Field immobilization of feral 'Judas' donkeys (Equus asinus) by remote injection of medetomidine and ketamine and antagonism with atipamezole

The Judas technique is a method used for landscape control of feral donkeys (Equus asinus) in northern Australia. Central to the success of any Judas program is the safe, efficient, and humane attachment of the telemetry device. For feral donkeys, this involves the use of field immobilization. We examine the replacement of the current chemical capture agent, succinylcholine, with contemporary immobilization agents to achieve positive animal welfare outcomes. A combination of medetomidine and ketamine delivered by remote injection from a helicopter was used to capture 14 free-ranging feral donkeys for the fitting of telemetry collars in Western Australia in November 2010. Dose rates of 0.14 mg/kg medetomidine and 4.1 mg/kg ketamine were appropriate to immobilize animals in 9 min (± SD = 3). Mean recovery time (total time in recumbency) was 21 min (± 14). All animals recovered uneventfully after being administered atipamezole, a specific antagonist of medetomidine, intramuscularly at 0.35 mg/kg. Physiologic parameters were recorded during recumbency, with environment-related hyperthermia being the only abnormality recognized. No significant complications were encountered, and this drug combination represents an efficient approach to capturing wild donkeys. This new method allows a rapid, safe, cost-effective approach to the immobilization of feral donkeys for use as Judas animals. This drug combination will replace the relatively inhumane succinylcholine for the field immobilization of feral donkeys.     

Immobilization of Himalayan tahr with a xylazine-ketamine mixture and reversal with atipamezole under field conditions

Twenty-nine free-ranging Himalayan tahr (Hemitragus jemlahicus) were darted in the Sagarmatha National Park (Nepal) using different combinations of xylazine and ketamine. Animals in Group 1 (n = 4) received a mean xylazine-ketamine dose of 2.77 +/- 0.99 mg/kg xylazine plus 3.32 +/- 0.19 mg/kg ketamine in males and 2.39 +/- 0.10 mg/kg xylazine plus 4.29 +/- 0.17 mg/kg ketamine in females. Animals in Group 2 (n = 25) received a mean xylazine-ketamine dose of 1.70 +/- 0.41 mg/kg xylazine plus 3.06 +/- 0.74 mg/kg ketamine in males and 1.82 +/- 0.29 mg/kg xylazine plus 3.29 +/- 0.52 mg/kg ketamine in females. No anesthetic-related mortality was recorded. Anesthesia was reversed by a standard dose of 11 mg/animal of atipamezole administered by intramuscular injection. Although all anesthetic dosages immobilized free-ranging tahr successfully, a quick and smooth recovery was obtained (11.1 +/- 5.6 min) only with the dosages of Group 2.     

Reversible immobilization of eurasian otters with a combination of ketamine and medetomidine

The efficacy and safety of the combination of medetomidine and ketamine was examined in order to establish an adequate chemical immobilization protocol in the Eurasian otter (Lutra lutra) for use during translocation projects in Spain. Thirty-eight Eurasian otters ranging in body mass from 3 to 8.7 kg (mean 5.3 kg) were successfully anesthetized on 82 occasions. The dosage of ketamine was 5.1+/-0.8 (3.4-6.6) mg/kg (mean +/- SD; range) combined with medetomidine at a dosage of 51+/-8 Rg/kg (34-66 microg/kg). In most cases anaesthetic effect occurred within 3 min and the mean induction time was 5.5+/-3.2 min. The mean pulse rate was 95 beats/min. The mean respiratory rate was 32 respirations/min while the relative oxyhemoglobin saturation was 93%. According to these results, this anesthetic protocol is considered safe and can be recommended in wild caught Eurasian otters for immobilization during translocation projects. It is safe, rapid and can be reversed when needed with atipamezole. However caution is required as heart depression resulting in bradychardia may occur.     

Effects of repeated anaesthesia with ketamine/medetomidine and of pre-anaesthetic administration of buprenorphine in rats

Two groups of rats were anaesthetized at weekly intervals for 6 weeks with either ketamine/medetomidine alone (60 mg/0.4 mg/kg i.p.) or ketamine/medetomidine (45 mg/0.3 mg/kg i.p.) one hour following buprenorphine (0.05 mg/kg s.c.). Animals that received buprenorphine had longer periods of surgical anaesthesia (P = 0.04) and a greater depression of both mean pedal withdrawal score (P < 0.01) and mean respiratory rate (P = 0.014). Mean total duration of anaesthesia was also greater in the buprenorphine group on day 1. Sleep times reduced with successive doses of anaesthetic in the buprenorphine group (P = 0.024). Two animals in the buprenorphine group died. Repeated anaesthesia with ketamine/medetomidine alone was not associated with anaesthetic mortality. These results indicate that although buprenorphine has a clear anaesthetic-sparing effect, its use with ketamine/medetomidine may be associated with an increased risk of anaesthetic-related mortality.     

Reversal of medetomidine-ketamine combination anesthesia in rabbits by atipamezole.

This study was performed to determine the optimal reversal dosage of atipamezole on medetomidine-ketamine combination anesthesia. The subject rabbits were divided into five groups (n=5/group), and all were anesthetized with intravenous medetomidine (0.35 mg/kg) and ketamine (5 mg/kg). Atipamezole was administered intravenously 35 min after administration of the medetomidine-ketamine mixture, at doses of a quarter, a half, equal, or two times higher than the preceding medetomidine -ketamine dose according to experimental group. Heart rate (HR), mean arterial pressure (MAP), respiratory rate (RR) and rectal temperature (RT) were measured every five minutes and the mean arousal time (MAT) was also recorded. This study revealed that the optimal atipamezole dosage to achieve reversal effects is equal to or double the dose of medetomidine. At these dosages, HR and MAP significantly recovered and MAT was significantly shortened with no side effects being observed (p<0.05).     

Immobilization of free-ranging Hoffmann's two-toed and brown-throated three-toed sloths using ketamine and medetomidine: a comparison of physiologic parameters

Free-ranging Hoffmann's two-toed sloths (Choloepus hoffmanni; n=26) and brown-throated three-toed sloths (Bradypus variegatus; n=15) were manually captured and immobilized with 2.5 mg/kg ketamine + 0.02 mg/kg medetomidine administered intramuscularly. Physical examinations were conducted on each sloth 10 min after initial injection, and blood, fecal, and ectoparasite samples were collected. Heart rate, respiratory rate, body temperature, indirect systolic blood pressure, and indirect peripheral oxygen saturation were monitored every 5 min for the duration of anesthesia. After 45 min, atipamazole (0.1 mg/kg) was administered intramuscularly, as an antagonist to medetomidine, in order to facilitate recovery. All recoveries were smooth, rapid, and uneventful. Physiologic parameters were compared across time, gender, and species. All sloths, regardless of species and gender, demonstrated a time-dependent decrease in heart rate and blood pressure, and an increase in respiratory rate, during the course of anesthesia. Peripheral oxygen saturation was similar for all sloths over time. There were significant species differences for heart rate (Choloepus > Bradypus), respiratory rate (Choloepus > Bradypus), and systolic blood pressure (Bradypus > Choloepus), while there were significant gender differences for body temperature (males > females) and blood pressure (males > females). Results of this study suggest that the ketamine-medetomidine mixture, as described above, is a safe and effective anesthetic combination in free-ranging two- and three-toed sloths, although peripheral blood pressure should be monitored during anesthesia.     

Anesthesia of wild red howler monkeys (Alouatta seniculus) with medetomidine/ketamine and reversal by atipamezole

Wild red howler monkeys (Alouatta seniculus) were translocated during the flooding of the forest at a hydroelectric dam site in French Guiana. For a variety of minor clinical procedures, 96 monkeys were anesthetized with various intramuscular injections of combinations of medetomidine and ketamine. The howler population was composed of healthy animals (42 males and 54 females) of various ages. Medetomidine (150 μg/kg) associated with ketamine (4 mg/kg) gave the best results and was used on 63 animals. The injection rapidly resulted in complete immobilization with good to excellent myorelaxation. The induction stage was quiet, with absence of both corneal and pedal withdrawal reflexes in 57 animals after 2.9 ± 1.4 min. Six animals required an additional injection. Rectal temperature and respiratory and heart rates decreased during anesthesia, whereas relative oxyhemoglobin saturation increased. One death occurred during anesthesia. One abortion and one death also occurred the day following anesthesia but were more probably a result of capture stress. Atipamezole given i.m. at a dose of five times the medetomidine dose 38.4 ± 8.0 min after the anesthetic injection led to standing recovery in 7.1 ± 4.5 min. Spontaneous recovery occurred in 17 animals before the atipamezole injection after an average of 30.6 ± 9.6 min. Total recovery time was shorter in young animals. Medetomidine/ketamine induced good myorelaxation and provided considerably shortened immobilization duration, which are two notable advantages for field studies. We recommend this association for short procedures including minor surgery in red howler monkeys. Am. J. Primatol. 45:399–410, 1998. © 1998 Wiley-Liss, Inc.     

Short duration anaesthesia with medetomidine and ketamine in cynomolgus monkeys

Cynomolgus monkeys were anaesthetized with either intramuscular ketamine (10 mg/kg or intramuscular ketamine 2 mg/kg and medetomidine 50 microg/kg. Various physiological measurements were made once the animals were safe to handle and again 10 min later. Cardiovascular and respiratory function were well maintained with both regimens but the heart rate was lower and arterial-alveolar carbon dioxide gradient was higher in the animals that received medetomidine. In those animals that received medetomidine, atipamezole was given to reverse the medetomidine but there was no difference in recovery times between the two regimens. Anaesthesia was not entirely reliable with medetomidine/ketamine and we recommend caution when using this mixture.     

Immobilization of sika deer with medetomidine and ketamine, and antagonism by atipamezole

Forty wild sika deer (Cervus nippon) were immobilized with medetomidine and ketamine and reversed by atipamezole in summer and fall captures from September 1994 to October 1995. For large yearling and older deer, mean +/- SD doses of 57.0+/-15.6 microg/kg medetomidine and 1.64+/-0.49 mg/kg (male) or 4.02+/-1.16 mg/kg (female) of ketamine were administered by intramuscular injection. For calves and small yearlings, 69.3+/-7.0 microg/kg medetomidine and 2.69+/-0.44 mg/kg ketamine were administered. While immobilized, deer were easy to handle, and muscles were well relaxed. After intramuscular administration of atipamezole (about 5 times the dose of medetomidine), deer recovered rapidly and smoothly.     

Pentobarbital versus medetomidine-ketamine-fentanyl anaesthesia: effects on haemodynamics and the incidence of ischaemia-induced ventricular fibrillation in swine

The present study was performed to compare haemodynamic variables at baseline and the incidence of ventricular fibrillation during the early phase of ischaemia in swine during pentobarbital or medetomidine-ketamine-fentanyl anaesthesia. Twenty-two swine (mean +/- SD: 29+/- 3 kg) were anaesthetized with sodium pentobarbital (induction with 36 mg/kg intraperitoneally, and maintenance with 5-20 mg/kg/h intravenously [i.v.]) and 6 swine (27+/- 3 kg) were anaesthetized with ketamine and fentanyl (premedicated with medetomidine 0.1 mg/kg and ketamine 10 mg/kg intramuscularly, induction with ketamine 20 mg/kg and fentanyl 0.025 mg/kg i.v., and maintenance with ketamine 20 mg/kg/h and fentanyl 0.025 mg/kg/h i.v.). After a stabilization period of 30 min, the left anterior descending coronary artery (LAD) was occluded for 10 min. Haemodynamic data and occurrence of ventricular fibrillation were recorded. The ischaemic area was measured by fluorescing microspheres. Swine anaesthetized with medetomidine-ketamine-fentanyl had significantly lower heart rate, myocardial contractility, peak left ventricular pressure, arterial blood pressure, aortic blood flow, myocardial blood flow and cardiac index at baseline, than swine anaesthetized with pentobarbital. Whereas none of the swine anaesthetized with pentobarbital fibrillated during the LAD occlusion, ventricular fibrillation occurred in 83% of the animals anaesthetized with medetomidine-ketamine-fentanyl (P< 0.001). No significant difference was found in size of ischaemic area between the two groups. Thus, we show a depression in haemodynamic variables at baseline and a higher incidence of ventricular fibrillation during the early phase of ischaemia in swine anaesthetized with medetomidine-ketamine-fentanyl compared to swine anaesthetized with pentobarbital.     

Comparison of intravenous medetomidine and medetomidine/ketamine for immobilization of free-ranging variable flying foxes (Pteropus hypomelanus)

Medetomidine (0.03 mg/kg) and medetomidine/ketamine (0.05/5.0 and 0.025/2.5 mg/kg), administered by intravenous injection, were evaluated for short-term immobilization of wild-caught variable flying foxes (Pteropus hypomelanus). Medetomidine alone produced incomplete chemical restraint and a stressful, prolonged induction. Both ketamine/medetomidine doses produced a smooth induction and complete immobilization. The combined medetomidine/ketamine dose of 0.025/2.5 mg/kg produced a rapid induction (232±224 sec) with minimal struggling and vocalization, a complete and effective immobilization period, and tended to lead to a faster and better quality recovery than medetomidine alone or a higher dose of medetomidine and ketamine (0.05/5.0 mg/kg), thus reducing holding time and permitting an earlier release of the bat back into the wild.     

Capture and immobilization of wild brown palm civets in Western Ghats

A mixture of 15 mg/kg body weight ketamine hydrochloride (KE) and 1.5 mg/kg body weight xylazine hydrochloride (XY) was used to successfully immobilize free-ranging brown palm civets (Paradoxurus jerdoni). Between March 1998 and June 1999, 10 immobilizations of 7 individuals were carried out in tropical rainforests of the Kalakad-Mundanthurai Tiger Reserve (India). Five males and two females were captured in Havahart live traps, using banana as bait. The mean dosage for the animals, whose weight (mean +/- SD) was 2.4 kg +/- 0.8 was 36.0 +/- 11.0 mg KE and 3.7 +/- 1.1 mg XY, administered intramuscularly. Mean time for lateral recumbency was 6.1 +/- 3.78 min (n = 10) and the mean time taken for complete recovery was 84.9 +/- 28.8 min (n = 9). Recovery was gradual and no fatalities or injuries occurred during the operation. The drug combination used was effective and has the potential for immobilizing other viverrids.     

Transplacental transfer of medetomidine and ketamine in pregnant ewes

The extent of placental transfer of medetomidine and ketamine is unknown in pregnant ewes. Date-mated singleton (n = 8) and twin (n = 8) pregnant merino cross ewes were anaesthetized for Caesarean delivery of preterm lamb fetuses. A combination of medetomidine (20 μg/kg) and ketamine (10 mg/kg) was administered by intravenous injection and surgery performed immediately thereafter. Blood samples were collected from the ewe at one, five and 10 min after intravenous injection and from the umbilical vein of the fetus at delivery. Non-pregnant ewes were also anaesthetized (n = 8). There was no difference in the plasma concentration of medetomidine or ketamine when comparing singleton and twin ewes or pregnant and non-pregnant ewes for the short duration of the study. Fetal plasma concentrations of each drug were comparable to the maternal concentrations at the same time. We conclude that both drugs cross the placenta readily and provide anaesthesia and analgesia for the fetus when it is delivered.     

Anesthesia of boma-captured Lichtenstein's hartebeest (Sigmoceros lichtensteinii) with a combination of thiafentanil,medetomidine, and ketamine

A dose range was determined for anesthesia of recently boma-captured Lichtenstein's hartebeest (Sigmoceros lichtensteinii) (n = 13) with the synthetic opiate thiafentanil (THIA) (formerly called A3080) combined with medetomidine (MED) and ketamine (KET) in the Kasungu National Park, Malawi on 4 to 5 September 1999. The dose range of 11-29 micrograms/kg THIA (mean +/- SD = 21 +/- 4 micrograms/kg) combined with 5-10 mg/kg MED (8 +/- 1 micrograms/kg) plus 0.7-1.4 mg/kg KET (1.1 +/- 0.2 mg/kg) was found to be safe and effective for the field conditions associated with this study. The anesthesia produced by this drug combination was very predictable and characterized by a short induction time (3:34 +/- 1:20 min:sec), good muscle relaxation, and acceptable physiologic parameters for anesthesia periods ranging from 22:30-35:00 min:sec (31:14 +/- 2:50). Within the range of doses used in this study, times to onset of initial effects and recumbency were not dependent on THAI, MED, or KET doses. Anesthesia was rapidly and completely reversed by intravenous injections of naltrexone at 30 times the THAI dosage (0.69 +/- 0.19 mg/kg) and atipamezole at about four times the MED dosage (38 +/- 14 micrograms/kg). There was no residual effect from ketamine noted following reversal of THIA and MED and no mortality or morbidity was associated with this anesthetic regimen.     

Chemical immobilization of raccoons (Procyon lotor) with ketamine-medetomidine mixture and reversal with atipamezole

Safe and reliable capture techniques for wild animals are important for ecologic studies and management operations. We assessed the efficiency of ketamine-medetomidine (K:M) injection and reversal with atipamezole. We anesthetized 67 raccoons (Procyon lotor; 34 males, 33 females) 103 times (individuals captured between one and five times) from April 2009-October 2010 in Mont-Orford Provincial Park, Quebec, Canada. We administered a 1:1 mixture by volume of ketamine and medetomidine by intramuscular injection. Mean (±SD) induction times for males and females were 6.1±2.8 and 6.6±3.7 min, respectively. Mean induction time was 2 min longer for juveniles than for adults (7.8±3.9 and 5.8±2.9 min, respectively) and longer in autumn than in spring for adults (7.7±3.8 and 5.4±2.9 min, respectively). Recovery time after administration of atipamezole was 9.6±3.8 and 8.4±4.4 min for males and females, respectively. Recovery time was longer in spring than in autumn (10.2±4 and 7.4±3.8 min, respectively) for adults. Induction time increased by 166% after five captures of the same individual. Immobilization did not affect body mass, adult survival, or female reproductive success. We suggest the K:M mixture used is a safe and reliable method for anesthetizing raccoons in field conditions.     

Immobilization of California sea lions using medetomidine plus ketamine with and without isoflurane and reversal with atipamezole

The use of medetomidine and ketamine, alone and in combination with isoflurane, with atipamezole reversal was evaluated for immobilizing 51 California sea lions (Zalophus californianus) for a variety of medical procedures at a rehabilitation center in northern California (USA) between May 1997 and August 1998. Animals were given 140 microg/kg medetomidine with 2.5 mg/kg ketamine intramuscularly. Mean (+/-SD) time to maximal effect was 8+/-5 min. At the end of the procedure, animals were given 200 microg/kg atipamezole intramuscularly. Immobilization and recovery times were, respectively, 25+/-12 and 9+/-7 min for 35 animals maintained with medetomidine and ketamine alone and 58+/-30 and 9+/-9 min for 16 animals intubated and maintained with isoflurane. No mortalities occurred as a result of the immobilizations. Disadvantages of the medetomidine and ketamine combination included a moderate variation in time to maximal effect and plane of sedation, a large injection volume and high cost. However, this combination offers safe and reversible immobilization that can be easily administered by the intramuscular route and that produces a plane of anesthesia that is sufficient to carry out most routine diagnostic procedures.     

Field immobilization and euthanasia of American opossum

Seventeen recently trapped opossum, Didelphis virginiana, (median weight 2.45 kg; range = 1.6-5.0 kg; quartiles = 1.8-3.3 kg) were immobilized with either telazol (15 or 30 mg/kg) or a mixture of medetomidine (100 micrograms/kg), butorphanol (0.2 mg/kg), and ketamine HCl (10 mg/kg) based on estimated weights. Anesthetized animals were subjected to cardiac puncture for blood withdrawal and toe pinch. Euthanasia was accomplished by intracardiac administration of 1 ml of concentrated pentobarbital sodium/phenytoin solution. Weights were underestimated for 14 of 17 animals, but were within 0.5 kg of the actual weight. Both drug combinations provided rapid and calm immobilization. Median time to recumbency for the medetomidine-butorphanol-ketamine group (n = 5) was 6 min (range = 4-10 min; quartiles = 6 and 8 min). The median time to recumbency was not statistically different for the low (n = 6) and high dose (n = 6) telazol groups, 3 and 3.5 min respectively (quartiles 3; 3.5 and 4; 5.5 min). The stronger heart beat with telazol immobilization facilitated cardiac puncture. All five animals administered the medetomidine-butorphanol-ketamine mixture and three of six animals given the low telazol dose reacted to cardiac puncture. Only one of six animals given the estimated 30 mg/kg dose of telazol reacted slightly to cardiac puncture. We conclude that 30 mg/kg telazol provides sufficient immobilization and analgesia to allow accurate cardiac puncture of the opossum if the procedure is performed within 5 to 10 min of recumbency. Intracardiac administration of concentrated pentobarbital sodium/phenytoin solution followed by bilateral thoracotomy provides appropriate euthanasia suitable for field situations.     

Immobilization of Chacoan peccaries (Catagonus wagneri) using medetomidine, Telazol, and ketamine

A combination of medetomidine, Telazol, and ketamine hydrochloride was used to immobilize captive Chacoan peccaries (Catagonus wagneri) for translocation within Paraguay during August-October 2002. Animals were darted in enclosed areas of varying size. The average dose used was 32.5+/-7.2 microg/kg of medetomidine, 0.63+/-0.2 mg/kg of Telazol, and 3.9+/-0.65 mg/kg of ketamine. First effects were noted at 4.3+/-2.1 min, and ability to handle the animals was achieved by 12.6+/-3.7 min. Heart and respiratory rates declined and oxygen saturation increased during anesthesia. Muscle relaxation was good. Atipamezole was used to antagonize the medetomidine, although recoveries were still slow. This drug combination provided adequate immobilization of Chacoan peccaries; however, this protocol would not be considered to be reversible, and confinement during recovery is recommended.     

Optimal medetomidine dose when combined with ketamine and tiletamine-zolazepam to immobilize white-tailed deer

Chemical immobilization is often needed for safe and effective capture and handling of wildlife. We evaluated medetomidine (125, 150, 175, or 200 μg/kg; for synergistic effects and relaxation) mixed with ketamine (1.5 mg/kg; for relatively shorter recovery) and tiletamine-zolazepam (1.0 mg/kg; for rapid induction) in 22 female white-tailed deer (Odocoileus virginianus) at the University of Georgia Whitehall Deer Research Facility in Athens, Georgia, USA, on 14-15 and 21 May 2009. Deer were weighed before treatment, hand-injected intramuscularly (IM) while restrained in a squeeze chute, and released into a pen for monitoring. We measured rectal temperature, respiration rate, heart rate, hemoglobin saturation (using pulse oximetry), and arterial blood gases at 0, 10, and 20 min postimmobilization. We found no differences in induction time with different doses of medetomidine. Deer became laterally recumbent for all treatments combined at a median of 4.2 (2.6-21.3) min and were approachable by a median of 4.8 (3.5-21.8) min. Twelve of the 22 deer had rectal temperatures >40 C at time 0 and were treated with a cold-water enema. Hemoglobin saturation, estimated using pulse oximetry, was 79.5, 82.0, and 82.3% at times 0, 10, and 20, respectively. We injected atipamezole (0.35 mg/kg, IM) for reversal. Recovery occurred sooner and was more consistent for 125 and 150 μg/kg medetomidine whereby deer stood with minimal sedation to moderate ataxia within 60-90 min after atipamezole administration. We recommend using 150 μg of medetomidine with ketamine (1.5 mg/kg) and tiletamine-zolazepam (1.0 mg/kg) to provide effective and safe chemical immobilization of white-tailed deer.     

The influence of pre-anaesthetic administration of buprenorphine on the anaesthetic effects of ketamine/medetomidine and pentobarbitone in rats and the consequences of repeated anaesthesia

Rats received pentobarbitone (60, 48 and 36 mg/kg i.p.) or ketamine/medetomidine (75/100, 60/80 and 45/60 mg/microg/kg i.p.) alone, or one hour following buprenorphine (0.5 mg/kg s.c.). Animals were anaesthetized once per week for 6 weeks with one of three anaesthetic doses according to a randomized block design. In the pentobarbitone group, animals which received buprenorphine had longer sleep times (236 +/- 22 cf. 204 +/- 21 min) and longer durations of surgical anaesthesia (83 +/- 14 cf. 27 +/- 8 min) (P<0.01), these effects being potentiated with increasing anaesthetic doses (P<0.01). A greater degree of respiratory depression was found in animals that received buprenorphine (P<0.01) although this was judged clinically acceptable in all cases. Unexpectedly high mortality and a high incidence of anaesthetic complications (nine of 16 animals) in the ketamine/medetomidine group made statistical analysis of these data impossible. We conclude that for pentobarbitone, pre-anaesthetic administration of buprenorphine reduces the dose of anaesthetic required to produce surgical anaesthesia, in addition to the presumed benefits of pre-emptive analgesia. In view of the high mortality encountered, we advise caution when considering pre-anaesthetic use of opioids in combination with ketamine/medetomidine in rats.