Clinical Comparison of Medetomidine-butorphanol and Medetomidine-buprenorphine Combinations for Intravenous Premedication of General Anaesthesia in the Dog

Rau‰er P. , L. Lexmaulová: Clinical Comparison of Mmedetomidine-butorphanol and Medetomidine-buprenorphine Combinations for Intravenous Premedication of General Anaesthesia in the Dog. Acta Vet. Brno 2002, 71: 69-76. In this study we compared effects of medetomidine (10 μg/kg) with butorphanol (0.1 mg/kg) and medetomidine (10 μg/kg) with buprenorphine (0.01 mg/kg) used for intravenous premedication of general anaesthesia during surgical procedures in clinical practice. The combination of α-adrenergic substances and opioids induced within 5 min good or moderately good sedation. Anaesthesia was induced by intravenous administration of propofol to achieve loss of laryngeal reflex. General anaesthesia was maintained by a mixture of O2/N2O/halothane and, at moments of insufficient depth of anaesthesia, it was intensified by propofol re-administration. There was no difference in the dose of propofol for induction of anesthesia between abovementioned combinations used for premedication. The number of re-administrations and the total dose of propofol re-administered, however, were significantly (p < 0.05) lower when premedicating by buprenorphine. We found neither differences in respiratory and heart rates, nor in SpO2. We found significant (p < 0.05) differences in ETCO2 values at the end of anaesthesia, when its concentration was higher in dogs premedicated by the combination of medetomidinebuprenorphine. α-adrenergic drugs, opioids, analgesia, sedation, dog Painful surgical procedures in a patient are possible only with high-quality anaesthesia including good analgesia and myorelaxation. Premedication plays an important role in this respect, because analgesic and myorelaxant effects of substances used for premedication may have prime importance for the whole anaesthesia. Analgesia is also a parameter, which influences the postoperative period and recovery of the patient from anaesthesia. Analgesia and myorelaxation can be induced by a number of substances of which α2-adrenergic agonists and opioids belong to commonly used drugs recently. Medetomidine is a potent selective α2-adrenergic agonist that has sedative, myorelaxant and analgesic effects (Ko et al. 1996). The level of sedation and analgesia is dependent on the dose administered. Increments of the dose do not result in qualitative changes to the effect, only the duration of anaesthesia changes (Pypendop and Verstegen 1998). Following intravenous administration, medetomidine assumes action within 2 min; analgesia and sedation last approximately 45 and 60-90 min, respectively. Medetomidine has depressive cardiovascular (bradycardia, cardiac output drop, rise in systemic vascular resistance) and respiratory (bradypnoe) effects. Values of blood pressure, however, remain at the same level or are slightly elevated (Pypendop and Verstegen 1998; Pypendop and Verstegen 1999). Butorphanol is an opioid agonist-antagonist with good analgesic effects (Pfeffer et al. 1980). It induces only mild sedation and has minimum adverse effects to the cardiovascular system. It may cause mild lowering of the heart rate and arterial pressure or slight respiratory depression (Greene et al. 1990; Trim 1983). Its depressive action on respiratory system ACTA VET. BRNO 2002, 71: 69–76 Address for correspondence: MVDr. Petr Rau‰er Department of Surgery and Orthopedics, Small Animal Clinic, Faculty of Veterinary Medicine, University of Veterinary and Pharmaceutical Sciences Palackého 1-3, 612 42 Brno, Czech Republic Phone: +420 5 4256 2362 Fax + 420 5 4156 2344 E-mail: rauserp@vfu.cz http://www.vfu.cz/acta-vet/actavet.htm is, nevertheless, considerably lower than in morphine (Trim 1983; Hosgood 1990). The onset of butorphanol effects after intravenous administration is noted within minutes (e.g., after i.v. administration of 0.4 mg/kg it acts within 3 min). Its effects should last for 2 to 4 h (Hosgood 1990). Buprenorphine is a partial opioid agonist of a similar character as butorphanol but with higher analgesic potency. The onset of its action is later (15-30 min) and the analgesic effects last for a longer period (8-10 h). Apart from good analgesic effect, it is also characterised by mild sedative and cardiovascular depressive actions (Cowan et al. 1977; Martinez et al. 1997). Medetomidine administered alone induces sedation (Clarke and England 1989; Young et al. 1990). When combined with opioids, much lower doses are needed for the same sedation effect (Bartram et al. 1993; Bartram et al. 1994; Muir III et al. 1999). Young et al. (1990) mention the same level of sedation induced by a combination of medetomidine (10 μg/kg) with butorphanol (0.1 mg/kg) as after the use of medetomidine alone in the dose of 40 μg/kg. Muir III et al. (1999) consider the sedation by medetomidine alone in middleaged and older dogs as insufficient. The combination of medetomidine and butorphanol results in optimal sedation together with the subsequent reduction in doses of other anaesthetics needed for the induction and maintenance of anaesthesia. Higher levels and duration of analgesia after the use of reduced doses of medetomidine and opioids are mentioned by some other authors (Grimm et al. 2000; Ko et al. 2000; Ko et al. 1996; Muir III et al. 1999), who also emphasise the reduction of adverse effects of medetomidine to the cardiovascular system. The heart rate is, nevertheless, reduced up to 55% (Bartram et al. 1994) together with mild increase in the blood pressure (Ko et al. 1996). Analgesia following the administration of medetomidine-butorphanol combination lasts even for several hs after the procedure (Grimm et al. 1998). The level of sedation makes diagnostic and simple therapeutic procedures possible (Bartram et al. 1994). This study is aimed at clinical comparison of anaesthesia levels after premedication by combinations of medetomidine with butorphanol (a less potent and shorter acting opioid characterised by quick onset) and medetomidine with buprenorphine (a more potent and longer acting opioid characterised by slow onset). The dose of propofol used for the induction of anaesthesia or its prolongation at times of insufficient level of inhalation anaesthesia maintained by halothane was used as the main parameter for the evaluation of efficacy of the combination of α2-adrenergic substances with opioids. Materials and Methods Study group of animals In all, 60 dogs (32 males and 28 females) of 29 breeds at the age of 4.6 ± 3.9 years and weighing 31.6 ± 4.92 kg were included in the study. All the patients were clinically healthy. They were divided into two groups of 30 individuals. They were fasted for 24 h prior to the operation; water was supplied ad libitum. Standard clinical examination preceeded general anaesthesia. Anaesthesia was induced for the purpose of performing following surgical procedures: 30 orthopaedic operations (20 arthrotomies, 9 osteosynteses, 1 implant removal), 21 soft tissue surgeries (16 tumour and cyst excisions, 2 external ear canal ablations, 1 treatment of injury, 1 ventral hernia, 1 castration), 7 laparotomies (4 operations on the urogenital tract and 3 procedures on the gastrointestinal tract) and 2 neurosurgical operations (of the spine). Animals were randomly divided into two groups. Group A comprised 14 dog breeds including mongrels (19 males and 11 females, aged 4.11 ± 3.84 years, weighing 27.9 ± 12.36 kg). Animals of group A were subjected to 15 orthopaedic procedures, 10 soft tissue operations and 5 laparotomies. Group B comprised 15 dog breeds at the age of 5.2 ± 3.94 years and weighing 35.6 ± 16.67 kg. There were 14 males and 16 females in the group B. Group B animals were subjected to 15 orthopaedic procedures, 11 soft tissue surgeries, 2 laparotomies and 2 neurosurgical operations. Both groups comprised similar breeds of dogs. Four breeds (Schnauzer, mongrel, Terrier, Great Dane) were represented in each group. Protocol of the experiment To all animals we inserted an intravenous catheter into v. cephalica antebrachii or v. saphena lateralis (depending on the surgical site). This catheter was then used to administer the mixture of medetomidine (Domitor®) with butorphanol (Beforal®) (MED-BUT, group A) or medetomidine with buprenorphine (Temgesic®) (MED-BUP, 70

is, nevertheless, considerably lower than in morphine (Trim 1983;Hosgood 1990).The onset of butorphanol effects after intravenous administration is noted within minutes (e.g., after i.v.administration of 0.4 mg/kg it acts within 3 min).Its effects should last for 2 to 4 h (Hosgood 1990).
Buprenorphine is a partial opioid agonist of a similar character as butorphanol but with higher analgesic potency.The onset of its action is later (15-30 min) and the analgesic effects last for a longer period (8-10 h).Apart from good analgesic effect, it is also characterised by mild sedative and cardiovascular depressive actions (Cowan et al. 1977;Martinez et al. 1997).
Medetomidine administered alone induces sedation (Clarke and England 1989;Young et al. 1990).When combined with opioids, much lower doses are needed for the same sedation effect (Bartram et al. 1993;Bartram et al. 1994;Muir III et al. 1999).Young et al. (1990) mention the same level of sedation induced by a combination of medetomidine (10 µg/kg) with butorphanol (0.1 mg/kg) as after the use of medetomidine alone in the dose of 40 µg/kg.Muir III et al. (1999) consider the sedation by medetomidine alone in middleaged and older dogs as insufficient.The combination of medetomidine and butorphanol results in optimal sedation together with the subsequent reduction in doses of other anaesthetics needed for the induction and maintenance of anaesthesia.Higher levels and duration of analgesia after the use of reduced doses of medetomidine and opioids are mentioned by some other authors (Grimm et al. 2000;Ko et al. 2000;Ko et al. 1996;Muir III et al. 1999), who also emphasise the reduction of adverse effects of medetomidine to the cardiovascular system.The heart rate is, nevertheless, reduced up to 55% (Bartram et al. 1994) together with mild increase in the blood pressure (Ko et al. 1996).Analgesia following the administration of medetomidine-butorphanol combination lasts even for several hs after the procedure (Grimm et al. 1998).The level of sedation makes diagnostic and simple therapeutic procedures possible (Bartram et al. 1994).
This study is aimed at clinical comparison of anaesthesia levels after premedication by combinations of medetomidine with butorphanol (a less potent and shorter acting opioid characterised by quick onset) and medetomidine with buprenorphine (a more potent and longer acting opioid characterised by slow onset).The dose of propofol used for the induction of anaesthesia or its prolongation at times of insufficient level of inhalation anaesthesia maintained by halothane was used as the main parameter for the evaluation of efficacy of the combination of α 2 -adrenergic substances with opioids.

Study group of animals
In all, 60 dogs (32 males and 28 females) of 29 breeds at the age of 4.6 ± 3.9 years and weighing 31.6 ± 4.92 kg were included in the study.All the patients were clinically healthy.They were divided into two groups of 30 individuals.They were fasted for 24 h prior to the operation; water was supplied ad libitum.Standard clinical examination preceeded general anaesthesia.Anaesthesia was induced for the purpose of performing following surgical procedures: 30 orthopaedic operations (20 arthrotomies, 9 osteosynteses, 1 implant removal), 21 soft tissue surgeries (16 tumour and cyst excisions, 2 external ear canal ablations, 1 treatment of injury, 1 ventral hernia, 1 castration), 7 laparotomies (4 operations on the urogenital tract and 3 procedures on the gastrointestinal tract) and 2 neurosurgical operations (of the spine).
Animals were randomly divided into two groups.Group A comprised 14 dog breeds including mongrels (19 males and 11 females, aged 4.11 ± 3.84 years, weighing 27.9 ± 12.36 kg).Animals of group A were subjected to 15 orthopaedic procedures, 10 soft tissue operations and 5 laparotomies.Group B comprised 15 dog breeds at the age of 5.2 ± 3.94 years and weighing 35.6 ± 16.67 kg.There were 14 males and 16 females in the group B. Group B animals were subjected to 15 orthopaedic procedures, 11 soft tissue surgeries, 2 laparotomies and 2 neurosurgical operations.Both groups comprised similar breeds of dogs.Four breeds (Schnauzer, mongrel, Terrier, Great Dane) were represented in each group.

Protocol of the experiment
To all animals we inserted an intravenous catheter into v. cephalica antebrachii or v. saphena lateralis (depending on the surgical site).This catheter was then used to administer the mixture of medetomidine (Domitor ® ) with butorphanol (Beforal ® ) (MED-BUT, group A) or medetomidine with buprenorphine (Temgesic ® ) (MED-BUP, group B) in one syringe.We used following doses: medetomidine 10 g/kg (group A and B), butorphanol 0.2 mg/kg (group A) and buprenorphine 0.01 mg/kg (group B).
The mixture was injected and five min later, after the onset of its effect, the level of sedation was assessed.It was classified as good (level 1), moderately good (level 2) or poor (level 3).Good sedation was such a state when the animal resumed lateral recumbence and it was easy to handle without any defence reactions.Moderately good sedation was such a state when the animal took up lateral or sternal recumbence, handling, however, resulted in defence responses.Poor sedation resulted in the animal not resuming either lateral or sternal recumbence, reacting by defence responses and being able to walk (with a various degree of ataxia).Occurrence of adverse reactions of both substances with regard to possible excitations was carefully monitored during the onset of sedation.
After the onset of sedation, animals were intravenously administered propofol (Propofol Abbott ® ) in the dose necessary to result in loss of laryngeal reflex that enabled endotracheal intubation.Animals were then put on a halfclosed breathing circuit of the inhalation machine Anemat N8 (Chirana) and supplied with a mixture of oxygen, nitrous oxide and halothane (Narcotan ® ).The concentration of halothane in the breathing system was maintained at 1.5% during the anaesthesia.The animals that were wakening due to insufficient depth of anaesthesia (movements, rise in heart and respiratory rates) were re-administered propofol, even repeatedly if needed, in the dose necessary to the loss of responses.The number of re-administrations and the total dose of propofol were recorded.
Animals were monitored during the anaesthesia using the Cardiocap II (Datex-Ohmeda) machine.Every 10 min following the administration of sedatives (MED-BUT, MED-BUP) we recorded heart and respiratory rates (HR, RR), tissue saturation by oxygen (SpO 2 ) and the level of CO 2 in expired gasses (ETCO 2 ).Individual parameters were recorded for 70 min, i.e., the duration of medetomidine action (Pypendop and Verstegen 1998;Pypendop and Verstegen 1999).
Statistical evaluation included comparison of parameters characterising both groups of animals (age and weight) as well as parameters measured during the anaesthesia (HR, RR, SpO 2 and ETCO 2 ).Comparison also included the level of sedation and doses of propofol used for the induction of anaesthesia and during re-administrations.We also compared both groups with regard to the number of individual re-administrations of propofol.Regarding frequent disagreement of data with normal distribution, non-parametric methods were used for the statistical evaluation.As there were no paired data in the samples compared, we used the Mann-Whitney test.

Level of sedation
In both groups good and moderately good levels of sedation were achieved in 84% (25 individuals in group A, 25 cases in the group B) and 16% (5 individuals in group A, 5 cases in group B) of patients, respectively.There was no case of poor sedation in any group recorded.The level of sedation was the same in both groups of patients without statistical differences (Table 1).

Dose of propofol
All animals in group A animals were administered propofol in order to achieve the loss of laryngeal reflex.As far as animals in the group B are concerned, propofol was not used in two dogs of this group to induce anaesthesia.The average dose of propofol administered Table 1 Level of sedation, propofol dose for induction, number of re-administrations and the total dose of propofol as parameters for the evaluation of combinations of medetomidine-butorphanol (group A) and medetomidine-buprenorphine (group B) used for the premedication of general anaesthesia in dogs.

Parameters evaluated
Group A Group B Level of sedation (levels 1, 2, 3) Propofol dose for induction (mg/kg)

Number of readministrations
Total dose of propofol readministered (mg/kg) to induce anaesthesia in both groups A and B amounted to 1.3 ± 0.52 mg/kg and 1.1 ± 0.51 mg/kg (Table 1), respectively.There was no significant difference in the dose of propofol administered to induce anaesthesia between group A and B. The mean number of readministrations during the 70-minute anaesthesia amounted to 1.1 ± 1.31 and 0.4 ± 0.72 (Table 1) in groups A and B, respectively.The total dose of propofol re-administered during the same period amounted to 1.1 ± 1.69 mg/kg and 0.3 ± 0.52 mg/kg (Table 1) in groups A and B, respectively.There were differences in the number of re-administrations and the total dose of propofol re-administered between both groups.Values in group A (MED-BUT) were statistically significantly higher (p < 0.05) than in group B (MED-BUP).

Heart and respiratory rates, SpO 2
There were no significant differences between both groups (Fig 1 and 2) in heart or respiratory rates monitored during the 70-min anaesthesia.None of the seven measured time intervals showed significant difference from its counterpart.The value of SpO 2 (Fig 1 and 2) showed no significant differences.

ETCO 2
At the beginning of recording, there were no significant differences between group A and B in the concentration of CO 2 in the expired air (ETCO 2 ).At the 50 th and 60 th min of inhalation anaesthesia, however, the concentration of CO 2 in group B (MED-BUP) was significantly higher (p < 0.05) than in group A. Fig. 4 show that at the 70 th minute of anaesthesia the difference was even highly significant (p < 0.01).

Discussion
The level of sedation achieved by the administration of medetomidine with butorphanol or medetomidine with buprenorphine was very good in our patients as in those of Bartram et al. (1994) or Muir III et al. (1999).In both groups of patients 84% took up lateral recumbence and allowed handling without any defence responses.We observed no adverse reactions during the onset of sedation.Good or moderately good sedation effects started in most animals up to the time of its evaluation, i.e., within 5 min.Sedative effects of medetomidine after intravenous administration are noted within 2 min (England and Clarke 1989).Effects of butorphanol start also within several min (Hosgood 1990).time after induction (min) medetomidine-butorphanol medetomidine-buprenorphine respiratory rates (breaths per minute) Fig. 2. Changes in respiratory rates (RR) in combinations of medetomidine 10 µg/kg + butorphanol 0.1 mg/kg and medetomidine 10 µg/kg + buprenorphine 0.01 mg/kg used for the premedication of general anaesthesia in dogs.
Effects of buprenorphine, however, are noted much later, i.e., after 15 to 30 min (Covan et al. 1977) which do not fall to our time interval of sedation evaluation.It can, thus, be stated that the main criterion for the onset of sedation evaluated after 5 min of intravenous administration of both substances is the dose and way of medetomidine administration.Animals obtaining the combination of medetomidine with butorphanol were after five min under the influence of both substances, while those obtaining medetomidine with buprenorphine showed only effects of medetomidine.Medetomidine causes sedation of high quality (K o et al. 1996).Sedation after the use of butorphanol or buprenorphine is considered variable (Hosgood 1990;Covan et al. 1977).As far as the post-op period is concerned, buprenorphine induces analgesia of the same quality as morphine, however, without the outlasting sedation (Brodbelt et al. 1997).Effects of buprenorphine last longer than with butorphanol (Cowan et al. 1977).
The combination of medetomidinbutorphanol has good analgesic, sedative and muscle relaxing effects.This combination induces deep sedation, sufficient for performing procedures of intermediate level of pain, such as radiography of the hip and stifle joint instability (Neãas and Toombs 1999;Toombs and Neãas 1999;Zatloukal et al. 2000).Sufficient analgesia and muscle relaxation is essential for such examinations because it enables measurement of the passive joint laxity.The combination of α-adrenergic substances with opioids for the induction of general anaesthesia is suitable in neurosurgical patients, in particular, in which good sedative and analgesic effects can be employed, for example, for puncturing the subarachnoidal space as a part of diagnosing intervertebral disc disease in dogs (Neãas and Sedláková 1999).
There was no difference in the dose of propofol administered for the induction of anaesthesia (necessary for the laryngeal reflex loss) between the groups.The fact is attributable to the equal sedative action of medetomidine with minimum influence of the opioids.The number of re-administrations of propofol as well as the total dose readministered during the 70-min evaluation differed between the groups with statistical significance (p < 0.05).In group A propofol was re-administered more frequently and in a considerably higher dose.It may be related to analgesic action of both substances because in butorphanol it is lower than in buprenorphine (Pypendop et al. 1996a).For very painful surgical procedures it is better to use more potent buprenorphine, which induces better analgesia and thus lowers the need of propofol re-administration.It is also in relation with the time of buprenorphine action onset, because surgical procedures usually did not start earlier than 15 min after the administration, i.e. after the onset of its effects (Cowan et al. 1977).Butorphanol (Hosgood 1990) should also be in action at the start of the operation so it is possible to compare the effect of both substances administered together with medetomidine.
There were no significant differences between individual groups in the heart or respiratory rate.No statistically significant differences were found in values of SpO 2 .Medetomidine administered in the dose of 40 µg/kg caused cardiovascular depression characterised by bradycardia, in particular.The combination of α-adrenergic substances with opioids can be recommended for the premedication of general inhalation anaesthesia in dogs that are otherwise healthy such as many orthopedic patients.In this case it is possible to employ benefits of these substances without increasing the risk of anaesthesia by their cardiodepressive effects.In small animal practice patients suffering from diseases of the locomotor apparatus are rather numerous (Dvofiák et al. 2000;Neãas 1999;Neãas et al. 1999;Neãas et al. 2000), so the number of patients premedicated by α-adrenergic substances in combination with opioids is relatively high.There is no doubt that the reduction of medetomidine dose to 10 µg/kg results in decreasing of adverse cardiodepressive effects even though they may persist.This is evidenced by some heart rate reduction by the above-mentioned lower dose (B artram et al. 1994).In the framework of our study we noticed some drop in the heart rate in larger dog breeds, in particular.We did not, however, compare the pre-anaesthetic heart rates and those ones during the anaesthesia.
The level of ETCO 2 mirrors PaCO 2 in the blood, which reflects lung exchange of CO 2 based on sufficient lung ventilation and blood perfusion (H a s k i n s 1996).Changes of ETCO 2 are thus reflecting lung ventilation together with cardiovascular apparatus function.Pypendop et al. (1996) compared combinations of medetomidinemidazolam-butorphanol and medetomidine-midazolam-buprenorphine.They mention cardiorespiratory depressive actions of both combinations used, which are characterised by heart rate drop and PaCO 2 elevations.They found considerably more profound action of buprenorphine.It is also evident from our results on medetomidine and buprenorphine that the level of ETCO 2 (reflecting in relation to ventilation, which was stable, the level of PaCO 2 ) was significantly higher at the 50 th and 60 th min of anaesthesia and at the 70 th min it was even higher with high significance.It may correspond with a more profound action of buprenorphine to the cardiovascular system mentioned by P y p e n d o p et al. (1996).This action, however, is not clinically important in healthy dogs (M a r t i n e z et al. 1997).Significant differences in ETCO 2 observed only at the 50 th , 60 th and 70 th min might evidence later onset of buprenorphine with a 15-30 min delay as compared to butorphanol.There were, however, no significant differences in the ETCO 2 values measured in individual groups at the 30 th and 40 th min (Fig. 4).
The intravenous administration of medetomidine with butorphanol and buprenorphine, respectively, for the purpose of general anaesthesia premedication induces high-quality sedation with quick onset and considerably reduces the dose of anaesthetics administered during the surgical procedure.It is especially evident when using buprenorphine, which, however, results in the rise of ETCO 2 during the anaesthesia.