there were no sign&ant di&erences between groups for age, weight, height, or duration of surgery. There were no significant differences between groups for the 4 hourly VAS scores, although there was a tendency for Group III patients to have the lowest VAS scores (Figure 1). Also, there were no significant differences in morphine requirements between groups in the PACU (hr 1 = 10-15 mg/patient; hr 2,3 = Z-10 “g/patient), although Group III required much less morphine than the other two groups. Similarly, although there were no significant between-group differences in morphine requirements on the ward (probably related to the small sizes of the groups), Group II (JTS [fentanyl]dO) and Group III (TI’S [fentanyll-75) patients tended to use less PCA morphine (Figure 2). There were si@cantly more episodes of SRR in the first 24 postoperative hr in the TTS (fentanyl) groups (Figure 3) and a tendency to more episodes of AP in the ITS (fentanyl) groups up to 36 hr postoperatively (Figure 4). Hemoglobin saturation also decreased more prominently in the TTS (fentanyl) groups early in the postoperative period, although these changes were not significant (Figure 5). In addition,

?66.7.h40.3 (Suplbl.)April 1992

SUildlJi?r

S32

0

4

8

12

16

28

24 28 HOURS

32 36 AFTEFl

48 44 46 52 56 TTS APPLICATION

66

64

66

-St

FENT'YL-50

-+-

FEW'YL-75

72

76

60

84

Pig. 1. Mean 4hr visual analogue scale (VAS) pain scores in posthysterectomy patients enrolled in a pilot double-blind, placebo-controlled trial ofthe transdermal therapeutic system (TTS), TTS (fentanyl)30 and TTS (fentanyl)-75 patches. The high VAS scores at 4 hr denote the period in the Post-Anesthetic Care Unit. TTS (fentanyb-75 patients tended to have the lowest VAS scores. From references no. 18 and 19.

30

T I

PLACEBO a

l-K-50

0

lx-75

2.0 E a 5 z I P %

1.0

0.1 6-12

12.24

24-36

36.48

48-60

60-72

72.84

Time (hr) Fig. 2. Hourly morphine requirements (mean f SD) in posthysterectomy patients enrolled in a pilot double-blind, placebo-controlled trial of the transdermal therapeutic system (TTS), TTS (fentanyl)-50 and TIC’S(fentanyl)-75 patches. The placebo group used patient-controlled analgesia morphine alone and tended to have uniform morphine requirements for the 72hr postopemtive monitoring period, whereas the TTS (fentanyl) groups had reduced requirements. From references no. 18 and 19.

Vol.7 .y,. .3 (Suppl.)April 1992

Cznsdmnal FmtanykAcuteAnalgesicStudies

s33

PLACEBC %zITrsso 0 * p < 0.05

prsap

TO-T12

TlZ-T24

T24-T36

T36-T46

lime

-ITS75 PLACEBO:

T46-T60

TTSBO:

TTSYS

T60-772

T72-T64

(hr)

Fig. 3. Episodes

of slow respiratory rate (mean F SD, see text) in posthysterectomy patients enrolled in a pilot double-blind, placebo-controlled trial of the transdennal therapeutic system (TTS), TTS (fentanyl)50 and ITS (fentanyl)-75 patches. There were more SRR episodes in the TTS (fentanyl) groups in the first 24 postoperative hr, especially in the TTS-75 (fentanyl) group. From references no. 18 and 19.

PLACEBO

24

e3 TX50 0

TO-T12

T12.TZ4

Ti4-T36

TX-T48

?-rs75

T44-T63

T6C.-:2

-72.-d&

Time (hr) Rg. 4. Apncic episodes (mean f SD, see text) in posthysterectomy

patients enrolled in a pilot double-blind, placebo-controlled trial ofthe tramdcrmal therapeutic system (FT.S),,TTS (fcntanyl)30 and TTS (fentanyl)-75 patches. The TTS (fentanyl) goups tended to have more apneic episodes in the first 2-I -36 postoperative hr. From references no. 18 and 19.

Vol.7&o. 3 (St@l,) April 1992

&t&l

S34

PiACEBO

98

1

TT

, T12-T24

T24.T36

T36.T46

T46-T60

T60-T72

T72-T64

Time (hr)

Eg. 5. Hemoglobin saturation (mean zk SD, see text) in posthysterectomy patients enrolled in a pilot double-blind, placebo-controlled trial of the transdermal therapeutic system (TTS), ‘ITS (fentanyl)-50, ‘ITS (fentanyl)-75 patches. Hemoglobin saturation was lower in the TTS (fentanyl) groups for up to 48 postoperative hr. From references no. 18 and 19.

preoperatively, thus possibly decreasing the supplementary opioid analgesic requirements in the PACU. A further definitive, large-scale study similar to the pilot study is currently under way in our institution.

8 patients, all in the TTS (fentanyl) groups, required ABG determination for the criteria described above (Table 7). This pilot study found results similar to the other comparative studies discussed above but has also indicated that the early postoperative period may be the time when patients are most vulnerable to respiratory depression with TTS (fentanyl) patches. This problem may be decreased if the TTS (fentanyl) patch is applied earlier than 2 hr

Conclusion TTS (fentanyl) patches are probably as efficacious as IV infusions of the same dose but lack the rapid Table 7

TTS (Fentanyl) Group TTS75 (jv= 5)

T-B-503) (Jv=

Tie

(hr)

for Posthysterectomy Analgesia: Arterial Blood Gas Measurements PH

PaCO,

PaO,

HCO,

9.9 34 24 13 27

7.36 7.38 7.41 7.35 7.42

48 42 46 47 47

63 59 61 78 63

29 26 29 27 30

RR/O,Sat RR 0,Sat

29 10

7.37 7.31

53 47

71 67

27 28

RR OPSat

8

7.34

48

71

26

RR

Reason RR

0,Sat

m, mmsdermal therapeuticsystem;RR, respiratory rate; O$at, hemoglobin saturation c 90%; Time, time aTter‘ITS (fentanyl) application. See-text for discwion of Table 5. Note: Placebo N = 0. See Sandier et al.Ws

Vol. 7 No. 3 (&p/11.)April 1992

Tramdtmal Fentmyk AcuteAnakesic Studies

adjustability of IV infusions.” Many patients, however, require analgesic supplementation. The application of the patch 2 hr preoperatively requires the administration of relatively large amounts of opioid analgesic in the PACU, and this may be a contributing factor to early postoperative respiratory depression. Nimmoz3 has summarized the advantages and disadvantages of TTS (fentanyl) as follows: advantages: ease of use, physician controlled, high patient acceptability, effective analgesic method, nonlabor intensive; disadvantages: nontitratable, preselected dose, slow onset, preoperative patch application, requires supplemental analgesic especially in PACU, possible (although unlikely) toxic effects atier patch removal. Nimmo emphasizes, and we agree, that there is a need for the same nursing monitoring used for the same dose of systemic opioid given by any alternative route when TTS (fentanyl) patches (or any form of effective opioid analgesic technique) are used.

C?S 1. Nairn JG. Transdermal therapeutic systems:some &u&mental considerations. Can J Hasp Pharm 1988;41:85-88. MG. Clinical pharmacokineticsof gyceryl following the use of systemic and topical preparations. Clin Pharmacokinet 1987; 12: l-l 1. 2. Bogaert

&Grate

3. Uppington Jr Dunnet hyoscine and postoperative thesia 1986;41:16-20.

J, Blogg CE. Txtnsdemxal nausea and vomiting. Anaes-

4. Shaw JE. Pharmacokinetics of nitroglycerin and clonidine delivered by the transdexmal route. Am Heart J 1984;108:217-223. 5. Laufer J_R, DeFazio JL, Lu KJH, et al. Estrogen replacement therapy by tmnsdermal estradiol administration. Am J Obstet Gynecol 1983; 146~533-540. 6. Hill HF. Clinical pharmacology fentanyl. Eur J Pain 199&l 1:81-91. 7. McIeskey CH. Fentanyl TTS analgesia. Eur J Pain 1990;11:92-97.

of transdermal for postoperative

8. Tarver SD, Stanley TH. Alternative routes of drug . . admuustmtion and new drug delivery systems. In: Stoelting RK, Barash P, Gallagher TJ, eds. Advances in anesthesia, ~017. Chicago: Year Book Medical Publishers, 1990:337. 9. VarvelJR, Shafer SL, Hwang SS, Coen PA, Stanski DR. Absorption characteristics of transdennally administered fentanyl. Anesthesiology 1989;70:928-934.

s35

10. plezia RM, Linford J, Kramer TH, Iacono I@, Hameroff SR. Transdermal therapeutic system (fentanyl) for postoperative pain: an eficacy, toxicity, and pharmacokinetic trial. Anesthesiology 1986;65:A210, 11. HOLY FO, van Steennis 6. Postoperative analgesia with fentanyl: pharmacokinetics aad pharmacodyna_r&s of constant-rate i.v. and transdetmal delivery. Br J Anaestb 1988;60:608-6 13. 12. Gourlay GK, Kowalski SR, Phunmer JL, Cherq DA, Gaukroger P, Cousins MJ. The transdermd administration of fentanyl in the treatment of postoperative pain: pharmacokinetics and pharmacodynamic effects. Pain 1989;37: 193-202. 13. Bell SD, Goldberg ME. Comparison of single patch multi-day versus multiple patch single-day TTS fentanyl. Can J Anaesth 1989;36:Sll6. 14. Plezia PM, Linford J, Kramer TH, Iacono RP, Hameroff SR. Transdermally administered fentanyl for postoperative pain: a randomized double blind placebo controlled trial. Anesthesiology 1988;69:A364. 15. Von Bormann B, Ratthey K, Schwetlick G, Schneider C, Muller H, Hempehnan (G. Postoperative Schmentherapie durch transdermales Fentanyl. Anasth Intensitier NodXlmed 1988;23:3-8. 16. Caplan RA, Ready LB, Oden RV, h4Asen FA, Nessly ML, Olsson GL. Transdermal fentanyl for postoperative pain management: a double blind placebo study. JAMA 1989;261:1036-1039. 17. Rowbotham DJ, Wyld R, PeacockJE, Dutbie DJR, Niimo WS. Transdermal fentanyl for the relief of pain after upper abdominal surgery. Br J Anaesth 1989;63:56-59. 18. Sandier AN, Baxter AD, Norman P, et al. A double blind, placebo-controlled trial of transdermal fentanyl for post-hysterectomy pain relief. II. P.cspiratoty effects. Can J Anaesth 1991;38:A114 19. Sandler AN, Baxter AD, Norman P, Samson B, Lawson S, Hull K. A double blind, placebo-controlled trial of transdermal fentanyl for post-hysterectomy analgesia. Anesth Analg 1991;72:S233. 20. Duthie Dfi Rowbotham DJ, Wyld R, Henderson PD, Nimmo WS. Plasma fentanyl concentrations during transdermal delivery of fentanyl to surgical patients. Br J Anaesth 1988;60:614-618. 21. Sandier AN, Chovaz P, Whiting W. Resphatory depression following epidural morphine: a clinical study. Can Anaesth Sot J 1986;3:542-549. 22. Sackner MA, Watson H, Belsito AS, et al. Calibration of respiratory inductive plethysmogmph d&g natural breathing. J Appl Physiol1989;66:410-420.

23. Nimmo WS. Clinical summary: transdermalfentanyl. EurJ Pain 1990;11:102-103.