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Transdermal fentanyl in postoperative pain
Regional Anesthesia 22(1):24-28, 1997
Transdermal Fentanyl in Postoperative Pain Lance J. Lehmann, M.D.,* John M. DeSio, M.D.,* Tibor Radvany, M.D.,t and George B. Bikhazi, M.D.t
Backgrottnd and Objectives. The aim of this study was to determine tile safety and effectiveness of a transdermal fentanyl delivcry system for the relief of pain lollowing abdominal surgery. Methods. In a nonblindcd, noncrossover, placebo-controlled study, 40 ASA I and II patients of both sexes, 18-69 years of age, who were scheduled for abdominal surgery u n d e r general anesthesia, wcrc randomly divided into two groups of 20 patients each. Patients in group I received a trandermal patch containing 0.16 mg/cm 2 of fentanyl, which was applied to the skin over the subdavian area 60 minutes before the induction of anesthesia. For body weight less than 60 kg, a 30 cm 2 patch was applied, and for weight greater than 60 kg, a 40 cm 2 patch was used. A second group of 20 patients received placebo patches of identical size. Approximately 20 to 30 minutes before tile expected end of surgery, 60 mg kctorolac was administered intramuscularly. Patients were observed for 36 hours after placement of the patch. II patients reported their pain at rest as 5 or greater at rest on a 0 - I 0 visual analog scale, they were given 30-rag increments of ketorolac 5 to 7 hours apart. If this regimen did not relieve their pain, they received 1,300 mg acetaminophen between two ketorolac doses. If despite this, they still had pain 30 minutes afterward, intravenous morphine was given, and the patients were excluded from further study. The patch was removed in four patients in the fentanyl group and seven in tile placebo group for various reasons, which i n d u d c d inadequate pain relief requiring additional analgesia postoperativcly and more than 1 I.tg/kg of sufentanil given intraoperatively or immediately prior to the end of surgery. During the 36-hour observation period, 30 doses of 30 mg ketorolac and 14 doses of 1.3 g acetaminophen were given to 13 patients in the placebo group and 18 doses of ketorolac and 8 doses of acetaminophen were administered to 16 in the fentanyl group. Results. The differences in postoperative analgesic requirements were significant. Plasma fentanyl concentrations at 12 and 24 hours after the application of the fentanyl patch were 0.98 + 0.14 ng/mL and 1.22 + 0.17 ng/mL, respectively. At 8, 16, 24, and 36 hours after application of the patch, the pain relief, assessed by a VAS at rest and with movement, was similar in the two groups. In tile fentanyl and control groups, 12 and 5 patients, respectively, experienced nausea, and 2 and 3 patients, respectively, vomited. Conchtsions. Similar postoperative analgesia was achieved with less parentcral analgesics in patients who received transdermal fentanyl prcoperatively than in control patients. Fentanyl, 50-75 I.tg/h, administered in a transdermal delivery system, did not depress respiratory rate or
From the *Department o[ Anesthesiology, tlarvard University, Beth Israel llospital, Boston, Massachusetts, and the tDepartment of Anesthesiology, University of Miami School of Medicine, Jackson Memorial Medical Center, Miami, Florida. Supported in part by Anaquest, a division o1 BOC, Inc. Accepted for publication January 25, 1996. Reprint requests: Lance J. Lehmann, M.D., Pain Medicine Center, 501 Glades Road, Boca Raton, FL 33432.
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Lehmann et al.
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hemoglobin oxygen saturation. Although the exact role of continuously administered opioids in managing acute postoperative pain has yet to be clearly defined, it is concluded that if properly used, this new transdermal device can be effective in providing a background of analgesia, which may assist in the management of acute postoperative pain as well as some chronic pain states. Reg Anesth 1997: 22: 24--28. Key words: fentanyl, transdermal pain relief, postoperative analgesia.
Satisfactory pain relief occurs w h e n the plasma concentration of an opioid agent is maintained at or above a critical level. If the analgesic concentration is below this level, analgesia will be inadequate, and if it is m u c h above this level, the incidence and severity of u n w a n t e d side effects will increase (1,2). Continuous intravenous infusion is frequently used to maintain the plasma concentration of analgesics at the optimal level (2-4). The continuous infusion technique requires specially trained personnel and expensive equipment, and its success depends on the uninterrupted flow of the intravenous infusion. It has been reported that postoperative analgesia is satisfactory w h e n the plasma level of fentanyl is maintained at 1-3 ng/mL (5-7). This range of fentanyl concentrations can be maintained for up to 48 hours with a 20- to 40-cm2 patch of a transdermal delivery system (Duragesic, Janssen, Palo Alto, CA) containing 0.25 mg/cm 2 of fentanyl (8-11). With this system, using 10-, 20-, 30-, or 40cm2 patches, the a m o u n t of fentanyl delivered was 25, 50, 75, and 100 Hg/h, respectively. W h e n the predicted delivery of fentanyl was 50 ~g/h, the delay of analgesia was 18.9 _+ 10.9 hours (10). After removal of the patch, it took 14 to 25 hours before fentanyl was cleared from the plasma (5). In another study, w h e n an estimated 75 lag/h of fentanyl was administered transdermally, respiratory depression, nausea, vomiting, and "urinary retention were encountered in 14%, 77%, 73%, and 27% of cases, respectively (12). Other investigators reported respiratory depression in 5% (13), 14% (14), and 23% (9) of patients. These side effects could be antagonized by naloxone (5,11,14). Since the onset of action of Duragesic is relatively slow, its usefulness for the relief of postoperative pain is limited. Recently, a n o t h e r transdermal delivery system became available, which has a faster (4- to 6-hour) onset of action (15) and therefore appears to be more suitable for postoperative pain relief. With this transdermal delivery system, an initial distribution equilibrium developed within 10-12 hours after the application of a 30-40 cm z patch, which delivered 70-80 [Ltg/h of fentanyl (15). To maxi-
mize the patch's effect, it could be placed preoperatively, several hours before the proposed operation. This study was designed to d e t e r m i n e the efficacy and safety of this n e w transdermal fentanyl delivery system for the relief of postoperative pain.
Materials and Methods The investigation was carried out o n 40 ASA I and II, 18- to 69-year-old patients scheduled for abdominal surgery, including cholecystectomy, colostomy, oophorectomy, total abdominal hysterectomy, and total vaginal hysterectomy. Patients signed informed consent forms to participate in the study, which was approved by o u r internal review board. Prior to surgery, medical history was obtained and a physical examination was performed on all patients, as well as routine h e m a t o logic and clinicopathologic tests. Prernedication consisted of 0.2 mg glycopyrrolate and 2 nag mi dazolam administered intramuscularly about 4 0 - 6 0 minutes before induction of anesthesia. At the same time, a fentanyl patch was applied to 20 patients. If the patient's body weight was less than 60 kg, the surface area of the patch was 30 cm 2, and if it was m o r e than 60 kg, a 40-cm 2 patch was used. Each patch contained 0.16 m g / c m 2 fentanyl. Twenty o t h e r patients received patches of identical size w i t h o u t fentanyl. Anesthesia was induced with 4 - 8 mg/kg thiopental and 0.3-1 Hg/kg sufentanil with 3 L/rain nitrous oxide and 2 L/rain oxygen. Tracheal intubation was facilitated with 1.5 mg/kg succinylcholine, preceded by 3 mg d-tubocurarine. Anesthesia was maintained with a m i x t u r e of 3 L/rain nitrous oxide and 2 L/rain oxygen containing 0.4 to 1% isoflurane. Sufentanil was given in 10-/.lg increments w h e n necessary intraoperatively, as w h e n heart rate or blood pressure increased 15-20% above baseline. The total intraoperative dose was limited to 1 pg/kg to be given up to 30 minutes prior to the end of the operation. Sufentanil was used instead of fentanyl because its short half-life ~vould not influence postoperative pain
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Regional Anesthesia Vol. 22 No. 1 January-February 1997
scores. Relaxation was maintained with an initial dose of 0.05 mg/kg vecuronittm followed by increments of 1.0 rag. During anesthesia, patients were mechanically ventilated (respiratory rate 10/rain, tidal v o l u m e 10 mL/kg). At the end of anesthesia, residual n e u r o m u s c u l a r block was antagonized with a mixture of 4 0 - 7 0 tag/kg of neostigmine and 8-16 I.lg/kg of glycopyrrolate. Isoflurane was discontinued 30 minutes before the expected end of surgery, and at the same time 60 mg ketorolac was administered intramuscularly. Before induction, during the maintenance of anesthesia, and during the 36-hour observation period (calculated from the time of application of the patch), blood pressure, heart rate, respiratory rate, and hemoglobin oxygen saturation by pulse oximeter were determined. After extubation, patients were transferred to the postanesthelic recovery room. Pain relief was assessed at rest and with m o v e m e n t on a visual analog scale (VAS). If patients reported pain greater than 5 on the VAS at rest, 30 mg ketorolac was injected intramuscularly at 5- to 7 - h o u r intervals. If after a dose of ketorolac, pain persisted or recurred in less than 5 hours, 1,300 mg acetaminophen was administered rectally. If the patient's pain could not be relieved with ketorolac a n d / o r acetaminophen, an intravenous narcotic analgesic was administered, and the patient was eliminated from the study. This was the case for seven patients in the placebo group and one in the fentanyl group. Plasma levels of fentanyl were determined in both groups before and at 12 and 24 hours after application of the patch. The incidence of skle effects were recorded for 36 hours. Tile ketorolac and acetaminophen requirements during the live 7 - h o u r observation periods, commencing with the intraoperative injection of ketorolac, were compared in the fentanyl and control groups with the test for proportions (16), z > 1.645 being considered significant. The significance was verified by Fisher's exact test and the chi-sqttare test (17). The total n u m b e r of ketorolac doses administered during the 36-hour observation period in tile fentanyl and control groups were compared with the M a n n - W h i m e y U lest (18), P < .05 being consklered significant.
Table 1. Demographic Data Group
Age (years)
lleight
Weight
I
44.15+3.12" (27.0-66.0)t 45.94+3.09 (28.0-69.0)
162.31 4- 2.77 (155.0-180.0) 161.93+2.05 {152.4-180.0)
70.05 + !.74 (63.0-79.8) 66.264-2.13 (50.0-80.0)
II
*Mean 4- SEM; ~range.
utes in the control and fentanyl groups, respectively. The duration of surgery was also similar, 178.1 _+ 21.9 minutes and 163.4 +_ 22.6 minutes, respectively. The time b e t w e e n administration of tile intraoperative dose and the first supplenlental dose of ketorolac was 310.0 _+ 100.2 minutes in the control group and 553.5 _+ 125.0 minutes in the [entanyl group. During the first two 7 - h o u r observation periods, a higher percentage of patients required ketorolac in the control group than in the fentanyl group (test for proportions !16] z > 1.645). The total n u m ber of doses of ketorolac administered during tile 36-hour observation period was also higher in the control than in the [entanyl group ( M a n n - W h i t n e y U test [18], P < .05), as may be seen from Table 3. In the [enlanyl group, the plasma level of fentanyl was 0.98 +_ 0.14 (range, 0.35-2.15) ng/mL at 12 hours and 1.22 _+ 0.16 (range 0.45-2.53) ng/mL at 24 hours after application of the patch. (Table 4). No fentanyl was detected in the control group. Satisfactory postoperative analgesia as defined by a VAS score less than 5 at rest is usually observed with plasma levels of 1-3 ng/mL. The median values of pain relief calculated from VAS scores at rest and with m o v e m e n t showed no difference in pain relief between the control and [entanyl groups in any of the four observation periods (Table 5). There were no significant changes in heart rate, blood pressure, respiratory rate, or hemoglobin oxygen saturation t h r o u g h o u t the 3 6 - h o u r observation period. The incidence of nausea was higher in tile fentanyl than in the control group, a h h o u g h the dilference Was not statistically significant.
Table 2. Sufentanil Requirements
Results
Dose
Age, body weight, and height of the patients (Tablc 1) were similar in the two groups, as was the a m o u n t of sufentanil used during anesthesia (Table 2). The mean times + SEM from application of the patch to intraoperalive injection of ketorolac were 156.9 + 24.5 nfinutes and 136.1 + 16.8 rain-
Group
Total (lag)
Control
60.4 4_ 16.6" (15.0-2 lO.O)t 41.9 + 4.5 (20.0-90.0)
FcnlanyI
"Mean
+
SEM: ~rangc.
pg/kg/h 0.34 __ 0.07 (0.07-0.82) 0.29 + 0.04 (0.09-0.61 )
Transdermal Fentanyl in Postoperative Pain
9
Lehmannelal.
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Table 3. Postoperative Pain Requirements N u m b e r of P a t i e n t s ' R e c e i v i n g Kctorolac T i m e (IO t
Placebo G r o u p (n = t3)
1-7 7-14 14-21 21-28 28-35
11 9 9 9 3
F e n l a n y l Grot,p (n = 16) 0t 2' 5t 4t 6
*Seven patients in the placebo group a n d four patients in the fentanyl g r o u p had to be excluded becavse of breach of protocol, tAfter administration of t h e first dose of ketorolac, tSignificantly different (P < .05) from placebo group.
There were few other side effects noted in the control or the fentanyl group.
Discussion In addition to parenteral narcotics, a variety of methods have been developed to help alleviate postoperative pain. These include transcutaneous electrical nerve stimulation, continuous spinal or epidural infusions, and intrapleural catheters. Patient-controlled analgesia (PCA), the latest of these methods, provides a simple way to better litrate ol,ioid (lose to the patient's needs. Unfortunately, all these tecimiques involve expensive drugs and equipment and most importantly, a level of expertise that prevents their widespread use. More recently, trandermal delivery systems have come into use. The transdermal fentanyl system is a rectangular transparent unit consisting of a protective liner and four functional layers: (I) a backing layer of polyester film; (2) a drug reservoir of fentanyl and alcohol, made into a gel with hydroxyethylcellulose; (3) an ethylene-vinyl acetate copolymer membrane~ which controls the rate of fentanyl delivery to the skin; and (4) a fentanylcontaining silicone adhesive (19). A transdermal fentanyl delivery system could provide a reliable background of analgesia for acute postoperative pain as well as for chronic pain, if an effective fentanyl plasma level could be maintained while minimizing unwanted side effects, such as respiratory depression. In fact, several publications state that the maintenance of an effective, steady-state plasma level of analgesics is the ideal metl]od for the relief of post-
operative or chronic pain (I-15,20,21). However, several other studies (22,23) demonstrate increased side effects, with no increase in analgesia or benefit, for continuous opioid infusions plus PCA versus PCA alone. In our study, fenlanyl plasma levels were in tile "analgesic" range of 1-3 ng/mL at 12 and 24 hours after application of the patch. In agreement with this, during the first two 7-hour observation periods, patients in tile fentanyl group required significantly less ketorolac than those in the control group. Similarly, in the first 7-hour observation period, acetaminophen supplementation was necessary in 31% and 69% of the patients in the fentanyl and control groups, respectively, tlowever, ahhough a lower dose of ketorolac was required in tile fentanyl group, the analgesic levels were no better for patients receiving fentanyl. The lack of randomization and the dropout rate may have influenced the results of the study. "Ikvo apparent disadvantages of the transdermal fentanyl patch were its delayed onset of action, requiring up to 7 hours for the analgesic effect to be manifest, and the higher incidence of nausea in the fentanyl group. Ahhough severe respiratory depression has been reported with Duragesic patches, these cases were isolated instances of misuse during pediatric outpatient surgery. Ahhough our study, evaluating a new transdermal delivery system (Anaquest, Madison, WI) did not demonstrafe any significant incidence of respiratory
Table 5. Median Values (Ranges) of Visual Analog Scores O b s e r v a t i o n T i m e (h) 8
T a b l e 4. F c n t a n y l P l a s m a C o n c e n t r a t i o n s T i m e (h) 12 24
Level ( n g / m L )
Range (ng/mL)
0.98 __ 0.14 1.22 + 0.16
0.35-2.15 0.45-2.53
AI rest Control g r o u p FentanyIgroup With ino',,'t.lllen I Control group Fentanyl g r o u p
16
24
36
6 (9-4) 5 (8-3)
6 (9-3) 4 (8-1)
5 (9-1) 3 (7-0)
3 (6-0) 2 (4-0)
8 (10-5) 6 (8-2)
8 (10-4) 5 (8-0)
6 (9-3) 4 (6-0)
5 (7-2) 3 (6-0)
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Regional Anesthesia Vol. 22 No. 1 January-February 1997
depression, it is presently r e c o i n m e n d e d that Duragesic patches (Janssen) should only be used for the treatment of severe chronic pain that cannot be m a n a g e d by less drastic m e a n s (ie, nonsteroidal analgesics or prn opioids). Individual variations in pain intensity and analgesia can pose problems w h e n evaluating the efficacy of a n y drug in a small population. However, from the data we obtained, this n e w transdermal fentanyl delivery system, which delivers 7 0 - 8 0 lag/h, seems capable of serving as a useful adjunct in controlling acute postoperative pain, as well as chronic pain, by providing a background of analgesia, which in addition to a more rapidly acting analgesic, can provide significant postoperative pain relief. U n w a n t e d side effects were minimal, with particular attention paid to respiratory status. Although the role of c o n t i n u o u s opioids in m a n aging postoperative pain is questionable w h e n c o m p a r e d with patient-controlled methods, continuous opioids m a y be useful for subsets of patients w h o cannot use PCA. Examples include elderly or dentented patients, handicapped patients, or patients with poor intravenous access. Further studies of this controversial topic are clearly indicated, in order to better deIine the role of this approach in tile reahn of pain m a n a g e m e n t .
References 1. Staplcton TV, Austin KL, Mather LE. A pharmacokinetic approach to postoperative pain: Continuous infusion of pethidine. Anaesth Intensive Care 1979: 7: 25-32. 2. Foldcs E The role of drugs in the managcment of intractable pain." Monogr in Anestheskfl 1983:13: 84-124. 3. Nimmo WS, Todd TG: Fentanyl by constant rate i.v. infusion for postoperative analgesia. Br J Anaesth 1985: 57: 250-254. 4. Duthie DJR, McLaren AD, Nimmo WS. Pharmacokinetics of fentanyl during constant rate i.v. infusion for the relief of pain after surgery. Br J Anaesth 1986: 58: 950-956. 5. Calis KA, Kohler DR, Corso DM: Transdennally administered fentanyl for pain management. Clin Pharm 1992:11: 22-36. 6. Rowbotham DJ, Wyld R, Peacock JE, Duthie DJR, Nimmo WS. Transdermal fentanyl for the relief of pain after ul)per abdominal surgery. Br J Anaesth 1989: 63: 56-59. 7. Duthie DJR, Rowbotham DJ, Wyld R, ttendersnn PD, Nimmo WS. Plasma fentanyl concenirations during lransdermal delivery of fentanyl to surgical patients. BrJ Anaesth 1988: 60: 614-618.
8. Gourlay GK, Kowalski SR, Plummer JL, Cherry DA, Szekely SM, Mather LE, Owen tt, Cousins MJ. Tile efficacy of transdermal fcntanyl in the treatment of postoperative pain: A double-blind comparison of fentanyl and placebo systems. Pain 1990: 40: 21-28. 9. Gourlay GK, Kowalski SR, Plummer JL, Cherry DA, Gankroger P, Cousins MJ. The transdermal administration of fentanyl in the treatment of postoperative pain: Pharmacokinetics and pharmacodynamic effects. Pain 1989: 37: 193-202. 10. Lehmann KA, Zech D. Transdermal fentanyl: Clinical pharmacology. J Pain Symptonl Management 1992: 7(3)(suppl): $8-S16. 11. Sandier A. "IYansdermal fentanyl: Acute analgesic clinical studies. J Pain Symptom Management 1992: 7(3)(suppl): S.27-$35. 12. Caplan RA, Ready LB, Oden RV, Masten FA, Nessly ML, Olsson GL. Transdermal femanyl for postoperative pain management. JAMA 1989: 261: 1036-1039. 13. Von Bormann B, Ratthey K, Schwetlick G, Schneider C, Muller H, Hempclman G. Postoperative Schmerztherapie durch transdermales Fentanyl. Anasth Intensivther Notfallmed 1988: 23: 3-8. 14. Plezia PM, Linford J, Kramer TH, Iacono RP, Hameroff SR. Transdermally administered fentanyl for postot)eralive pain: Randomized doubleblind placebo controlled trial. Anesthesiology 1988: 69: A364. 15. Miguel R, Kreitzer J, Rcinhart D et al. Utility of a new transdermal fentanyl delivery system for postoperative pain control: A multicenter trial. Anesthesiology 1992: 77: A886. 16. Fleiss JL. Statistical methods for rates and proporlions. New York, Wiley & Sons, 1981. 17. Colton T. Statistics in medicine. Boston, Little, Brown, 1974: 162-170. 18. Daniel WW. Biostafistics: A foundation for analysis in the health sciences. New York, J Wiley & Sons, 1991: 528-575. 19. DeSio JM, Bacon DR, Peer G, Lema MJ. Intravenous abuse of transdermal fentanyl therapy in a chronic pain patient. Anesth Analg 1993: 79:1139-1141. 20. Levy MH, Rosen SM, Kedziera P. Transdermal fentanyl: Seeding trial in patients with chronic cancer pain. J Pain Symptom Management 1992: 7(3) (suppl): S48-S50. 21. Herbst LH, Strause LG. Transdcrmal fentanyl use in hospice home-care patients with chronic cancer pain. J Pain Symptom Management 1992: 7(3) (suppl): $54-$57. 22. ttoltman B, White PF. Effects of a nighttime opioid infusion with PCA therapy on patient comfort and analgesic requirements after abdominal hysterectomy. Aneslhesiogy 1992: 76: 362-367. 23. Parker RK, Hohman B, White PF. Patient-controlled analgesia. Does a current opioid infusion in]prove pain management after surgery? JAMA 1991: 266: 1947-1952.
Transdermal Fentanyl in Postoperative Pain Lance J. Lehmann, M.D.,* John M. DeSio, M.D.,* Tibor Radvany, M.D.,t and George B. Bikhazi, M.D.t
Backgrottnd and Objectives. The aim of this study was to determine tile safety and effectiveness of a transdermal fentanyl delivcry system for the relief of pain lollowing abdominal surgery. Methods. In a nonblindcd, noncrossover, placebo-controlled study, 40 ASA I and II patients of both sexes, 18-69 years of age, who were scheduled for abdominal surgery u n d e r general anesthesia, wcrc randomly divided into two groups of 20 patients each. Patients in group I received a trandermal patch containing 0.16 mg/cm 2 of fentanyl, which was applied to the skin over the subdavian area 60 minutes before the induction of anesthesia. For body weight less than 60 kg, a 30 cm 2 patch was applied, and for weight greater than 60 kg, a 40 cm 2 patch was used. A second group of 20 patients received placebo patches of identical size. Approximately 20 to 30 minutes before tile expected end of surgery, 60 mg kctorolac was administered intramuscularly. Patients were observed for 36 hours after placement of the patch. II patients reported their pain at rest as 5 or greater at rest on a 0 - I 0 visual analog scale, they were given 30-rag increments of ketorolac 5 to 7 hours apart. If this regimen did not relieve their pain, they received 1,300 mg acetaminophen between two ketorolac doses. If despite this, they still had pain 30 minutes afterward, intravenous morphine was given, and the patients were excluded from further study. The patch was removed in four patients in the fentanyl group and seven in tile placebo group for various reasons, which i n d u d c d inadequate pain relief requiring additional analgesia postoperativcly and more than 1 I.tg/kg of sufentanil given intraoperatively or immediately prior to the end of surgery. During the 36-hour observation period, 30 doses of 30 mg ketorolac and 14 doses of 1.3 g acetaminophen were given to 13 patients in the placebo group and 18 doses of ketorolac and 8 doses of acetaminophen were administered to 16 in the fentanyl group. Results. The differences in postoperative analgesic requirements were significant. Plasma fentanyl concentrations at 12 and 24 hours after the application of the fentanyl patch were 0.98 + 0.14 ng/mL and 1.22 + 0.17 ng/mL, respectively. At 8, 16, 24, and 36 hours after application of the patch, the pain relief, assessed by a VAS at rest and with movement, was similar in the two groups. In tile fentanyl and control groups, 12 and 5 patients, respectively, experienced nausea, and 2 and 3 patients, respectively, vomited. Conchtsions. Similar postoperative analgesia was achieved with less parentcral analgesics in patients who received transdermal fentanyl prcoperatively than in control patients. Fentanyl, 50-75 I.tg/h, administered in a transdermal delivery system, did not depress respiratory rate or
From the *Department o[ Anesthesiology, tlarvard University, Beth Israel llospital, Boston, Massachusetts, and the tDepartment of Anesthesiology, University of Miami School of Medicine, Jackson Memorial Medical Center, Miami, Florida. Supported in part by Anaquest, a division o1 BOC, Inc. Accepted for publication January 25, 1996. Reprint requests: Lance J. Lehmann, M.D., Pain Medicine Center, 501 Glades Road, Boca Raton, FL 33432.
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Transdermal Fentanyl in Postoperative Pain
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Lehmann et al.
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hemoglobin oxygen saturation. Although the exact role of continuously administered opioids in managing acute postoperative pain has yet to be clearly defined, it is concluded that if properly used, this new transdermal device can be effective in providing a background of analgesia, which may assist in the management of acute postoperative pain as well as some chronic pain states. Reg Anesth 1997: 22: 24--28. Key words: fentanyl, transdermal pain relief, postoperative analgesia.
Satisfactory pain relief occurs w h e n the plasma concentration of an opioid agent is maintained at or above a critical level. If the analgesic concentration is below this level, analgesia will be inadequate, and if it is m u c h above this level, the incidence and severity of u n w a n t e d side effects will increase (1,2). Continuous intravenous infusion is frequently used to maintain the plasma concentration of analgesics at the optimal level (2-4). The continuous infusion technique requires specially trained personnel and expensive equipment, and its success depends on the uninterrupted flow of the intravenous infusion. It has been reported that postoperative analgesia is satisfactory w h e n the plasma level of fentanyl is maintained at 1-3 ng/mL (5-7). This range of fentanyl concentrations can be maintained for up to 48 hours with a 20- to 40-cm2 patch of a transdermal delivery system (Duragesic, Janssen, Palo Alto, CA) containing 0.25 mg/cm 2 of fentanyl (8-11). With this system, using 10-, 20-, 30-, or 40cm2 patches, the a m o u n t of fentanyl delivered was 25, 50, 75, and 100 Hg/h, respectively. W h e n the predicted delivery of fentanyl was 50 ~g/h, the delay of analgesia was 18.9 _+ 10.9 hours (10). After removal of the patch, it took 14 to 25 hours before fentanyl was cleared from the plasma (5). In another study, w h e n an estimated 75 lag/h of fentanyl was administered transdermally, respiratory depression, nausea, vomiting, and "urinary retention were encountered in 14%, 77%, 73%, and 27% of cases, respectively (12). Other investigators reported respiratory depression in 5% (13), 14% (14), and 23% (9) of patients. These side effects could be antagonized by naloxone (5,11,14). Since the onset of action of Duragesic is relatively slow, its usefulness for the relief of postoperative pain is limited. Recently, a n o t h e r transdermal delivery system became available, which has a faster (4- to 6-hour) onset of action (15) and therefore appears to be more suitable for postoperative pain relief. With this transdermal delivery system, an initial distribution equilibrium developed within 10-12 hours after the application of a 30-40 cm z patch, which delivered 70-80 [Ltg/h of fentanyl (15). To maxi-
mize the patch's effect, it could be placed preoperatively, several hours before the proposed operation. This study was designed to d e t e r m i n e the efficacy and safety of this n e w transdermal fentanyl delivery system for the relief of postoperative pain.
Materials and Methods The investigation was carried out o n 40 ASA I and II, 18- to 69-year-old patients scheduled for abdominal surgery, including cholecystectomy, colostomy, oophorectomy, total abdominal hysterectomy, and total vaginal hysterectomy. Patients signed informed consent forms to participate in the study, which was approved by o u r internal review board. Prior to surgery, medical history was obtained and a physical examination was performed on all patients, as well as routine h e m a t o logic and clinicopathologic tests. Prernedication consisted of 0.2 mg glycopyrrolate and 2 nag mi dazolam administered intramuscularly about 4 0 - 6 0 minutes before induction of anesthesia. At the same time, a fentanyl patch was applied to 20 patients. If the patient's body weight was less than 60 kg, the surface area of the patch was 30 cm 2, and if it was m o r e than 60 kg, a 40-cm 2 patch was used. Each patch contained 0.16 m g / c m 2 fentanyl. Twenty o t h e r patients received patches of identical size w i t h o u t fentanyl. Anesthesia was induced with 4 - 8 mg/kg thiopental and 0.3-1 Hg/kg sufentanil with 3 L/rain nitrous oxide and 2 L/rain oxygen. Tracheal intubation was facilitated with 1.5 mg/kg succinylcholine, preceded by 3 mg d-tubocurarine. Anesthesia was maintained with a m i x t u r e of 3 L/rain nitrous oxide and 2 L/rain oxygen containing 0.4 to 1% isoflurane. Sufentanil was given in 10-/.lg increments w h e n necessary intraoperatively, as w h e n heart rate or blood pressure increased 15-20% above baseline. The total intraoperative dose was limited to 1 pg/kg to be given up to 30 minutes prior to the end of the operation. Sufentanil was used instead of fentanyl because its short half-life ~vould not influence postoperative pain
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Regional Anesthesia Vol. 22 No. 1 January-February 1997
scores. Relaxation was maintained with an initial dose of 0.05 mg/kg vecuronittm followed by increments of 1.0 rag. During anesthesia, patients were mechanically ventilated (respiratory rate 10/rain, tidal v o l u m e 10 mL/kg). At the end of anesthesia, residual n e u r o m u s c u l a r block was antagonized with a mixture of 4 0 - 7 0 tag/kg of neostigmine and 8-16 I.lg/kg of glycopyrrolate. Isoflurane was discontinued 30 minutes before the expected end of surgery, and at the same time 60 mg ketorolac was administered intramuscularly. Before induction, during the maintenance of anesthesia, and during the 36-hour observation period (calculated from the time of application of the patch), blood pressure, heart rate, respiratory rate, and hemoglobin oxygen saturation by pulse oximeter were determined. After extubation, patients were transferred to the postanesthelic recovery room. Pain relief was assessed at rest and with m o v e m e n t on a visual analog scale (VAS). If patients reported pain greater than 5 on the VAS at rest, 30 mg ketorolac was injected intramuscularly at 5- to 7 - h o u r intervals. If after a dose of ketorolac, pain persisted or recurred in less than 5 hours, 1,300 mg acetaminophen was administered rectally. If the patient's pain could not be relieved with ketorolac a n d / o r acetaminophen, an intravenous narcotic analgesic was administered, and the patient was eliminated from the study. This was the case for seven patients in the placebo group and one in the fentanyl group. Plasma levels of fentanyl were determined in both groups before and at 12 and 24 hours after application of the patch. The incidence of skle effects were recorded for 36 hours. Tile ketorolac and acetaminophen requirements during the live 7 - h o u r observation periods, commencing with the intraoperative injection of ketorolac, were compared in the fentanyl and control groups with the test for proportions (16), z > 1.645 being considered significant. The significance was verified by Fisher's exact test and the chi-sqttare test (17). The total n u m b e r of ketorolac doses administered during the 36-hour observation period in tile fentanyl and control groups were compared with the M a n n - W h i m e y U lest (18), P < .05 being consklered significant.
Table 1. Demographic Data Group
Age (years)
lleight
Weight
I
44.15+3.12" (27.0-66.0)t 45.94+3.09 (28.0-69.0)
162.31 4- 2.77 (155.0-180.0) 161.93+2.05 {152.4-180.0)
70.05 + !.74 (63.0-79.8) 66.264-2.13 (50.0-80.0)
II
*Mean 4- SEM; ~range.
utes in the control and fentanyl groups, respectively. The duration of surgery was also similar, 178.1 _+ 21.9 minutes and 163.4 +_ 22.6 minutes, respectively. The time b e t w e e n administration of tile intraoperative dose and the first supplenlental dose of ketorolac was 310.0 _+ 100.2 minutes in the control group and 553.5 _+ 125.0 minutes in the [entanyl group. During the first two 7 - h o u r observation periods, a higher percentage of patients required ketorolac in the control group than in the fentanyl group (test for proportions !16] z > 1.645). The total n u m ber of doses of ketorolac administered during tile 36-hour observation period was also higher in the control than in the [entanyl group ( M a n n - W h i t n e y U test [18], P < .05), as may be seen from Table 3. In the [enlanyl group, the plasma level of fentanyl was 0.98 +_ 0.14 (range, 0.35-2.15) ng/mL at 12 hours and 1.22 _+ 0.16 (range 0.45-2.53) ng/mL at 24 hours after application of the patch. (Table 4). No fentanyl was detected in the control group. Satisfactory postoperative analgesia as defined by a VAS score less than 5 at rest is usually observed with plasma levels of 1-3 ng/mL. The median values of pain relief calculated from VAS scores at rest and with m o v e m e n t showed no difference in pain relief between the control and [entanyl groups in any of the four observation periods (Table 5). There were no significant changes in heart rate, blood pressure, respiratory rate, or hemoglobin oxygen saturation t h r o u g h o u t the 3 6 - h o u r observation period. The incidence of nausea was higher in tile fentanyl than in the control group, a h h o u g h the dilference Was not statistically significant.
Table 2. Sufentanil Requirements
Results
Dose
Age, body weight, and height of the patients (Tablc 1) were similar in the two groups, as was the a m o u n t of sufentanil used during anesthesia (Table 2). The mean times + SEM from application of the patch to intraoperalive injection of ketorolac were 156.9 + 24.5 nfinutes and 136.1 + 16.8 rain-
Group
Total (lag)
Control
60.4 4_ 16.6" (15.0-2 lO.O)t 41.9 + 4.5 (20.0-90.0)
FcnlanyI
"Mean
+
SEM: ~rangc.
pg/kg/h 0.34 __ 0.07 (0.07-0.82) 0.29 + 0.04 (0.09-0.61 )
Transdermal Fentanyl in Postoperative Pain
9
Lehmannelal.
27
Table 3. Postoperative Pain Requirements N u m b e r of P a t i e n t s ' R e c e i v i n g Kctorolac T i m e (IO t
Placebo G r o u p (n = t3)
1-7 7-14 14-21 21-28 28-35
11 9 9 9 3
F e n l a n y l Grot,p (n = 16) 0t 2' 5t 4t 6
*Seven patients in the placebo group a n d four patients in the fentanyl g r o u p had to be excluded becavse of breach of protocol, tAfter administration of t h e first dose of ketorolac, tSignificantly different (P < .05) from placebo group.
There were few other side effects noted in the control or the fentanyl group.
Discussion In addition to parenteral narcotics, a variety of methods have been developed to help alleviate postoperative pain. These include transcutaneous electrical nerve stimulation, continuous spinal or epidural infusions, and intrapleural catheters. Patient-controlled analgesia (PCA), the latest of these methods, provides a simple way to better litrate ol,ioid (lose to the patient's needs. Unfortunately, all these tecimiques involve expensive drugs and equipment and most importantly, a level of expertise that prevents their widespread use. More recently, trandermal delivery systems have come into use. The transdermal fentanyl system is a rectangular transparent unit consisting of a protective liner and four functional layers: (I) a backing layer of polyester film; (2) a drug reservoir of fentanyl and alcohol, made into a gel with hydroxyethylcellulose; (3) an ethylene-vinyl acetate copolymer membrane~ which controls the rate of fentanyl delivery to the skin; and (4) a fentanylcontaining silicone adhesive (19). A transdermal fentanyl delivery system could provide a reliable background of analgesia for acute postoperative pain as well as for chronic pain, if an effective fentanyl plasma level could be maintained while minimizing unwanted side effects, such as respiratory depression. In fact, several publications state that the maintenance of an effective, steady-state plasma level of analgesics is the ideal metl]od for the relief of post-
operative or chronic pain (I-15,20,21). However, several other studies (22,23) demonstrate increased side effects, with no increase in analgesia or benefit, for continuous opioid infusions plus PCA versus PCA alone. In our study, fenlanyl plasma levels were in tile "analgesic" range of 1-3 ng/mL at 12 and 24 hours after application of the patch. In agreement with this, during the first two 7-hour observation periods, patients in tile fentanyl group required significantly less ketorolac than those in the control group. Similarly, in the first 7-hour observation period, acetaminophen supplementation was necessary in 31% and 69% of the patients in the fentanyl and control groups, respectively, tlowever, ahhough a lower dose of ketorolac was required in tile fentanyl group, the analgesic levels were no better for patients receiving fentanyl. The lack of randomization and the dropout rate may have influenced the results of the study. "Ikvo apparent disadvantages of the transdermal fentanyl patch were its delayed onset of action, requiring up to 7 hours for the analgesic effect to be manifest, and the higher incidence of nausea in the fentanyl group. Ahhough severe respiratory depression has been reported with Duragesic patches, these cases were isolated instances of misuse during pediatric outpatient surgery. Ahhough our study, evaluating a new transdermal delivery system (Anaquest, Madison, WI) did not demonstrafe any significant incidence of respiratory
Table 5. Median Values (Ranges) of Visual Analog Scores O b s e r v a t i o n T i m e (h) 8
T a b l e 4. F c n t a n y l P l a s m a C o n c e n t r a t i o n s T i m e (h) 12 24
Level ( n g / m L )
Range (ng/mL)
0.98 __ 0.14 1.22 + 0.16
0.35-2.15 0.45-2.53
AI rest Control g r o u p FentanyIgroup With ino',,'t.lllen I Control group Fentanyl g r o u p
16
24
36
6 (9-4) 5 (8-3)
6 (9-3) 4 (8-1)
5 (9-1) 3 (7-0)
3 (6-0) 2 (4-0)
8 (10-5) 6 (8-2)
8 (10-4) 5 (8-0)
6 (9-3) 4 (6-0)
5 (7-2) 3 (6-0)
28
Regional Anesthesia Vol. 22 No. 1 January-February 1997
depression, it is presently r e c o i n m e n d e d that Duragesic patches (Janssen) should only be used for the treatment of severe chronic pain that cannot be m a n a g e d by less drastic m e a n s (ie, nonsteroidal analgesics or prn opioids). Individual variations in pain intensity and analgesia can pose problems w h e n evaluating the efficacy of a n y drug in a small population. However, from the data we obtained, this n e w transdermal fentanyl delivery system, which delivers 7 0 - 8 0 lag/h, seems capable of serving as a useful adjunct in controlling acute postoperative pain, as well as chronic pain, by providing a background of analgesia, which in addition to a more rapidly acting analgesic, can provide significant postoperative pain relief. U n w a n t e d side effects were minimal, with particular attention paid to respiratory status. Although the role of c o n t i n u o u s opioids in m a n aging postoperative pain is questionable w h e n c o m p a r e d with patient-controlled methods, continuous opioids m a y be useful for subsets of patients w h o cannot use PCA. Examples include elderly or dentented patients, handicapped patients, or patients with poor intravenous access. Further studies of this controversial topic are clearly indicated, in order to better deIine the role of this approach in tile reahn of pain m a n a g e m e n t .
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8. Gourlay GK, Kowalski SR, Plummer JL, Cherry DA, Szekely SM, Mather LE, Owen tt, Cousins MJ. Tile efficacy of transdermal fcntanyl in the treatment of postoperative pain: A double-blind comparison of fentanyl and placebo systems. Pain 1990: 40: 21-28. 9. Gourlay GK, Kowalski SR, Plummer JL, Cherry DA, Gankroger P, Cousins MJ. The transdermal administration of fentanyl in the treatment of postoperative pain: Pharmacokinetics and pharmacodynamic effects. Pain 1989: 37: 193-202. 10. Lehmann KA, Zech D. Transdermal fentanyl: Clinical pharmacology. J Pain Symptonl Management 1992: 7(3)(suppl): $8-S16. 11. Sandier A. "IYansdermal fentanyl: Acute analgesic clinical studies. J Pain Symptom Management 1992: 7(3)(suppl): S.27-$35. 12. Caplan RA, Ready LB, Oden RV, Masten FA, Nessly ML, Olsson GL. Transdermal femanyl for postoperative pain management. JAMA 1989: 261: 1036-1039. 13. Von Bormann B, Ratthey K, Schwetlick G, Schneider C, Muller H, Hempclman G. Postoperative Schmerztherapie durch transdermales Fentanyl. Anasth Intensivther Notfallmed 1988: 23: 3-8. 14. Plezia PM, Linford J, Kramer TH, Iacono RP, Hameroff SR. Transdermally administered fentanyl for postot)eralive pain: Randomized doubleblind placebo controlled trial. Anesthesiology 1988: 69: A364. 15. Miguel R, Kreitzer J, Rcinhart D et al. Utility of a new transdermal fentanyl delivery system for postoperative pain control: A multicenter trial. Anesthesiology 1992: 77: A886. 16. Fleiss JL. Statistical methods for rates and proporlions. New York, Wiley & Sons, 1981. 17. Colton T. Statistics in medicine. Boston, Little, Brown, 1974: 162-170. 18. Daniel WW. Biostafistics: A foundation for analysis in the health sciences. New York, J Wiley & Sons, 1991: 528-575. 19. DeSio JM, Bacon DR, Peer G, Lema MJ. Intravenous abuse of transdermal fentanyl therapy in a chronic pain patient. Anesth Analg 1993: 79:1139-1141. 20. Levy MH, Rosen SM, Kedziera P. Transdermal fentanyl: Seeding trial in patients with chronic cancer pain. J Pain Symptom Management 1992: 7(3) (suppl): S48-S50. 21. Herbst LH, Strause LG. Transdcrmal fentanyl use in hospice home-care patients with chronic cancer pain. J Pain Symptom Management 1992: 7(3) (suppl): $54-$57. 22. ttoltman B, White PF. Effects of a nighttime opioid infusion with PCA therapy on patient comfort and analgesic requirements after abdominal hysterectomy. Aneslhesiogy 1992: 76: 362-367. 23. Parker RK, Hohman B, White PF. Patient-controlled analgesia. Does a current opioid infusion in]prove pain management after surgery? JAMA 1991: 266: 1947-1952.