BUTORPHANOL TARTRATE

3. History Morphine was isolated first in 1806 by Sertüner Codeine was discovered in 1832 In 1848 Introduction of Papaverine Between 1940 and 1950 synthetic substances were introduced into clinical medicine (meperidine, methadone) In the late 1950‘s Nalorphine was used for analgesia: serious side effects like anxiety and dysphoria In 1975 Butorphanol was synthesised by Monkovic In 1806 morphine was discovered by Sertüner, a swiss citizen who isolated the substance out of opium and named it after the greek god of dreams. Shortly later other natural occuring alkaloids codeine and papaverine were introduced into the medical world and tried to be used for medical purposes. They showed a lot of unwanted side effects, due to their structure, their side chains and affinity to different receptor types, so research went on. Synthetic substances were introduced a little bit later. Meperidine which is still used in Canada and USA as an opioid analgesic and methadone currently used in France Austria and the USA as an analgesic for the detoxification of addicts. In the 1950-ties Nalorphine as a synthetic substance was introduced into medicine (and veterinary medicine a little bit later) it is an antagonist to morphine action an prevented sucessfully respiratory depression. But it produced still some severe side effects like anxiety and dysphoria In 1975 butorphanol was synthesised by a Canadian called Monkovich and this was a really new approach, using a sysnthetic substance with partly agonistic and partly agonistic actions on the opiate receptors.In 1806 morphine was discovered by Sertüner, a swiss citizen who isolated the substance out of opium and named it after the greek god of dreams. Shortly later other natural occuring alkaloids codeine and papaverine were introduced into the medical world and tried to be used for medical purposes. They showed a lot of unwanted side effects, due to their structure, their side chains and affinity to different receptor types, so research went on. Synthetic substances were introduced a little bit later. Meperidine which is still used in Canada and USA as an opioid analgesic and methadone currently used in France Austria and the USA as an analgesic for the detoxification of addicts. In the 1950-ties Nalorphine as a synthetic substance was introduced into medicine (and veterinary medicine a little bit later) it is an antagonist to morphine action an prevented sucessfully respiratory depression. But it produced still some severe side effects like anxiety and dysphoria In 1975 butorphanol was synthesised by a Canadian called Monkovich and this was a really new approach, using a sysnthetic substance with partly agonistic and partly agonistic actions on the opiate receptors.

4. Butorphanol Tartrate This slide shows the close relationship between Morphine as the „source-substance“ and Butorphanol at the on hand, and the close relationship of all morphine derivates in general. Nalorphine is the substance with the morphine antagonistic features and especially effective against respiratory depression. The substance on the right side down is of great importance: Naloxone is a pure antagonist on all receptors and therefore is THAT antidote for all morphine like drugs available. Now we jump into pharmacology....This slide shows the close relationship between Morphine as the „source-substance“ and Butorphanol at the on hand, and the close relationship of all morphine derivates in general. Nalorphine is the substance with the morphine antagonistic features and especially effective against respiratory depression. The substance on the right side down is of great importance: Naloxone is a pure antagonist on all receptors and therefore is THAT antidote for all morphine like drugs available. Now we jump into pharmacology....

5. Pharmacology Total synthetic morphinan with narcotic agonistic-antagonistic features Potent analgesic properties Proposed effects by binding on endogenous opioid receptors: Especially the pharmacodynamics of Butorphanol: As we said it is a synthetic agonistic antagonistic acting morphinan but what for can it be used? It is a potent analgetic, showing a broad safety spectrum as we want see later. Therefore it can be used as monotherapeutic agent in horses and small animals to prevent pain, but also in combination with other substances as a preanaesthetic agent. It works by activating opioid receptors! Where are these receptors located? Most of them can be found in the brain and spinal cord, but some of them are also present in the periphery, for example in the gastrointestinal tract. Normally they react with endogenous physiological endorphins, like encephalin and metencephalin, but they are also able to interact with systemically administered therapeutically used opioids like Butorphanol.Especially the pharmacodynamics of Butorphanol: As we said it is a synthetic agonistic antagonistic acting morphinan but what for can it be used? It is a potent analgetic, showing a broad safety spectrum as we want see later. Therefore it can be used as monotherapeutic agent in horses and small animals to prevent pain, but also in combination with other substances as a preanaesthetic agent. It works by activating opioid receptors! Where are these receptors located? Most of them can be found in the brain and spinal cord, but some of them are also present in the periphery, for example in the gastrointestinal tract. Normally they react with endogenous physiological endorphins, like encephalin and metencephalin, but they are also able to interact with systemically administered therapeutically used opioids like Butorphanol.

6. Opioid Receptors Here you see a table with the currently known receptors in the first column, their location in the second column and their proposed actions in the third column. Column 1: at the moment 4 receptor types are known, the mu and kappa receptors showing subtypes which are very impotant in interaction with butorphanol. Column 2: mu receptors-subtypes are located and active on different sites of the CNS, for the others it is clear that they are working mainly on supraspinal and spinal levels. Their effects are shown to be analgesia, influence on the cardiovascular, respiratory and gastrointestinal system, where they evoke different actions, being explained in detail later. They also effect physical dependence (addictive behaviour) and lead to euphoria. The most important columns are the next three ones showing the affinity of different morphine like drugs to these receptors. Morphine for example is thought to be a pure agonist, binding preferably on mu receptors and only to a very small extent on kappa receptors. Investigations in dogs confirmed that activation of mu receptors lead to mainly supraspinal analgesia, respiratory depression, euphoria, decreased gastrointestinal motility and physical dependance. Butorphanol, listed in the fifth column showes ist greates affinity to the kappa receptor, which is believed to be of primary importance in analgesia. There it acts as an agonist, by this way producing potent spinal analgesia. Kappa receptors are also known to produce sedation and here the three subtypes come into play: Kappa 1 is the main target of Butorpahnol, by this way having more influence on analgesia, while the other two subtypes Kappa 2 and –3 are thought to be responsible to a greater extent for th accompanying sedation. Butorphanol action on mu receptors is antagonistic, affecting mainly mu 2receptors, but it shows also minimal agonistic action on mu 1 receptors. On delta receptors it works agonistic as it does on sigma receptors, the first producing further analgesia the latter stimulating the respiratory system. Again: Naloxone and naltrexone are ure antagonists and naloxone (in Europe known under the trade name narcanti) is an antidote to Butorphanol and other morphine like drugs activity. The compete with the opioids and once the receptor is blocked no further action of the oipiods can be provoked.Here you see a table with the currently known receptors in the first column, their location in the second column and their proposed actions in the third column. Column 1: at the moment 4 receptor types are known, the mu and kappa receptors showing subtypes which are very impotant in interaction with butorphanol. Column 2: mu receptors-subtypes are located and active on different sites of the CNS, for the others it is clear that they are working mainly on supraspinal and spinal levels. Their effects are shown to be analgesia, influence on the cardiovascular, respiratory and gastrointestinal system, where they evoke different actions, being explained in detail later. They also effect physical dependence (addictive behaviour) and lead to euphoria. The most important columns are the next three ones showing the affinity of different morphine like drugs to these receptors. Morphine for example is thought to be a pure agonist, binding preferably on mu receptors and only to a very small extent on kappa receptors. Investigations in dogs confirmed that activation of mu receptors lead to mainly supraspinal analgesia, respiratory depression, euphoria, decreased gastrointestinal motility and physical dependance. Butorphanol, listed in the fifth column showes ist greates affinity to the kappa receptor, which is believed to be of primary importance in analgesia. There it acts as an agonist, by this way producing potent spinal analgesia. Kappa receptors are also known to produce sedation and here the three subtypes come into play: Kappa 1 is the main target of Butorpahnol, by this way having more influence on analgesia, while the other two subtypes Kappa 2 and –3 are thought to be responsible to a greater extent for th accompanying sedation. Butorphanol action on mu receptors is antagonistic, affecting mainly mu 2receptors, but it shows also minimal agonistic action on mu 1 receptors. On delta receptors it works agonistic as it does on sigma receptors, the first producing further analgesia the latter stimulating the respiratory system. Again: Naloxone and naltrexone are ure antagonists and naloxone (in Europe known under the trade name narcanti) is an antidote to Butorphanol and other morphine like drugs activity. The compete with the opioids and once the receptor is blocked no further action of the oipiods can be provoked.

7. Summary Agonistic action: ?-receptors: analgesia (cortical levels) d-receptors: analgesia s-receptors: stimulating respiratory drive Antagonistic action: µ-receptors: little or no euphoria, very low dependence potential Reversal possible with Naloxone: µ-receptor antagonist ?-receptor antagonist d-receptor antagonist This slide is a summary of Butorphanol‘s actions: It can be concluded that Butorphanol resembles morphine in its analgesic properties, and nalorphine with respect of antagonism to opiate side effects and physical dependence potential. This features (potent sedation in combination with mild sedation) makes butorphanol a very useful tool for a veterinarian either as an analgesic or as an preanaesthetic.This slide is a summary of Butorphanol‘s actions: It can be concluded that Butorphanol resembles morphine in its analgesic properties, and nalorphine with respect of antagonism to opiate side effects and physical dependence potential. This features (potent sedation in combination with mild sedation) makes butorphanol a very useful tool for a veterinarian either as an analgesic or as an preanaesthetic.

8. Pharmacokinetics Absorption: In horses (0.1mg/kg): peak serum concentrations: 342.5 ± 42.5ng/ml after iv.administration: in about 15 minutes Analgesic activity as long as plasma concentration above 20 to 30ng/ml. Mean duration of analgesic activity 75 ± 14 and 92 ± 19 minutes (data from own study). Now let us take a glance on the pharmacokinetics of Butorphanol: Firslty we will take about PK in horses then in small animals (especially dogs and cats) After iv administration absorption begins immediately and full onset of action after administration of the recommended dose of 0.1mg/kg can be expected after about 10 to 15 minutes, then decreasing slowly. Peak plasma concentrations are about 340 to 380 ng/ml. At this point of the presentation I would like to point out that nearly all of the pharmacokinetic parameters in horses were taken from our own study, which we performed last year in cooperation with the university of veterinary medicine in Vienna. (only one further PK study in horses is available in literature, performed in 2001). Now going back to analgesic activity – duration of action can be expected as long as plasma concentration is above 30 to 20 ng/ml, which brings a mean duration of analgesia of about 70 to 100 minutes.Now let us take a glance on the pharmacokinetics of Butorphanol: Firslty we will take about PK in horses then in small animals (especially dogs and cats) After iv administration absorption begins immediately and full onset of action after administration of the recommended dose of 0.1mg/kg can be expected after about 10 to 15 minutes, then decreasing slowly. Peak plasma concentrations are about 340 to 380 ng/ml. At this point of the presentation I would like to point out that nearly all of the pharmacokinetic parameters in horses were taken from our own study, which we performed last year in cooperation with the university of veterinary medicine in Vienna. (only one further PK study in horses is available in literature, performed in 2001). Now going back to analgesic activity – duration of action can be expected as long as plasma concentration is above 30 to 20 ng/ml, which brings a mean duration of analgesia of about 70 to 100 minutes.

9. Pharmacokinetics In dogs and cats (0.25mg/kg): peak serum concentrations: about 29ng/ml after iv. administration: very shortly after i.m. administration about 40 min. after s.c. administration 28 min. Duration of analgesia: about one hour in dogs. 350 minutes ±10 minutes in cats (visceral analgesia after 0.1mg/kg administration). In small animals Butrorphanol can be administred in different ways. Intravenously, intramuscularly and subcutaneously. After iv administration of a 0.25mg/kg dose, action begins almost immediately, if administration is sc or im absorption begins immediately. Peak serum concentrations are about 29ng/ml, reached after 40 minutes (im) or 28 minutes (sc). Concerning cats animal specific data are hardly available in literature, in one scientific article it was stated that PK in dogs and cats are quite similar! Duration of analgesia was found to last about one hour in dogs (measured by duration of the sedative effect) and about 6 hours in cats (visceral analgesia).In small animals Butrorphanol can be administred in different ways. Intravenously, intramuscularly and subcutaneously. After iv administration of a 0.25mg/kg dose, action begins almost immediately, if administration is sc or im absorption begins immediately. Peak serum concentrations are about 29ng/ml, reached after 40 minutes (im) or 28 minutes (sc). Concerning cats animal specific data are hardly available in literature, in one scientific article it was stated that PK in dogs and cats are quite similar! Duration of analgesia was found to last about one hour in dogs (measured by duration of the sedative effect) and about 6 hours in cats (visceral analgesia).

10. Pharmacokinetics Protein-Binding: Basing on in-vivo data, about 80% low bioavailability due to significant first pass effect in the liver! Distribution: Major distribution tissues: liver, kidney, intestine Highly perfused tissues: lung, spleen, heart, endocrine tissues Further PK parameters are: Estimated protein binding is high, distribution is rapid in horses and small animals as well!Further PK parameters are: Estimated protein binding is high, distribution is rapid in horses and small animals as well!

11. Pharmacokinetics Half times: In horses: distribution half life 1.8 (±2.8) minutes elimination half life 27.9 (±7.8) minutes final elimination half life 217.3 (± 171) minutes In dogs and cats: absorption half life 5.7 and 6.8 minutes (i.m., s.c. administration) mean serum half life 1.62 hours Plasma half times were taken from our own study again, after administration of a 0.1mg/kg dose intravenously.Plasma half times were taken from our own study again, after administration of a 0.1mg/kg dose intravenously.

12. Pharmacokinetics Metabolism: In horses and small animals: Extensive metabolism in liver by several processes: ? hydroxylation ? O-dealkylation ? conjugation with glucuronide Metabolites: In horses and small animals: ? Hydroxybutorphanol ? Norbutorphanol Both of them are inactive Metabolism is rather fast in all species investigated: Due to the rather complex structure of the molecule more metabolizing steps are necessary to make it excretable:Metabolism is rather fast in all species investigated: Due to the rather complex structure of the molecule more metabolizing steps are necessary to make it excretable:

13. Pharmacokinetics Excretion: In all species investigated: In horses half of a 0.1mg/kg dose is eliminated after 44 minutes Major route of elimination is renal (small animals: 86%). to a smaller extent faecal ( about 14% in dogs and cats). Excretion is fast as well in all species investigated:Excretion is fast as well in all species investigated:

14. Indications Horses: Monotherapeutic Use: ? Analgesic for abdominal pain especially for horses suffering from moderate to severe pain due to enteric volvulus and colic. ? Analgesic Premedication for horses undergoing painful surgical intervention. Now we come to the point which is most interesting for horse practitioners: Just to explain: firstly we will talk about indications and dosage in horses then we will focus on indications and dosages of small animals Well, Butorphanol has been proven to be very successful as a monotherapeutic agent in horses suffering from painful abdominal conditions. Especially in colics emerging from impaction, intussusception, torsion, spasmodic, tympanic ad postpartum colic. It can be used as already mentioned as an analgesic premedication for painful surgical interventions like fracture fixation and arthroscopy. Very important: in the recommended dose it proved to reduce the need for further postsurgical analgesia!Now we come to the point which is most interesting for horse practitioners: Just to explain: firstly we will talk about indications and dosage in horses then we will focus on indications and dosages of small animals Well, Butorphanol has been proven to be very successful as a monotherapeutic agent in horses suffering from painful abdominal conditions. Especially in colics emerging from impaction, intussusception, torsion, spasmodic, tympanic ad postpartum colic. It can be used as already mentioned as an analgesic premedication for painful surgical interventions like fracture fixation and arthroscopy. Very important: in the recommended dose it proved to reduce the need for further postsurgical analgesia!

15. Saw Horse Stands due to colic This picture is surely very familiar to horse practitioners! The classic saw horse stand and the messed horse rug , in this case with saw mill waste from rolling on the floor is some kind of pathognomic for abdominal pain due to colic. A classical indication for an analgesic: one that reliefes or alleviates pain, This picture is surely very familiar to horse practitioners! The classic saw horse stand and the messed horse rug , in this case with saw mill waste from rolling on the floor is some kind of pathognomic for abdominal pain due to colic. A classical indication for an analgesic: one that reliefes or alleviates pain,

16. Ileus .......but does not mask the need for surgery. For instance in the case of ileus! Butorphanol has been proven not to mask necessary surgical intervention, by this way being ideal not only for first aid but also for example for transport from the stable to the operation theatre........but does not mask the need for surgery. For instance in the case of ileus! Butorphanol has been proven not to mask necessary surgical intervention, by this way being ideal not only for first aid but also for example for transport from the stable to the operation theatre.

17. Indications Horses: Combination Use: Most often butorphanol in horses is combined with alpha-2-agonists: detomidine xylazine romifidine To enhance desired effects and reduce the side effects (by reduction of the required dose). A lot of studies describe combination use of Butorphanol in horses but in small animals as well! The combination partners most often used are alpha-2-agonists. Why do we combine two different substances in treatment of horses and small animals as well? Firstly analgesic and other properties (in the case of alpha-2-agonists sedative properties) are combined perfectly. Secondly the desired effects are enhanced (potent analgesia and slight sedation of Butorphanol with potent sedation and analgesia of alpha-2-agonists) Thirdly the risk of potential side effects are reduced, because a lower dosage of each combination partner can be used. Alpha-2-agonists inhibit intraneural transmission, are CNS depressive and lead to dose dependant sleep. So the result of this combination is a totally calmed down animal which is time dependant resistant against painful procedures! Xylazine is a very well known, well established substance, is often used in Europe and in Austria for big animal husbandry as well as for small animals. Detomidine is a „younger“ ones and began to spread out from the UK. In literature it is described that monotherapeutic use sometimes led to violent and well aimed kicks in horses that seemed to be deeply sedated (which was confirmed from the department of internal medicine for horses and small animals of the Veterinary University of Vienna, they prefer xylazine). Romifidine is also a newer Alpha-2-agonist, but to my knowledge not available in Russia (at the moment). A lot of studies describe combination use of Butorphanol in horses but in small animals as well! The combination partners most often used are alpha-2-agonists. Why do we combine two different substances in treatment of horses and small animals as well? Firstly analgesic and other properties (in the case of alpha-2-agonists sedative properties) are combined perfectly. Secondly the desired effects are enhanced (potent analgesia and slight sedation of Butorphanol with potent sedation and analgesia of alpha-2-agonists) Thirdly the risk of potential side effects are reduced, because a lower dosage of each combination partner can be used. Alpha-2-agonists inhibit intraneural transmission, are CNS depressive and lead to dose dependant sleep. So the result of this combination is a totally calmed down animal which is time dependant resistant against painful procedures! Xylazine is a very well known, well established substance, is often used in Europe and in Austria for big animal husbandry as well as for small animals. Detomidine is a „younger“ ones and began to spread out from the UK. In literature it is described that monotherapeutic use sometimes led to violent and well aimed kicks in horses that seemed to be deeply sedated (which was confirmed from the department of internal medicine for horses and small animals of the Veterinary University of Vienna, they prefer xylazine). Romifidine is also a newer Alpha-2-agonist, but to my knowledge not available in Russia (at the moment).

18. Indications Standing chemical restraint for therapeutic and diagnostic procedures (castration, lacerations, wound debridement, excisional biopsies, removal of orthopaedic implants, vaginoplasty, cast application in foals, opthalmic and upper respiratory tract procedures, laparotomy) Premedication to general anaesthesia Combatibility with inhalants, other sedatives, other analgesics Now we know which combination can be used safely: Indications where the partly additive and synergistic features of Alpha-2-agonists with Butorphanol can be used are listed on this slide: Stnding chemical restraint for diagnostic and therapeutic procedures for example standing castration of stallions and other painful procedures which have to be done in the daily routine. Intractable patients can be safely calmed down and the combination can be also used for dental work As a premedication to general anaesthesia Butorphanol can also be combined, and it is scientifically confirmd that presurgery use of Butorphanol diminish the need for postsurgical analgesia. It is furthermore a very valuable and important feature of this substance Butorphanol that ist preanaesthetic use is fully compatible with the agents normally used for Anaesthesia (halothane, isoflurane, other sedatives or other analgesics)Now we know which combination can be used safely: Indications where the partly additive and synergistic features of Alpha-2-agonists with Butorphanol can be used are listed on this slide: Stnding chemical restraint for diagnostic and therapeutic procedures for example standing castration of stallions and other painful procedures which have to be done in the daily routine. Intractable patients can be safely calmed down and the combination can be also used for dental work As a premedication to general anaesthesia Butorphanol can also be combined, and it is scientifically confirmd that presurgery use of Butorphanol diminish the need for postsurgical analgesia. It is furthermore a very valuable and important feature of this substance Butorphanol that ist preanaesthetic use is fully compatible with the agents normally used for Anaesthesia (halothane, isoflurane, other sedatives or other analgesics)

19. Dosage HORSE Monotherapeutic use: 0.1mg/kg i.v. (can be repeated after 3 to 4 hours if necessary) Combination use: ?Xylazine plus butorphanol : 0.5mg/kg i.v, followed after 3 to 5 minutes by 50 to 100µg/kg (0.5 to 1ml/100kg) ? Detomidine plus butorphanol: 12µg/kg followed immediately by 25µg (0.25ml/100kg) Monotherapeutic intervention needs 0.1mg/kg which complies with 1ml per 100kg Bodyweight applicated intravenously. Several studies dealt with dosage finding of Butorphanol in horses. It was found out that even a 10-fold overdosage was well tolerated without problems. Therefore there is no risk if Butorphanol administration is repeated after 3 to 4 hours if necessary. But treatment should not be prolonged for more than 48 hours! Butorphanol shows a so called ceiling effect that means higher dosages than 0.4mg/kg Bodyweight do not increase analgesia but can increase possible side effects! Combination use: to my knowledge Romifidin is not available in Russia therefore the dosage is not listed here: for those who want to know or use it: 45µg/kg Bodyweight of romifidine plus 20µg/kg of Butorphanol (complies with 0.2ml/100kg of Butomidor)Monotherapeutic intervention needs 0.1mg/kg which complies with 1ml per 100kg Bodyweight applicated intravenously. Several studies dealt with dosage finding of Butorphanol in horses. It was found out that even a 10-fold overdosage was well tolerated without problems. Therefore there is no risk if Butorphanol administration is repeated after 3 to 4 hours if necessary. But treatment should not be prolonged for more than 48 hours! Butorphanol shows a so called ceiling effect that means higher dosages than 0.4mg/kg Bodyweight do not increase analgesia but can increase possible side effects! Combination use: to my knowledge Romifidin is not available in Russia therefore the dosage is not listed here: for those who want to know or use it: 45µg/kg Bodyweight of romifidine plus 20µg/kg of Butorphanol (complies with 0.2ml/100kg of Butomidor)

20. HorseDosage of Butomidor plus detomidine Here you can see a graphic account of the relationship between dosage of Butomidor plus detomidine (Domosedan) and body weight of horses It can be clearly seen that up from 200kg a dosage of 1ml Butomidor and 0.5ml of Detomidine is sufficient, to reach the desired effect (potent analgesia plus effective sedation). This effect was proven by clinical experience.Here you can see a graphic account of the relationship between dosage of Butomidor plus detomidine (Domosedan) and body weight of horses It can be clearly seen that up from 200kg a dosage of 1ml Butomidor and 0.5ml of Detomidine is sufficient, to reach the desired effect (potent analgesia plus effective sedation). This effect was proven by clinical experience.

21. Indications DOGS, CATS as an analgesic: - for severe pre- or postsurgical pain dogs and cats: mainly orthopedic surgery, abdominal surgery, dentistry, onychectomy (cats), antitussive agent (dogs) - posttraumatic pain humeral fractures, cervical vertrebral malformation or -malarticulation, cervical luxation This slide shows the indications where Butorphanol can be used in small animals namely in dogs and cats. It may be of interest for small animal practitioner present today, that in Canada Butorphanol is the most often used analgesic in small animal practice and accounts for about 40% and 41% in dogs and cats, respectively. In literature they are not great differences concerning indications for use in cats and dogs, and this slide reflects that fact as well. As listed here the main indication for Butorphanol in small animals is as a monotherapeutic analgesic for severe pain due to traumatic injuries like fractures, luxations and malformations. It is often used for pain arising from pathological changes in the body: for example tumours in lung and bones and for pain coming from surgical intervention like orthopaedic surgery (reconstruction of the cruciate ligament in the knee, patellar luxation, arthroplasty of of the femural head and neck, triple pelvic osteotomy and total hip replacement). Abdominal surgery is another field for Butorphanol use as is thoracal surgery (thoracotomy and treatment of pleural effusion), it is an indication for analgesia after dental work and especially in cats for onychectomy which means declawing. A special indication but not in all countries where butorphanol is licensed is the prevention of unproductive cough like kennel cough. In this indication butorphanol has shown to be 100 times more potent than codein!This slide shows the indications where Butorphanol can be used in small animals namely in dogs and cats. It may be of interest for small animal practitioner present today, that in Canada Butorphanol is the most often used analgesic in small animal practice and accounts for about 40% and 41% in dogs and cats, respectively. In literature they are not great differences concerning indications for use in cats and dogs, and this slide reflects that fact as well. As listed here the main indication for Butorphanol in small animals is as a monotherapeutic analgesic for severe pain due to traumatic injuries like fractures, luxations and malformations. It is often used for pain arising from pathological changes in the body: for example tumours in lung and bones and for pain coming from surgical intervention like orthopaedic surgery (reconstruction of the cruciate ligament in the knee, patellar luxation, arthroplasty of of the femural head and neck, triple pelvic osteotomy and total hip replacement). Abdominal surgery is another field for Butorphanol use as is thoracal surgery (thoracotomy and treatment of pleural effusion), it is an indication for analgesia after dental work and especially in cats for onychectomy which means declawing. A special indication but not in all countries where butorphanol is licensed is the prevention of unproductive cough like kennel cough. In this indication butorphanol has shown to be 100 times more potent than codein!

22. Dosage dogs monotherapy DOGS Monotherapeutic use for analgesia: 0.1 to 0.4mg/kg bodyweight s.c., i.m. and i.v. For postsurgery pain control: administer 15 minutes before end of surgery This is the dosage for monotherapeutic use of Butomidor in dogs – for every following monotherapeutic and combination therapy for dogs and cats as well, you will find a table below, showing the relationship between bodyweight and dosage in ml of Butomidor, Medetomidine (Domitor) and ketamine (ketamidor). If these tables are of bad legibility, we have prepared some colour copies which are available here. They summarise all the tables one one side! Anoher important hind concerning administration of Butorphanol for postsurgery control: it should be administered at that time point when the inhalator is turned off (about 15 minutes before the end of surgery) to guarantee the most reliable result in the recovery period. This rule is also valid for cats!This is the dosage for monotherapeutic use of Butomidor in dogs – for every following monotherapeutic and combination therapy for dogs and cats as well, you will find a table below, showing the relationship between bodyweight and dosage in ml of Butomidor, Medetomidine (Domitor) and ketamine (ketamidor). If these tables are of bad legibility, we have prepared some colour copies which are available here. They summarise all the tables one one side! Anoher important hind concerning administration of Butorphanol for postsurgery control: it should be administered at that time point when the inhalator is turned off (about 15 minutes before the end of surgery) to guarantee the most reliable result in the recovery period. This rule is also valid for cats!

23. Dosage dogs combination DOGS: Preanaesthetic Combination use: ? Butorphanol plus medetomidine (i.v. or i.m) 0.1mg/kg.(0.1ml/10kg) followed by 10µg/kg

24. Dosage dogs combination DOGS: Preanaesthetic Combination use: ? Butorphanol plus medetomidine plus ketamine (i.m.) 0.1mg/kg (0.1ml/10kg) plus 0.25µg/kg, after 15 minutes 5mg/kg Adding of ketamine as an neuroleptic anaesthetic allows longer lasting more invasive proceduresAdding of ketamine as an neuroleptic anaesthetic allows longer lasting more invasive procedures

25. Dosage cats monotherapy CATS: Monotherapeutic use for analgesia: 0.1mg/kg bodyweight i.v. 0.4mg/kg bodyweight s.c. For postsurgery pain control: administer 15 minutes before end of surgery

26. Dosage cats combination CATS: Preanaesthetic Combination use: ? Butorphanol plus medetomidine (s.c.) 0.4mg/kg.(0.04ml/kg) followed by 50µg/kg

27. Dosage cats combination CATS: Preanaesthetic Combination use: ? Butorphanol plus medetomidine plus ketamine (i.v.) 0.1mg/kg (0.01ml/kg) plus 40µg/kg, 1.5mg/kg The next few slides are about a very sensitive topic: I would like to talk about safety issues now. There is no drug available worldwide, with only benefical, therapeutic effects, every drug can show unwanted, so called side effects arising from their structure or further interaction in the body of the animal concerned. Especially with overdosage or too often repeated medication the tend to occur. But we should keep in mind that with recommended therapeutic dosages no hazard can be expected and this is valid for opioids as well, and also for Butorphanol The next few slides are about a very sensitive topic: I would like to talk about safety issues now. There is no drug available worldwide, with only benefical, therapeutic effects, every drug can show unwanted, so called side effects arising from their structure or further interaction in the body of the animal concerned. Especially with overdosage or too often repeated medication the tend to occur. But we should keep in mind that with recommended therapeutic dosages no hazard can be expected and this is valid for opioids as well, and also for Butorphanol

28. Possible Side Effects HORSES: In literature most described: ?behavioural side effects: restlessness, mild excitement, ataxia, mild sedation ?cardio respiratory side effects: increased heart rate, elevation of blood pressure tachypnea ? gastrointestinal side effects: decreased motility, mild constipation What you see here are the side effects most described in literature. They arise from the membership of butorphanol to the opioids and are not a special feature of Butorphanol itself! Most described are behavioural effects. Cardiovascular and respiratory effects were investigated very intensively in horses because vets feared their occurence. It could be confirmed that all of them were mild and transient and in none of the studies led to life threatening situations or endangered the therapeutic success of treatment. In our own trial from 2004 we investigated these side effects also, by using behavioural-, ataxia- and sedation scores. What we found out with our 10 horses where 5 were older than 18 year, was: that in 2 of 10 horses we found mild restlessness, some showed really mild ataxia and sedation, bowel motility remained unaffected (by measuring the frequency of defaecation) What you see here are the side effects most described in literature. They arise from the membership of butorphanol to the opioids and are not a special feature of Butorphanol itself! Most described are behavioural effects. Cardiovascular and respiratory effects were investigated very intensively in horses because vets feared their occurence. It could be confirmed that all of them were mild and transient and in none of the studies led to life threatening situations or endangered the therapeutic success of treatment. In our own trial from 2004 we investigated these side effects also, by using behavioural-, ataxia- and sedation scores. What we found out with our 10 horses where 5 were older than 18 year, was: that in 2 of 10 horses we found mild restlessness, some showed really mild ataxia and sedation, bowel motility remained unaffected (by measuring the frequency of defaecation)

29. Possible Side Effects Most feared by Veterinarians using Opioids: DOGS: ? Respiratory depression ? Bradycardia ? Sedation CATS: ? Mydriasis ? Respiratory depression ?(Excitation) For this slide it is really important to keep in mind that the listed side effects are not those most often seen, but these are the most feared side effects in dogs and cats (evaluated in a survey of canadian vets). Especially for dogs influence on the cardiovascular– and rspiratory system was mild, the oxygen values always staid within physiological ranges. Sedation was no point of concern as well (compared wth other oipid drugs). In cats the most feared effects were mydriasis what is difficult to understand because this effect was seen with doses up to 0.2mg/kg iv. (lasted for three hours) which is the doubled therapeutic dose at the one side and is surely never life threatening! Respiratory depression was mild and transient. The last Side effect hold in brackets is a kind of historical one, the dosages used in cats were much higher in the early stages of oipiod use. With the recommended doses use of opioids and especially Butomidor in cats is safe!For this slide it is really important to keep in mind that the listed side effects are not those most often seen, but these are the most feared side effects in dogs and cats (evaluated in a survey of canadian vets). Especially for dogs influence on the cardiovascular– and rspiratory system was mild, the oxygen values always staid within physiological ranges. Sedation was no point of concern as well (compared wth other oipid drugs). In cats the most feared effects were mydriasis what is difficult to understand because this effect was seen with doses up to 0.2mg/kg iv. (lasted for three hours) which is the doubled therapeutic dose at the one side and is surely never life threatening! Respiratory depression was mild and transient. The last Side effect hold in brackets is a kind of historical one, the dosages used in cats were much higher in the early stages of oipiod use. With the recommended doses use of opioids and especially Butomidor in cats is safe!

30. Tolerance HORSES: data from own trial, treatment was very well tolerated Local tolerance: inspection of injection site up to 48 hours post treatment Systemic tolerance: kidney function (urea and creatinine) liver function (ALP, GLDH and ?-GT) muscle damage (AST) DOGS,CATS: No reports available. Some authors indicated that i.m. injection in cats could be painful. Systemic tolerance is not described in literature, studies confirm, tolerability in older dogs is excellent Another impotant safety issue is tolerance. Studies describing local and systemic tolerance of Butorphanol are really rare and because we assessed tolerance in our trial as well, I would like to give you some information about it. Half of our trial animals were older than 18 which could be a cause for already impaired organic function! Local tolerance was measured in all horses after a single dose of Butorphanol. No problems occured neither on skin hair nor on jugular vein used for injection. Systemic tolerance was tested by using so called indicator enzyms. We chose urea and creatinine for kidney, urea is specific but influenced by diet, therefore we added crea which is a very reliable parameter for glomerular filtration rate. All the values staid within normal ranges therefore we concluded that Butorphanol is not nephrotoxic (after a single shot of the recommended dose) Liver marker enzymes were the listed. ALP is also specific for bones and intestine, the other two are liverspecific. No change could be observed therefore we concluded that Butorphanol is not livertoxic as well. The last parameter we assessed was AST for muscle damage. This marker also staid within the normal range! As a summary I would say toxicity of Butorphanol is very low because of high tolerability even in older animals! Concerning small animals no reports are available concerning local tolerance. We know that im administration in cats could be painful therefore we recommend sc and iv administration. Systemic tolerance is not described but there was a study with older dogs available, where tolerability concerning organic function was assessed. And was found to be excellent!Another impotant safety issue is tolerance. Studies describing local and systemic tolerance of Butorphanol are really rare and because we assessed tolerance in our trial as well, I would like to give you some information about it. Half of our trial animals were older than 18 which could be a cause for already impaired organic function! Local tolerance was measured in all horses after a single dose of Butorphanol. No problems occured neither on skin hair nor on jugular vein used for injection. Systemic tolerance was tested by using so called indicator enzyms. We chose urea and creatinine for kidney, urea is specific but influenced by diet, therefore we added crea which is a very reliable parameter for glomerular filtration rate. All the values staid within normal ranges therefore we concluded that Butorphanol is not nephrotoxic (after a single shot of the recommended dose) Liver marker enzymes were the listed. ALP is also specific for bones and intestine, the other two are liverspecific. No change could be observed therefore we concluded that Butorphanol is not livertoxic as well. The last parameter we assessed was AST for muscle damage. This marker also staid within the normal range! As a summary I would say toxicity of Butorphanol is very low because of high tolerability even in older animals! Concerning small animals no reports are available concerning local tolerance. We know that im administration in cats could be painful therefore we recommend sc and iv administration. Systemic tolerance is not described but there was a study with older dogs available, where tolerability concerning organic function was assessed. And was found to be excellent!

31. Butorphanol Use Efficacy and Safety confirmed in many clinical trialsBasing on available literature data a lot of horses sucessfully treated. Serious adverse events never occured (even with 10 fold overdose). Butomidor® is available in many countriesSeven further countries with about 100,000 horses treated, a lot of small animals as well.No adverse events were reported to Richter Pharma until now. This is just a short summary of Butorphanol safety and efficacy assessment. Firstly it was evaluated in a lot of trials showing to own no hazardous features. Even 10 fold overdosage in horses is well tolerated. The lethal doses in dogs were found to be 10-15mg/kg iv, 17 to 29mg/kg im and more than 50mg/kg sc!This is just a short summary of Butorphanol safety and efficacy assessment. Firstly it was evaluated in a lot of trials showing to own no hazardous features. Even 10 fold overdosage in horses is well tolerated. The lethal doses in dogs were found to be 10-15mg/kg iv, 17 to 29mg/kg im and more than 50mg/kg sc!

32. Russian Products available These are the products available in Russia now for treatemnt of pain in horses and small animals also, sold by Richter Pharma!These are the products available in Russia now for treatemnt of pain in horses and small animals also, sold by Richter Pharma!

33. Won‘t happen with Butorphanol! ...and with this slide I would like to finish my presentation, thank you very much for your attention!...and with this slide I would like to finish my presentation, thank you very much for your attention!