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Plasma fentanyl concentrations in awake cats and cats undergoing anesthesia and ovariohysterectomy using transdermal administration
Veterinary Anaesthesia and Analgesia, 2003, 30, 229^236
Plasma fentanyl concentrations in awake cats and cats undergoing anesthesia and ovariohysterectomy using transdermal administration Christine M Egger DVM, MVSc, Diplomate ACVA, Leigh E Glerum & Michelle Haag BS
DVM, Diplomate ACVS,
Sheila W Allen
DVM, MS, Diplomate
ACVS
Department of Small Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
Correspondence: Dr C Egger, Department of Small Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA. E-mail: [email protected].
Abstract Objective To measure the plasma fentanyl concentrations achieved over time with transdermal fentanyl patches in awake cats and cats undergoing anesthesia and ovariohysterectomy. Study design Randomized prospective experimental study.
concentrations over time, mean plasma fentanyl concentrations at speci¢c times (8, 25, 49, and 73 hours after patch placement), time to ¢rst detectable plasma fentanyl concentration, time to reach maximum plasma fentanyl concentration, maximum plasma fentanyl concentration, mean plasma fentanyl concentration from 8 to 73 hours, elimination half-life, and total area under concentration (AUC) were not statistically di¡erent among the groups.
Animals Twenty-four purpose-bred cats. Methods Cats were randomly assigned to three groups for Part I of a larger concurrent study. Group P received only a 25 mg hour1 transdermal fentanyl patch. Group P/A received the patch and anesthesia. Group A received only anesthesia. After a minimum 1-week washout period, the cats were randomly reassigned to two groups for Part II of the larger study. Group P/A/O received the patch, anesthesia and ovariohysterectomy. Group A/O received anesthesia and ovariohysterectomy. Patches were left in place for 72 hours and plasma samples were obtained for fentanyl analysis while the patches were in place, and for 8 hours after patch removal for cats in Group P, P/A, and P/A/O. Results The 25 mg hour1 transdermal fentanyl patches were well tolerated by the cats in this study (mean body weight of 3.0 kg) and no overt adverse e¡ects were noted. Mean plasma fentanyl
Conclusions Halothane anesthesia and anesthesia/ ovariohysterectomy did not signi¢cantly alter the plasma fentanyl concentrations achieved or pharmacokinetic parameters measured, when compared with awake cats. There was a high degree of individual variability observed both within and between groups of cats in parameters measured. Clinical signi¢cance The high degree of variability observed suggests that careful observation of cats with fentanyl patches in place is required to assess e⁄cacy and any potential adverse e¡ects. Anesthesia and anesthesia/ovariohysterectomy do not appear to alter plasma fentanyl concentrations achieved by placement of a 25 mg hour1 transdermal fentanyl patch when compared to cats not undergoing these procedures. Keywords anesthesia, cats, fentanyl plasma concentrations, transdermal fentanyl. 229
Transdermal fentanyl in cats CM Egger et al.
Introduction Cats are given inadequate pain relief in veterinary clinical practice for a number of reasons (Benson et al. 1991; Hansen & Hardie 1993; Dohoo & Dohoo 1996a). Many clinicians rely on visible indicators of pain such as vocalization, anxiousness, guarding of the a¡ected body area, reluctance to move, and trembling (Morton & Gri⁄ths 1985; Sanford et al. 1986; Pottho¡ & Carithers 1989; Tranquilli & Ra¡e 1989; Johnson 1991).While these indicators of pain may be fairly reliable in dogs, cats behave in a di¡erent manner. Painful cats remain silent, hide, or assume a sti¡ and hunched posture, and this behavior may be overlooked (Smith et al. 1996; Cambridge et al. 2000). Opioids, such as morphine and oxymorphone, can result in central nervous system excitation and dysphoria in cats. As a result, some clinicians are reluctant to use potent opioids in this species (Benson & Thurmon 1987; Muir & Swanson 1994; Dohoo & Dohoo 1996b). Nonsteroidal anti-in£ammatory drugs used commonly in dogs are not well metabolized in cats, and can be toxic to the kidneys, liver and gastrointestinal tract (McKellar et al.1991; Jones et al.1992; Runk et al.1999). Many of the current methods of providing analgesia rely on the periodic administration of analgesic agents, particularly opioids. Frequent dosing requirements may not be convenient in the clinical veterinary setting, and animals requiring long-term analgesia may not be provided with adequate pain control over an extended period of time. In addition to being inconvenient, periodic dosing results in peak and trough plasma concentrations that can lead to toxicosis and undesirable side e¡ects such as excessive sedation and respiratory depression (Cardocki & Yelnosky1964; Hug & Murphy1979; Cartwright et al. 1983; Andrews et al. 1983; Duke et al. 1994a; Duke et al. 1994b). Transdermal delivery of opioid analgesics o¡ers a means of maintaining analgesia for an extended period of time, without many of the disadvantages of periodic administration. Transdermal fentanyl patch systems may be an ideal way to provide pre-emptive, peri-operative and long-term analgesia for our feline patients.While several studies have been published describing their use in dogs (Schultheiss et al. 1995; Kyles et al. 1996; Egger et al. 1998; Kyles et al. 1998; Robinson et al. 1999; Moore et al. 1999), only four studies have been published describing the use of transdermal fentanyl patches in cats (Scherk-Nixon 1996; Lee et al. 2000; Franks et al. 2000; Glerum et al. 2001). Plasma fentanyl con230
centrations in awake cats have neither been compared to those in anesthetized cats, nor in cats undergoing anesthesia and surgery. The objectives of this study were to measure the plasma fentanyl concentrations achieved over time with transdermal fentanyl patches in awake cats and to compare those values with those obtained in cats undergoing anesthesia, and cats undergoing anesthesia and ovariohysterectomy. Observation of any potential adverse a¡ects from the patches was also an objective of the study.
Materials and methods Twenty-four female purpose-bred cats were obtained from the University of Georgia, College of Veterinary Medicine Laboratory Animal Resources Unit. The experimental protocol was approved by the University of Georgia Animal Care and Use Committee, and husbandry was provided according to established guidelines. The mean age of the cats was 11.7 months (range 11^14 months). The mean body weight was 3.0 kg (range 2.3^4.3 kg) and cats in each group were weighed daily throughout the study to monitor for weight loss. All cats were determined to be normal by physical examination and measurement of packed cell volume and plasma protein, blood urea nitrogen, and blood glucose concentrations. Twenty-four cats were equally and randomly assigned to group P (25 mg hour1 patch only), group P/A (25 mg hour1 patch and anesthesia), or group A (anesthesia only) for Part I of a larger concurrent study. After a minimum 1-week washout period, the cats were reassigned randomly and equally to group P/A/O (25 mg hour1 patch, anesthesia and ovariohysterectomy) or group A/O (anesthesia and ovariohysterectomy) for Part II of the larger study. The concurrent study evaluated plasma cortisol concentrations, physiological variables (heart rate, respiratory rate, systolic blood pressure, rectal temperature), and behavior (pain and excitement/sedation scores) in all groups of the study (Glerum et al. 2001). The study reported here investigated plasma fentanyl concentrations achieved in groups P, P/A, and P/A/O and compared body weight changes among all the groups, including those not receiving fentanyl patches. Group P (transdermal fentanyl patch only, 8 cats): Venous catheters (18 SWG, 8 inch (20.3 cm); I-Cath, Chartermed Inc., Lakewood, NJ, USA) were placed in either a jugular or medial saphenous vein for a minimum of12 hours prior to transdermal fentanyl patch
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placement. To aid with catheter placement, cats were sedated with a single intramuscular injection of 10 mg kg1 ketamine HCl (Ketaset; Fort Dodge AnimalHealth, Fort Dodge, IA, USA), 0.05 mg kg1 acepromazine maleate (Fermenta Animal Health Co., Kansas City, MO, USA), and 0.04 mg kg1 atropine sulfate (Phoenix Scienti¢c, Saint Joseph, MO, USA). Future patch placement sites on either the right or left lateral hemithorax were shaved. A 25 mg hour1 transdermal fentanyl patch (Duragesic; ALZA Corporation, PaloAlto, CA, USA) was placed on the lateral thorax and covered with a light wrap (encompassing the patch and thorax) at time 0 hour. Blood samples were obtained from the venous catheter for measurement of plasma fentanyl concentrations (1 mL whole blood placed in a tube containing EDTA) at time 0, 2, 4, 6, 8, 12, 13.5, 15, 17, 25, 37, 49, 61, and 73 hours. The fentanyl patch was removed after sampling at time 73 hours, and additional blood samples were taken at 74,75,77, and 81 hours for plasma fentanyl analysis. Normal saline (0.9% NaCl) was administered intravenously at three times the blood volume removed at each sampling period, and the catheter was £ushed with 1 mL of heparinized saline. All blood samples were stored under refrigeration for less than 2 hours before centrifugation for plasma extraction. Plasma samples were stored at 70 8C until assays were performed. Group P/A (transdermal fentanyl patch and anesthesia, 8 cats): Cats in group P/A were treated identically to group P prior to anesthesia. The anesthesia sequence began at time 11.5 hours. Pre-medication of 5 mg kg1 ketamine, 0.05 mg kg1 acepromazine, and 0.04 mg kg1 atropine were all administered intramuscularly. A catheter (22 SWG, 2 inch (5.1 cm); Sovereign Indwelling Catheter; Sherwood Medical Industries, Tullamore, Ireland) was placed in a cephalic vein for administration of anesthetic induction drugs and intravenous £uid support. Anesthesia was induced with 8 mg kg1 ketamine intravenously, 30^40 minutes after pre-medication. A surgical plane of anesthesia was maintained for approximately 30 minutes with halothane and oxygen administered via an endotracheal tube and rebreathing circuit. Lactated Ringer’s solution (McGaw Inc., Irvine, CA, USA) was administered intravenously throughout the anesthetic period at 10 mL kg1 hour1. The following time points correspond approximately with peri-anesthetic events: 12 hours ¼ pre-induction; 12.5 hours ¼ post-induction; 13 hours ¼ termination of halothane administration; 13.5 hours ¼ extubation; and
14 hours ¼ 1 hour following cessation of halothane administration. Blood samples for plasma fentanyl analysis were obtained in the same manner and at the same time as indicated for group P. Group P/A/O (transdermal fentanyl patch, anesthesia, and ovariohysterectomy, 12 cats): Cats in group P/A/O were managed preoperatively as described for groups P and P/A, and a 25 mg hour1 transdermal fentanyl patch was placed on the lateral thorax and covered with a light wrap at time 0 hour. The anesthesia/surgery sequence began at time 11.5 hours, at which time the cats were pre-medicated and anesthetized as described for group P/A. A surgical plane of anesthesia was maintained for up to 60 minutes, depending upon surgery time, with halothane and oxygen administered via an endotracheal tube and a rebreathing system. Lactated Ringer’s solution was administered intravenously throughout the anesthetic period at 10 mL kg1 hour1. Ovariohysterectomy was performed during the general anesthetic period by the same surgeon in all cats. The following time points correspond approximately with perianesthetic events: 12 hours ¼ pre-induction; 12.5 hours ¼ post-induction; 13 hours ¼ termination of halothane administration; 13.5 hours ¼ extubation; and 14 hours ¼ 1 hour following cessation of halothane administration. Blood samples for plasma fentanyl analysis were obtained in the same manner and at the same times as indicated for groups P and P/A. The fentanyl patch was removed after sampling at time 73 hours, and subsequent monitoring and sampling were as described for group P/A. Cats were re-assigned to a long-term nutritional study of spayed female cats following completion of this investigation. Plasma fentanyl concentrations were measured using a radioimmunoassay (RIA) kit (Janssen Biotech N.V., Olen, Belgium) (Michiels et al. 1977; Schuttler & White 1984). Samples were analyzed in duplicate and the values obtained were averaged to obtain the ¢nal plasma concentrations. The mean plasma fentanyl concentrations (SD) for each group were plotted over time. Mean plasma fentanyl concentrations from 24 to 73 hours were calculated by averaging the plasma fentanyl concentration for each cat in each group during that time period. It was determined that the decline in plasma fentanyl concentrations after patch removal was best described using a one-compartment model after plotting the natural logarithm of the concentration over time and obtaining a straight line.The apparent elimination rate constant (Kel) was then determined by
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Group
Group Group Group Group Group
P P/A A P/A/O A/O
Begin weight (kg)
End weight (kg)
Weight changes (kg)
2.9 0.3 3.2 0.5 3.1 0.4 3.0 0.3 3.1 0.4
3.0 0.3 3.2 0.5 3.1 0.3 3.0 0.3 3.1 0.5
0.03 0.1 0.07 0.14 0.02 0.17 0.04 0.1 0.02 0.14
Table 1 Beginning and end weights and weight changes for all groups
No significant difference between groups P, P/A, A for any parameter. No significant difference between groups P/A/O and A/O for any parameter. Data are expressed as mean SD.
performing linear regression on the terminal portion of the natural log (ln) concentration versus time curve after patch removal for each cat, and these values were averaged to obtain the mean (SD) apparent elimination rate constant (Kel) for each group (Shargel & Yu 1993). The apparent elimination half-life (t1/2 Kel) was calculated using the following formula (Shargel & Yu1993): t1=2 Kel ¼ 0:693=Kel The partial area under the concentration versus time curve (AUC ^ 0^81 hours after patch application) was determined for each group using the trapezoidal rule. The residual AUC (81 hours to in¢nity) was estimated by dividing the last concentration measured by the apparent elimination rate constant. The total AUC (0 hours to in¢nity) was obtained by adding the residual AUC to the partial AUC (Shargel & Yu1993). Pharmacokinetic analysis was performed using the LAGRAN software program (C. Ediss, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, copyright1991). A two-wayanalysis of variance (ANOVA) for repeated measures was used to compare the e¡ects of treatment (patch only, patch and anesthesia, and patch, anesthesia and surgery) and time after patch application on plasma fentanyl concentration. A one-way ANOVA with protected least signi¢cant di¡erence pairwise comparisons was used to compare the descriptive information (data in Tables 1 and 2) from the three groups. It was assumed that, given the rapid elimination of fentanyl from the plasma of the cats after patch removal, the crossover could be disregarded for the analysis. A p-value <0.05 was considered signi¢cant for all statistical analyses. Statistical analysis was performed using SAS (SAS Institute, Gary, IN, USA) and Microsoft Excel. 232
Table 2 Plasma fentanyl concentrations at 8, 25, 49 and 73 hours after patch placement
Time (hours after patch placement)
Group P
Group P/A
Group P/A/O
8 25 49 73
2.6 1.7 4.1 2.1 2.4 1.1 1.6 0.6
2.1 1.3 3.6 1.2 2.1 0.5 1.2 0.2
1.4 1.4 3.1 1.2 1.9 0.5 1.2 0.3
No significant difference between groups at any time. Data are expressed as mean SD.
Results The 25 mg hour1 fentanyl patches were well tolerated by all of the cats in the study, the patches did not loosen prematurely in any of the cats, nor did they have to be removed early because of adverse side e¡ects. No statistically signi¢cant di¡erences in physiological parameters or behavior scores were noted among the groups. Pre- and post-study body weights and body weight changes were compared among the nonsurgical groups (P, P/A and A) and then among the surgical groups (P/A/O and A/O) (Table 1). No statistically signi¢cant di¡erence in pre- or poststudy body weights or body weight changes were noted. Mean plasma fentanyl concentrations over time for groups P, P/A and P/A/O are presented in Fig. 1. The intra-assay coe⁄cient of variation for the plasma fentanyl radioimmunoassay for this study was 3.4%. Although time had a signi¢cant e¡ect on plasma fentanyl concentration in each group, the fentanyl concentrations of the three groups were not statistically di¡erent from each other. The mean plasma fentanyl concentrations for each of these three
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Figure 1 Mean plasma fentanyl concentration (mean SD) for cats from Group P (patch only; eight cats), Group P/A (patch and anesthesia; eight cats) and Group P/A/O (patch, anesthesia and ovariohysterectomy;12 cats). Patches were applied at 0 hour. Premedication, induction, maintenance, and recovery to extubation for groups P/A and P/A/O occurred from 11.5 to 13.5 hours. Patches were removed at 73 hours after patch placement in all three groups (PR ¼ patch removal).
groups were compared at 8,25,49, and 73 hours after patch application (Table 2). There was no statistically signi¢cant di¡erence among groups at any of these times. Table 3 shows data (mean SD) for each of the three groups (P, P/A, P/A/O) for time to ¢rst detectable
Table 3 Plasma concentration values and times, AUC and Kel for each group
plasma fentanyl concentration, time to reach maximum plasma fentanyl concentration, maximum plasma fentanyl concentration, mean plasma fentanyl concentration from 8 to 73 hours, elimination half-life, and total AUC. These parameters were not statistically di¡erent among the groups.
Parameter measured
Time (hours) to first detectable PFC Time (hours) to maximum PFC Maximum PFC (ng mL1) Mean PFC from 8 to 73 hours (ng mL1) Apparent t1/2 elimination (hours) (Harmonic mean and pseudo SD) Total AUC (ng hour mL1)
Group P
Group P/A/O
Group P/A/O
3.25 1.5 14.0 1.9 6.1 3.0 3.4 1.4
3.5 1.8 19.0 5.0 5.5 2.2 3.0 1.0
5.2 2.3 20.5 10.0 3.7 1.6 2.2 1.0
4.5 4.3
6.1 6.1
5.1 5.4
222.3 92.1
204 45.5
157.1 54.0
No significant difference between groups for any parameter. AUC: area under the concentration versus time curve; SD: standard deviation; PFC: plasma fentanyl concentration. Data are expressed as mean SD.
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Discussion Although there was a trend to lower plasma fentanyl concentrations achieved in groups P/A and P/A/O, anesthesia and anesthesia/ovariohysterectomy did not signi¢cantly alter the fentanyl concentrations achieved. Because alterations in cutaneous blood £ow and body and skin temperature can alter drug absorption, both halothane anesthesia and hypothermia could potentially result in a decrease in cutaneous blood £ow and impedance of drug absorption from a transdermal site (Longnecker 1984; Plezia et al.1989;Varvel et al.1989; Roy & Flynn1990; Jeal & Ben¢eld 1997), although this was not documented in this study. The time to ¢rst detectable plasma fentanyl concentration was not statistically di¡erent between the three groups of cats, although there was considerable individual variation (Table 3). The RIA is highly speci¢c for fentanyl, has no cross-reaction with metabolites of fentanyl, and has a limit of detection for fentanyl of 0.1 ng mL1 (Michiels et al. 1977; Schuttler & White 1984). Time to ¢rst detectable plasma fentanyl concentration in this study is considerably shorter in cats (3.25^6 hours) than dogs (13^ 16 hours), but slightly longer than in people (2 hours) (Plezia et al.1989; Egger et al.1998). In addition, the time to reach maximum plasma fentanyl concentrations (14^20.5 hours) is also less than in dogs (Schultheiss et al. 1995; Egger et al. 1998). In dogs, early absorption of fentanyl may be related to thickness of the cellular strata and epidermis of the skin, and di¡erences in skin thickness may account for the species variation seen in time to ¢rst detectable and maximum plasma fentanyl concentrations (Schultheiss et al.1995). In this study, no true steady state was achieved in any of the groups of cats due to the high degree of individual variability in plasma fentanyl concentrations while the patches were in place. Rather than investigate mean steady-state plasma fentanyl concentrations, this study looked at the mean plasma fentanyl concentration from 8 hours after patch application when it was believed that clinically signi¢cant plasma fentanyl concentrations were achieved in most cats, until 73 hours, when the patches were removed. There was no statistically signi¢cant di¡erence in this parameter between the three groups (see Table 3). Although the plasma fentanyl concentration required for analgesia in cats is undetermined, 1 ng mL1 is often quoted as analgesic in people. If 1 ng mL1 is also analgesic in cats, 234
most of the cats in all three groups had achieved analgesic levels by 8 hours, and maintained them until patch removal at 73 hours. A previous study evaluated the e¡ect of transdermal fentanyl patches on the minimum alveolar concentration (MAC) of iso£urane in cats, 24 hours after patch placement (Yackey et al.1997).While both 25 and 50 mg hour1 fentanyl patches signi¢cantly reduced iso£urane MAC by 24 hours, the investigators did not measure plasma fentanyl concentrations, making it impossible to compare plasma fentanyl concentrations in those cats with cats from this study. However, since there was signi¢cant MAC reduction by 24 hours, it is possible that there may also be signi¢cant analgesia obtained by 24 hours after patch placement. While the mean (8^73 hours) and maximum plasma fentanyl concentrations achieved in all groups of cats were quite high, the concentrations achieved and the degree of variability were comparable to those achieved in the studies by Lee et al. (2000) and Franks et al. (2000). In this study, total AUC and plasma fentanyl concentrations (Table 3) were considerably higher than those achieved in dogs in all previous studies (Schultheiss et al. 1995; Kyles et al.1996; Egger et al.1998). The apparent elimination half-life was also longer in cats (Table 3) than previously determined in dogs (Egger et al.1998). Cats have been shown to have a smaller volume of distribution and longer clearance for fentanyl compared to the dog, and this would certainly account for some of these species di¡erences (Lee et al. 2000). Di¡erences in cutaneous absorption due to dermal and/or epidermal thickness might also account for the higher values achieved in the cats in this study (Schultheiss et al. 1995).While it is certainly possible that the 25 mg hour1 patch size was too large for the cats in this study (3.0 1.3 kg), none of the cats demonstrated any signs of opioid overdosage or adverse e¡ects that might indicate fentanyl overdosage. The high degree of individual variability displayed in these cats is consistent with the results of numerous human and canine studies (Plezia et al. 1989; Schultheiss et al.1995; Kyles et al.1996; Jeal & Ben¢eld 1997; Egger et al. 1998; Franks et al. 2000; Lee et al. 2000). Variability in plasma fentanyl concentrations attained could arise from variations in drug release from the patch, absorption of drug across the epidermis and dermis, uptake by the cutaneous vasculature, and patient volume of distribution and metabolic clearance. The predicted delivery rate from transdermal fentanyl patches is subject to variation,
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with reported actual delivery rates in the range of 27^ 100% of the theoretical rate of delivery in dogs and 19^59% of the theoretical rate of delivery in cats (Kyles et al. 1996; Lee et al. 2000). Given the e¡ort in this study to treat each of the cats within a group as similarly as possible, this variability in plasma fentanyl concentrations is likely to be even greater within a clinical group of animals, with much greater variability in age, activity levels, hydration status, volume of distribution, and metabolic clearance. A previous study noted marked appetite suppression and loss of body weight in dogs with transdermal fentanyl patches applied (Schultheiss et al. 1995) and the authors have received anecdotal reports of inappetence in dogs and cats with the patches applied. In an attempt to determine if appetite suppression was a potential complication, we initially attempted to monitor food intake for all groups of cats. However, this proved very di⁄cult because of the di¡erences in fasting requirements for cats undergoing anesthesia and surgery. Body weights were monitored throughout the study, allowing comparison of pre- and post-study body weight and body weight changes among the nonsurgical groups (P, P/ A, A) and then among the surgical groups (P/A/O and A/O). As there were no statistically signi¢cant di¡erences in body weight or body weight changes among the groups, this could indicate that signi¢cant decreases in appetite and food intake did not occur in cats with transdermal fentanyl patches applied. In conclusion, the 25 mg hour1 fentanyl patches appeared to be well tolerated by all cats in the study, and no overt adverse e¡ects were noted. Anesthesia and anesthesia/ovariohysterectomy did not signi¢cantly alter the plasma fentanyl concentrations attained or the pharmacokinetic parameters measured. The high degree of individual variability observed both within and among groups of cats would suggest careful observation of cats with fentanyl patches in place is required both to assess the adequacy of analgesia and to detect any adverse e¡ects. Although the analgesic plasma fentanyl concentration for cats has not yet been determined, the average plasma fentanyl concentration was greater than 1 ng mL1 by 8 hours after patch placement in many cats, and by 12 hours after patch placement in the majority of the cats in the study. The results of this study would suggest that the 25 mg hour1 patch is an appropriate patch size for cats with a mean body weight of 3.0 kg (range 2.3^4.3 kg), the patches should be applied at least 12 hours before the time
analgesia is required, and supplemental analgesics should be provided in the interim.
Acknowledgements Supported by the University of Georgia Veterinary Medical Experiment Station and the American College of Veterinary Surgeons. The authors thank Dr Fred Thompson and Kenneth Smith for technical support and Guorong Chen for statistical support.
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Hansen B, Hardie E (1993) Prescription and use of analgesics in dogs and cats in a veterinary teaching hospital: 258 cases (1983^89). J AmVet Med Assoc 202,1485^1494. Hug CC, Murphy MR (1979) Fentanyl disposition in cerebrospinal £uid and plasma and its relationship to ventilatory depression in the dog. Anesthesiology 50,342^349. Jeal W, Ben¢eld P (1997) Transdermal fentanyl. A review of its pharmacological properties and therapeutic e⁄cacy in pain control. Drugs 53,109^138. Johnson JM (1991) The veterinarian’s responsibility: assessing and managing acute pain in dogs and cats. Part I. Compend Contin Educ Pract Vet13,804^807. Jones RD, Baynes RE, Nimitz CT (1992) Nonsteroidal antiin£ammatory drug toxicosis in dogs and cats: 240 cases (1989^90). J AmVet Med Assoc 201, 475^477. Kyles AE, Hardie EM, Hansen BD et al. (1998) Comparison of transdermal fentanyl and intramuscular oxymorphone on post-operative behaviour after ovariohysterectomy in dogs. ResVet Sci 65, 245^251. Kyles AE, Papich M, Hardie EM (1996) Disposition of transdermally administered fentanyl in dogs. Am J Vet Res 57, 715^719. Lee DD, Papich MG, Hardie EM (2000) Comparison of pharmacokinetics of fentanyl after intravenous and transdermal administration in cats. Am J Vet Res 61, 672^677. Longnecker DE (1984) E¡ects of general anesthetics on the microcirculation. Microcirc Endothelium Lymphatics 1, 129^150. McKellar QA, May SA, Lees P (1991) Pharmacology and therapeutics of nonsteroidal anti-in£ammatory drugs in the dog and cat: individual agents. J Small Anim Pract 32, 225^235. Michiels M, Hendriks R, Heykants J (1977) A sensitive radioimmunoassay for fentanyl plasma levels in dogs and man. Eur J Clin Pharmacol12,153^158. Moore K, Bjorling D, Manley P et al. (1999) Comparison of transdermal fentanyl and epidural morphine for analgesia after triple pelvic osteotomy in dogs. Proceedings of the Ninth Annual ACVS Symposium, Washington DC, USA, pp.15(Abstract). Morton DB, Gri⁄ths PHM (1985) Guidelines on the recognition of pain, distress and discomfort in experimental animals and a hypothesis for assessment. Vet Rec 116, 431^436. Muir WW, Swanson CR (1994) Principles and techniques of anesthesia and chemical restraint. In: The Cat, Diseases and Clinical Management. Sherding RG (ed).
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Churchill-Livingstone Inc., Philadelphia, PA, USA, pp. 91^132. Plezia PM, Kramer TH, Lindord J et al. (1989) Transdermal fentanyl: pharmacokinetics and preliminary clinical evaluation. Pharmacotherapy 9, 2^9. Pottho¡ A, Carithers RW (1989) Pain and analgesia in dogs and cats. Compend Contin Educ Pract Vet11,887^897. Robinson TM, Kruse-Eliott KT, Markel MD et al. (1999) A comparison of transdermal fentanyl versus epidural morphine for analgesia in dogs undergoing major orthopedic surgery. J Am Anim Hosp Assoc 35,95^100. Roy SD, Flynn GL (1990) Transdermal delivery of narcotic analgesics: pH, anatomical, and subject in£uences on cutaneous permeability of fentanyl and sufentanil. Pharmacol Res 7,842^847. Runk A, Kyles AE, Downs MO (1999) Duodenal perforation in a cat following the administration of nonsteroidal anti-in£ammatory medication. J Am Anim Hosp Assoc 35,52^55. Sanford J, Ewbank R, MolonyVet al. (1986) Guidelines for the recognition and assessment of pain in animals. Vet Rec 118,334^338. Scherk-Nixon M (1996) A study of the use of a transdermal fentanyl patch in cats. J Am Hosp Assoc 32,19^24. Schultheiss PJ, Morse BC, Baker WH (1995) Evaluation of a transdermal fentanyl system in the dog. Contemp Top LaboratoryAnim Sci 34,75^81. Schuttler J,White PF (1984) Optimization of the radioimmunoassays for measuring fentanyl and alfentanil in human serum. Anesthesiology 61,315^320. Shargel L, Yu ABC (1993) Applied Biopharmaceutics and Pharmacokinetics (3rd edn). Appleton & Lange, London, UK, pp.34^35, 47^48,172^173,195^200. SmithJD, Allen SW, Quandt JE et al. (1996) Indicators of postoperative pain in cats and correlation with clinical criteria. Am J Vet Res 57,1674^1678. Tranquilli WJ, Ra¡e MR (1989) Understanding pain and analgesic therapy in pets.Vet Med 84,680^686. Varvel JR, Shafer SL, Hwang SS et al. (1989) Absorption characteristics of transdermally administered fentanyl. Anesthesiology 50,928^934. Yackey M, Ilkiw JE, Pascoe PJ et al. (1997) The e¡ect of transdermallyadministered fentanyl on the minimum alveolar concentration of iso£urane in cats. Proceedings of the 6th International Congress of VeterinaryAnesthesiology, Thessalonika, Greece, pp.104(Abstract). Received 29 July 2001; accepted 28 January 2002.
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Plasma fentanyl concentrations in awake cats and cats undergoing anesthesia and ovariohysterectomy using transdermal administration Christine M Egger DVM, MVSc, Diplomate ACVA, Leigh E Glerum & Michelle Haag BS
DVM, Diplomate ACVS,
Sheila W Allen
DVM, MS, Diplomate
ACVS
Department of Small Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
Correspondence: Dr C Egger, Department of Small Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA. E-mail: [email protected].
Abstract Objective To measure the plasma fentanyl concentrations achieved over time with transdermal fentanyl patches in awake cats and cats undergoing anesthesia and ovariohysterectomy. Study design Randomized prospective experimental study.
concentrations over time, mean plasma fentanyl concentrations at speci¢c times (8, 25, 49, and 73 hours after patch placement), time to ¢rst detectable plasma fentanyl concentration, time to reach maximum plasma fentanyl concentration, maximum plasma fentanyl concentration, mean plasma fentanyl concentration from 8 to 73 hours, elimination half-life, and total area under concentration (AUC) were not statistically di¡erent among the groups.
Animals Twenty-four purpose-bred cats. Methods Cats were randomly assigned to three groups for Part I of a larger concurrent study. Group P received only a 25 mg hour1 transdermal fentanyl patch. Group P/A received the patch and anesthesia. Group A received only anesthesia. After a minimum 1-week washout period, the cats were randomly reassigned to two groups for Part II of the larger study. Group P/A/O received the patch, anesthesia and ovariohysterectomy. Group A/O received anesthesia and ovariohysterectomy. Patches were left in place for 72 hours and plasma samples were obtained for fentanyl analysis while the patches were in place, and for 8 hours after patch removal for cats in Group P, P/A, and P/A/O. Results The 25 mg hour1 transdermal fentanyl patches were well tolerated by the cats in this study (mean body weight of 3.0 kg) and no overt adverse e¡ects were noted. Mean plasma fentanyl
Conclusions Halothane anesthesia and anesthesia/ ovariohysterectomy did not signi¢cantly alter the plasma fentanyl concentrations achieved or pharmacokinetic parameters measured, when compared with awake cats. There was a high degree of individual variability observed both within and between groups of cats in parameters measured. Clinical signi¢cance The high degree of variability observed suggests that careful observation of cats with fentanyl patches in place is required to assess e⁄cacy and any potential adverse e¡ects. Anesthesia and anesthesia/ovariohysterectomy do not appear to alter plasma fentanyl concentrations achieved by placement of a 25 mg hour1 transdermal fentanyl patch when compared to cats not undergoing these procedures. Keywords anesthesia, cats, fentanyl plasma concentrations, transdermal fentanyl. 229
Transdermal fentanyl in cats CM Egger et al.
Introduction Cats are given inadequate pain relief in veterinary clinical practice for a number of reasons (Benson et al. 1991; Hansen & Hardie 1993; Dohoo & Dohoo 1996a). Many clinicians rely on visible indicators of pain such as vocalization, anxiousness, guarding of the a¡ected body area, reluctance to move, and trembling (Morton & Gri⁄ths 1985; Sanford et al. 1986; Pottho¡ & Carithers 1989; Tranquilli & Ra¡e 1989; Johnson 1991).While these indicators of pain may be fairly reliable in dogs, cats behave in a di¡erent manner. Painful cats remain silent, hide, or assume a sti¡ and hunched posture, and this behavior may be overlooked (Smith et al. 1996; Cambridge et al. 2000). Opioids, such as morphine and oxymorphone, can result in central nervous system excitation and dysphoria in cats. As a result, some clinicians are reluctant to use potent opioids in this species (Benson & Thurmon 1987; Muir & Swanson 1994; Dohoo & Dohoo 1996b). Nonsteroidal anti-in£ammatory drugs used commonly in dogs are not well metabolized in cats, and can be toxic to the kidneys, liver and gastrointestinal tract (McKellar et al.1991; Jones et al.1992; Runk et al.1999). Many of the current methods of providing analgesia rely on the periodic administration of analgesic agents, particularly opioids. Frequent dosing requirements may not be convenient in the clinical veterinary setting, and animals requiring long-term analgesia may not be provided with adequate pain control over an extended period of time. In addition to being inconvenient, periodic dosing results in peak and trough plasma concentrations that can lead to toxicosis and undesirable side e¡ects such as excessive sedation and respiratory depression (Cardocki & Yelnosky1964; Hug & Murphy1979; Cartwright et al. 1983; Andrews et al. 1983; Duke et al. 1994a; Duke et al. 1994b). Transdermal delivery of opioid analgesics o¡ers a means of maintaining analgesia for an extended period of time, without many of the disadvantages of periodic administration. Transdermal fentanyl patch systems may be an ideal way to provide pre-emptive, peri-operative and long-term analgesia for our feline patients.While several studies have been published describing their use in dogs (Schultheiss et al. 1995; Kyles et al. 1996; Egger et al. 1998; Kyles et al. 1998; Robinson et al. 1999; Moore et al. 1999), only four studies have been published describing the use of transdermal fentanyl patches in cats (Scherk-Nixon 1996; Lee et al. 2000; Franks et al. 2000; Glerum et al. 2001). Plasma fentanyl con230
centrations in awake cats have neither been compared to those in anesthetized cats, nor in cats undergoing anesthesia and surgery. The objectives of this study were to measure the plasma fentanyl concentrations achieved over time with transdermal fentanyl patches in awake cats and to compare those values with those obtained in cats undergoing anesthesia, and cats undergoing anesthesia and ovariohysterectomy. Observation of any potential adverse a¡ects from the patches was also an objective of the study.
Materials and methods Twenty-four female purpose-bred cats were obtained from the University of Georgia, College of Veterinary Medicine Laboratory Animal Resources Unit. The experimental protocol was approved by the University of Georgia Animal Care and Use Committee, and husbandry was provided according to established guidelines. The mean age of the cats was 11.7 months (range 11^14 months). The mean body weight was 3.0 kg (range 2.3^4.3 kg) and cats in each group were weighed daily throughout the study to monitor for weight loss. All cats were determined to be normal by physical examination and measurement of packed cell volume and plasma protein, blood urea nitrogen, and blood glucose concentrations. Twenty-four cats were equally and randomly assigned to group P (25 mg hour1 patch only), group P/A (25 mg hour1 patch and anesthesia), or group A (anesthesia only) for Part I of a larger concurrent study. After a minimum 1-week washout period, the cats were reassigned randomly and equally to group P/A/O (25 mg hour1 patch, anesthesia and ovariohysterectomy) or group A/O (anesthesia and ovariohysterectomy) for Part II of the larger study. The concurrent study evaluated plasma cortisol concentrations, physiological variables (heart rate, respiratory rate, systolic blood pressure, rectal temperature), and behavior (pain and excitement/sedation scores) in all groups of the study (Glerum et al. 2001). The study reported here investigated plasma fentanyl concentrations achieved in groups P, P/A, and P/A/O and compared body weight changes among all the groups, including those not receiving fentanyl patches. Group P (transdermal fentanyl patch only, 8 cats): Venous catheters (18 SWG, 8 inch (20.3 cm); I-Cath, Chartermed Inc., Lakewood, NJ, USA) were placed in either a jugular or medial saphenous vein for a minimum of12 hours prior to transdermal fentanyl patch
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placement. To aid with catheter placement, cats were sedated with a single intramuscular injection of 10 mg kg1 ketamine HCl (Ketaset; Fort Dodge AnimalHealth, Fort Dodge, IA, USA), 0.05 mg kg1 acepromazine maleate (Fermenta Animal Health Co., Kansas City, MO, USA), and 0.04 mg kg1 atropine sulfate (Phoenix Scienti¢c, Saint Joseph, MO, USA). Future patch placement sites on either the right or left lateral hemithorax were shaved. A 25 mg hour1 transdermal fentanyl patch (Duragesic; ALZA Corporation, PaloAlto, CA, USA) was placed on the lateral thorax and covered with a light wrap (encompassing the patch and thorax) at time 0 hour. Blood samples were obtained from the venous catheter for measurement of plasma fentanyl concentrations (1 mL whole blood placed in a tube containing EDTA) at time 0, 2, 4, 6, 8, 12, 13.5, 15, 17, 25, 37, 49, 61, and 73 hours. The fentanyl patch was removed after sampling at time 73 hours, and additional blood samples were taken at 74,75,77, and 81 hours for plasma fentanyl analysis. Normal saline (0.9% NaCl) was administered intravenously at three times the blood volume removed at each sampling period, and the catheter was £ushed with 1 mL of heparinized saline. All blood samples were stored under refrigeration for less than 2 hours before centrifugation for plasma extraction. Plasma samples were stored at 70 8C until assays were performed. Group P/A (transdermal fentanyl patch and anesthesia, 8 cats): Cats in group P/A were treated identically to group P prior to anesthesia. The anesthesia sequence began at time 11.5 hours. Pre-medication of 5 mg kg1 ketamine, 0.05 mg kg1 acepromazine, and 0.04 mg kg1 atropine were all administered intramuscularly. A catheter (22 SWG, 2 inch (5.1 cm); Sovereign Indwelling Catheter; Sherwood Medical Industries, Tullamore, Ireland) was placed in a cephalic vein for administration of anesthetic induction drugs and intravenous £uid support. Anesthesia was induced with 8 mg kg1 ketamine intravenously, 30^40 minutes after pre-medication. A surgical plane of anesthesia was maintained for approximately 30 minutes with halothane and oxygen administered via an endotracheal tube and rebreathing circuit. Lactated Ringer’s solution (McGaw Inc., Irvine, CA, USA) was administered intravenously throughout the anesthetic period at 10 mL kg1 hour1. The following time points correspond approximately with peri-anesthetic events: 12 hours ¼ pre-induction; 12.5 hours ¼ post-induction; 13 hours ¼ termination of halothane administration; 13.5 hours ¼ extubation; and
14 hours ¼ 1 hour following cessation of halothane administration. Blood samples for plasma fentanyl analysis were obtained in the same manner and at the same time as indicated for group P. Group P/A/O (transdermal fentanyl patch, anesthesia, and ovariohysterectomy, 12 cats): Cats in group P/A/O were managed preoperatively as described for groups P and P/A, and a 25 mg hour1 transdermal fentanyl patch was placed on the lateral thorax and covered with a light wrap at time 0 hour. The anesthesia/surgery sequence began at time 11.5 hours, at which time the cats were pre-medicated and anesthetized as described for group P/A. A surgical plane of anesthesia was maintained for up to 60 minutes, depending upon surgery time, with halothane and oxygen administered via an endotracheal tube and a rebreathing system. Lactated Ringer’s solution was administered intravenously throughout the anesthetic period at 10 mL kg1 hour1. Ovariohysterectomy was performed during the general anesthetic period by the same surgeon in all cats. The following time points correspond approximately with perianesthetic events: 12 hours ¼ pre-induction; 12.5 hours ¼ post-induction; 13 hours ¼ termination of halothane administration; 13.5 hours ¼ extubation; and 14 hours ¼ 1 hour following cessation of halothane administration. Blood samples for plasma fentanyl analysis were obtained in the same manner and at the same times as indicated for groups P and P/A. The fentanyl patch was removed after sampling at time 73 hours, and subsequent monitoring and sampling were as described for group P/A. Cats were re-assigned to a long-term nutritional study of spayed female cats following completion of this investigation. Plasma fentanyl concentrations were measured using a radioimmunoassay (RIA) kit (Janssen Biotech N.V., Olen, Belgium) (Michiels et al. 1977; Schuttler & White 1984). Samples were analyzed in duplicate and the values obtained were averaged to obtain the ¢nal plasma concentrations. The mean plasma fentanyl concentrations (SD) for each group were plotted over time. Mean plasma fentanyl concentrations from 24 to 73 hours were calculated by averaging the plasma fentanyl concentration for each cat in each group during that time period. It was determined that the decline in plasma fentanyl concentrations after patch removal was best described using a one-compartment model after plotting the natural logarithm of the concentration over time and obtaining a straight line.The apparent elimination rate constant (Kel) was then determined by
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Transdermal fentanyl in cats CM Egger et al.
Group
Group Group Group Group Group
P P/A A P/A/O A/O
Begin weight (kg)
End weight (kg)
Weight changes (kg)
2.9 0.3 3.2 0.5 3.1 0.4 3.0 0.3 3.1 0.4
3.0 0.3 3.2 0.5 3.1 0.3 3.0 0.3 3.1 0.5
0.03 0.1 0.07 0.14 0.02 0.17 0.04 0.1 0.02 0.14
Table 1 Beginning and end weights and weight changes for all groups
No significant difference between groups P, P/A, A for any parameter. No significant difference between groups P/A/O and A/O for any parameter. Data are expressed as mean SD.
performing linear regression on the terminal portion of the natural log (ln) concentration versus time curve after patch removal for each cat, and these values were averaged to obtain the mean (SD) apparent elimination rate constant (Kel) for each group (Shargel & Yu 1993). The apparent elimination half-life (t1/2 Kel) was calculated using the following formula (Shargel & Yu1993): t1=2 Kel ¼ 0:693=Kel The partial area under the concentration versus time curve (AUC ^ 0^81 hours after patch application) was determined for each group using the trapezoidal rule. The residual AUC (81 hours to in¢nity) was estimated by dividing the last concentration measured by the apparent elimination rate constant. The total AUC (0 hours to in¢nity) was obtained by adding the residual AUC to the partial AUC (Shargel & Yu1993). Pharmacokinetic analysis was performed using the LAGRAN software program (C. Ediss, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, copyright1991). A two-wayanalysis of variance (ANOVA) for repeated measures was used to compare the e¡ects of treatment (patch only, patch and anesthesia, and patch, anesthesia and surgery) and time after patch application on plasma fentanyl concentration. A one-way ANOVA with protected least signi¢cant di¡erence pairwise comparisons was used to compare the descriptive information (data in Tables 1 and 2) from the three groups. It was assumed that, given the rapid elimination of fentanyl from the plasma of the cats after patch removal, the crossover could be disregarded for the analysis. A p-value <0.05 was considered signi¢cant for all statistical analyses. Statistical analysis was performed using SAS (SAS Institute, Gary, IN, USA) and Microsoft Excel. 232
Table 2 Plasma fentanyl concentrations at 8, 25, 49 and 73 hours after patch placement
Time (hours after patch placement)
Group P
Group P/A
Group P/A/O
8 25 49 73
2.6 1.7 4.1 2.1 2.4 1.1 1.6 0.6
2.1 1.3 3.6 1.2 2.1 0.5 1.2 0.2
1.4 1.4 3.1 1.2 1.9 0.5 1.2 0.3
No significant difference between groups at any time. Data are expressed as mean SD.
Results The 25 mg hour1 fentanyl patches were well tolerated by all of the cats in the study, the patches did not loosen prematurely in any of the cats, nor did they have to be removed early because of adverse side e¡ects. No statistically signi¢cant di¡erences in physiological parameters or behavior scores were noted among the groups. Pre- and post-study body weights and body weight changes were compared among the nonsurgical groups (P, P/A and A) and then among the surgical groups (P/A/O and A/O) (Table 1). No statistically signi¢cant di¡erence in pre- or poststudy body weights or body weight changes were noted. Mean plasma fentanyl concentrations over time for groups P, P/A and P/A/O are presented in Fig. 1. The intra-assay coe⁄cient of variation for the plasma fentanyl radioimmunoassay for this study was 3.4%. Although time had a signi¢cant e¡ect on plasma fentanyl concentration in each group, the fentanyl concentrations of the three groups were not statistically di¡erent from each other. The mean plasma fentanyl concentrations for each of these three
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Transdermal fentanyl in cats CM Egger et al.
Figure 1 Mean plasma fentanyl concentration (mean SD) for cats from Group P (patch only; eight cats), Group P/A (patch and anesthesia; eight cats) and Group P/A/O (patch, anesthesia and ovariohysterectomy;12 cats). Patches were applied at 0 hour. Premedication, induction, maintenance, and recovery to extubation for groups P/A and P/A/O occurred from 11.5 to 13.5 hours. Patches were removed at 73 hours after patch placement in all three groups (PR ¼ patch removal).
groups were compared at 8,25,49, and 73 hours after patch application (Table 2). There was no statistically signi¢cant di¡erence among groups at any of these times. Table 3 shows data (mean SD) for each of the three groups (P, P/A, P/A/O) for time to ¢rst detectable
Table 3 Plasma concentration values and times, AUC and Kel for each group
plasma fentanyl concentration, time to reach maximum plasma fentanyl concentration, maximum plasma fentanyl concentration, mean plasma fentanyl concentration from 8 to 73 hours, elimination half-life, and total AUC. These parameters were not statistically di¡erent among the groups.
Parameter measured
Time (hours) to first detectable PFC Time (hours) to maximum PFC Maximum PFC (ng mL1) Mean PFC from 8 to 73 hours (ng mL1) Apparent t1/2 elimination (hours) (Harmonic mean and pseudo SD) Total AUC (ng hour mL1)
Group P
Group P/A/O
Group P/A/O
3.25 1.5 14.0 1.9 6.1 3.0 3.4 1.4
3.5 1.8 19.0 5.0 5.5 2.2 3.0 1.0
5.2 2.3 20.5 10.0 3.7 1.6 2.2 1.0
4.5 4.3
6.1 6.1
5.1 5.4
222.3 92.1
204 45.5
157.1 54.0
No significant difference between groups for any parameter. AUC: area under the concentration versus time curve; SD: standard deviation; PFC: plasma fentanyl concentration. Data are expressed as mean SD.
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Transdermal fentanyl in cats CM Egger et al.
Discussion Although there was a trend to lower plasma fentanyl concentrations achieved in groups P/A and P/A/O, anesthesia and anesthesia/ovariohysterectomy did not signi¢cantly alter the fentanyl concentrations achieved. Because alterations in cutaneous blood £ow and body and skin temperature can alter drug absorption, both halothane anesthesia and hypothermia could potentially result in a decrease in cutaneous blood £ow and impedance of drug absorption from a transdermal site (Longnecker 1984; Plezia et al.1989;Varvel et al.1989; Roy & Flynn1990; Jeal & Ben¢eld 1997), although this was not documented in this study. The time to ¢rst detectable plasma fentanyl concentration was not statistically di¡erent between the three groups of cats, although there was considerable individual variation (Table 3). The RIA is highly speci¢c for fentanyl, has no cross-reaction with metabolites of fentanyl, and has a limit of detection for fentanyl of 0.1 ng mL1 (Michiels et al. 1977; Schuttler & White 1984). Time to ¢rst detectable plasma fentanyl concentration in this study is considerably shorter in cats (3.25^6 hours) than dogs (13^ 16 hours), but slightly longer than in people (2 hours) (Plezia et al.1989; Egger et al.1998). In addition, the time to reach maximum plasma fentanyl concentrations (14^20.5 hours) is also less than in dogs (Schultheiss et al. 1995; Egger et al. 1998). In dogs, early absorption of fentanyl may be related to thickness of the cellular strata and epidermis of the skin, and di¡erences in skin thickness may account for the species variation seen in time to ¢rst detectable and maximum plasma fentanyl concentrations (Schultheiss et al.1995). In this study, no true steady state was achieved in any of the groups of cats due to the high degree of individual variability in plasma fentanyl concentrations while the patches were in place. Rather than investigate mean steady-state plasma fentanyl concentrations, this study looked at the mean plasma fentanyl concentration from 8 hours after patch application when it was believed that clinically signi¢cant plasma fentanyl concentrations were achieved in most cats, until 73 hours, when the patches were removed. There was no statistically signi¢cant di¡erence in this parameter between the three groups (see Table 3). Although the plasma fentanyl concentration required for analgesia in cats is undetermined, 1 ng mL1 is often quoted as analgesic in people. If 1 ng mL1 is also analgesic in cats, 234
most of the cats in all three groups had achieved analgesic levels by 8 hours, and maintained them until patch removal at 73 hours. A previous study evaluated the e¡ect of transdermal fentanyl patches on the minimum alveolar concentration (MAC) of iso£urane in cats, 24 hours after patch placement (Yackey et al.1997).While both 25 and 50 mg hour1 fentanyl patches signi¢cantly reduced iso£urane MAC by 24 hours, the investigators did not measure plasma fentanyl concentrations, making it impossible to compare plasma fentanyl concentrations in those cats with cats from this study. However, since there was signi¢cant MAC reduction by 24 hours, it is possible that there may also be signi¢cant analgesia obtained by 24 hours after patch placement. While the mean (8^73 hours) and maximum plasma fentanyl concentrations achieved in all groups of cats were quite high, the concentrations achieved and the degree of variability were comparable to those achieved in the studies by Lee et al. (2000) and Franks et al. (2000). In this study, total AUC and plasma fentanyl concentrations (Table 3) were considerably higher than those achieved in dogs in all previous studies (Schultheiss et al. 1995; Kyles et al.1996; Egger et al.1998). The apparent elimination half-life was also longer in cats (Table 3) than previously determined in dogs (Egger et al.1998). Cats have been shown to have a smaller volume of distribution and longer clearance for fentanyl compared to the dog, and this would certainly account for some of these species di¡erences (Lee et al. 2000). Di¡erences in cutaneous absorption due to dermal and/or epidermal thickness might also account for the higher values achieved in the cats in this study (Schultheiss et al. 1995).While it is certainly possible that the 25 mg hour1 patch size was too large for the cats in this study (3.0 1.3 kg), none of the cats demonstrated any signs of opioid overdosage or adverse e¡ects that might indicate fentanyl overdosage. The high degree of individual variability displayed in these cats is consistent with the results of numerous human and canine studies (Plezia et al. 1989; Schultheiss et al.1995; Kyles et al.1996; Jeal & Ben¢eld 1997; Egger et al. 1998; Franks et al. 2000; Lee et al. 2000). Variability in plasma fentanyl concentrations attained could arise from variations in drug release from the patch, absorption of drug across the epidermis and dermis, uptake by the cutaneous vasculature, and patient volume of distribution and metabolic clearance. The predicted delivery rate from transdermal fentanyl patches is subject to variation,
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with reported actual delivery rates in the range of 27^ 100% of the theoretical rate of delivery in dogs and 19^59% of the theoretical rate of delivery in cats (Kyles et al. 1996; Lee et al. 2000). Given the e¡ort in this study to treat each of the cats within a group as similarly as possible, this variability in plasma fentanyl concentrations is likely to be even greater within a clinical group of animals, with much greater variability in age, activity levels, hydration status, volume of distribution, and metabolic clearance. A previous study noted marked appetite suppression and loss of body weight in dogs with transdermal fentanyl patches applied (Schultheiss et al. 1995) and the authors have received anecdotal reports of inappetence in dogs and cats with the patches applied. In an attempt to determine if appetite suppression was a potential complication, we initially attempted to monitor food intake for all groups of cats. However, this proved very di⁄cult because of the di¡erences in fasting requirements for cats undergoing anesthesia and surgery. Body weights were monitored throughout the study, allowing comparison of pre- and post-study body weight and body weight changes among the nonsurgical groups (P, P/ A, A) and then among the surgical groups (P/A/O and A/O). As there were no statistically signi¢cant di¡erences in body weight or body weight changes among the groups, this could indicate that signi¢cant decreases in appetite and food intake did not occur in cats with transdermal fentanyl patches applied. In conclusion, the 25 mg hour1 fentanyl patches appeared to be well tolerated by all cats in the study, and no overt adverse e¡ects were noted. Anesthesia and anesthesia/ovariohysterectomy did not signi¢cantly alter the plasma fentanyl concentrations attained or the pharmacokinetic parameters measured. The high degree of individual variability observed both within and among groups of cats would suggest careful observation of cats with fentanyl patches in place is required both to assess the adequacy of analgesia and to detect any adverse e¡ects. Although the analgesic plasma fentanyl concentration for cats has not yet been determined, the average plasma fentanyl concentration was greater than 1 ng mL1 by 8 hours after patch placement in many cats, and by 12 hours after patch placement in the majority of the cats in the study. The results of this study would suggest that the 25 mg hour1 patch is an appropriate patch size for cats with a mean body weight of 3.0 kg (range 2.3^4.3 kg), the patches should be applied at least 12 hours before the time
analgesia is required, and supplemental analgesics should be provided in the interim.
Acknowledgements Supported by the University of Georgia Veterinary Medical Experiment Station and the American College of Veterinary Surgeons. The authors thank Dr Fred Thompson and Kenneth Smith for technical support and Guorong Chen for statistical support.
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