Antinociceptive activity of midazolam in sheep

The purpose of this study was to examine the effects of midazolam on the nociceptive threshold responses in sheep. The intravenous administration of midazolam (0. 1–0.3 mg/kg) produced a significant dose-dependent elevation of the mechanical and thermal nociceptive thresholds. The intravenous administration of flumazenil (20 μg/kg) markedly attenuated the antinociceptive activity of midazolam in the mechanical nociceptive test, whereas intravenous naloxone (0.2 mg/kg) had no significant effect on midazolam-mediated analgesia. The intrathecal administration of midazolam (1 mg), via chronically implanted cervical subarachnoid catheters, produced a significant elevation in the mechanical threshold responses. These results indicate that midazolam has antinociceptive actions in the sheep and suggest that this effect is, at least partially, mediated at the spinal level.     

The correlation of the thermal and mechanical antinociceptive activity of pethidine hydrochloride with plasma concentrations of the drug in sheep

The analgesic activity of pethidine was measured in eight sheep using both thermal and mechanical test systems. Pethidine, at a dose rate of 5 mg/kg body weight given intravenously, produced a significant degree of antinociception to thermal pain for 30 min (on average) but gave only a few minutes of significant analgesia when tested in the mechanical pressure system. Analgesia in both systems was abolished by pretreatment with naloxone. Pharmacokinetic analyses of plasma levels of pethidine after intravenous (i.v.) injection were carried out. Plasma concentrations of the drug exhibited a rapid biexponential pattern of decline with an average distribution half-life of 0.99 min and an elimination half-life of 12.8 min. Correlation of plasma levels of the drug with the presence of a significant degree of antinociception in the thermal test system enabled 'critical' analgesic levels of pethidine to be defined for sheep (0.93 microgram/ml).     

Cardiovascular effects of medetomidine-ketamine anaesthesia in sheep, with and without 100% oxygen, and its reversal with atipamezole.

The cardiovascular effects of intravenously (iv) administered medetomidine 20 μg/kg bodyweight (bwt) and ketamine (2 mg/kgbwt), with and without 100% inspired oxygen, were investigated in six domestic sheep. A second dose of medetomidine and ketamine was administered iv, at dose 10 μg/kg bwt and 1 mg/kg bwt respectively, 25 minutes after the initial injection. Heart rate, PaO₂ pH and haemoglobin saturation decreased whereas PaCO₂ and base excess increased post-injection. Transient hypertension and an increase in respiration rate were evident within the first 10 minutes of anaesthesia. Significant hypoxaemia (P<0.01) developed in sheep breathing room air. Inspired 100% oxygen improved PaO₂ (but the difference was not significant), and improved haemoglobin saturation significantly (P<0.05), however, this effect varied between individuals. One sheep breathing room air suffered a cardiac arrest immediately post-injection and had to be resuscitated. Atipamezole 125 μg/kg given intramuscularly 45 minutes after the initial injection rapidly reversed the effects of medetomidine. Recovery times did not significantly differ although time to extubation and standing tended to be longer in sheep breathing room air compared to the sheep breathing 100% oxygen. The quality of the recovery did not differ.     

Medetomidine/ketamine sedation in calves and its reversal with atipamezole

Atipamezole was used to reverse the sedation induced in calves by medetomidine/ketamine. Thirteen claves subjected to umbilical surgery received medetomidine 20 μg/kg bodyweight (bwt) and ketamine 0.5 mg/kg bwt intravenously (iv) from a mixture of the drugs in one syringe. Atipamezole was given at doses of 20 to 60 μg/kg iv and intramuscularly (im) to the calves at the end of the operation. Following the administration of medetomidine and ketamine, PaCO₂ increased whereas pH, PaO₂ and heart rate decreased. Reversing the effects of medetomidine with atipamezole did not cause undesirable effects; recovery was rapid and smooth, most of the animals reached a standing position within 1 to 3 mins after the atipamezole injection.     

Effects of α2-adrenergic drugs on blood platelets in sheep

Xylazine (0.2 mg/kg, iv) alone or preceded by atipame-zole (0.125 μg/kg, iv) or by aspirin (10 μg/kg, iv) was administered to 18 sheep. Medetomidine (60 μg/kg, iv) was also administered to 12 sheep. Xylazine, but not medetomidine, significantly reduced the number of platelets. Both atipamezole and aspirin prevented this reduction. It was concluded that α₂-agonists would seem to produce platelet aggregation that may contribute to the development of the respiratory changes that follow the administration of α₂-agonists in sheep, but probably not always to a degree that could result in a significant decrease in the number of circulating platelets.     

Further studies on the antinociceptive activity and respiratory effects of buprenorphine in sheep

The thermal and mechanical analgesic profile of buprenorphine at a dose rate of 1.5 micrograms/kg i.v. was investigated in five sheep. This dose produced significant analgesia for 40 min against the thermal stimulus, but no mechanical antinociception. A higher dose rate of 12 micrograms/kg also failed to produce antinociception to a mechanical stimulus. In addition, the effect of the drug (6 micrograms/kg) on respiratory gas tensions was determined and no significant changes were observed.     

Analgesic activity and respiratory effects of butorphanol in sheep

The analgesic drug butorphanol tartrate has proved useful clinically in horses and dogs but its analgesic profile had not yet been investigated in sheep. This study was initiated to determine the thermal and mechanical antinociceptive activity of butorphanol (at the dose rates 0.05, 0.1 and 0.2 mg kg-1) in sheep. The drug produced significant analgesia in the thermal test system, the duration of which was dose related but no significant elevation in mechanical pressure thresholds could be detected. In a further set of experiments the dose rate was increased to 0.4 mg kg-1 and mechanical testing was repeated. There was still no clinically significant elevation in pressure thresholds. At a dose rate of 0.2 mg kg-1 the drug had no detectable effect on respiratory blood gas tensions. Behavioural changes were severe if a dose rate of 0.2 mg kg-1 was exceeded.     

Propofol infusion anaesthesia in dogs pre-medicated with medetomidine

Ten laboratory beagles pre-medicated with medetomidine (40 μg/kg bodyweight [bwt]) were anaesthetised using a rapid injection of propofol, followed by propofol infusion. A loading dose of 4 mg/kg bwt of propofol was administered intravenously (iv) as a bolus and, immediately after, a 60 min iv propofol infusion (150 μg/kg bwt/min) was initiated. After a transient increase, mean arterial blood pressure decreased significantly below the pre-propofol level. However, the lowest values recorded (115 ± 11 mmHg) remained within the physiological limits. Heart rate increased significantly (from 41 ± 7.3 to 58 ± 11 beats/min) after initiation of the propofol infusion. No significant changes were seen in respiratory frequency; pO₂ decreased transiently; minimum values (10 ± 2.3 kPa) recorded 5 mins after initiation of the propofol infusion differed significantly from the starting level. pCO₂ increased significantly and the highest values recorded were 6.1 ± 0.35 kPa. Accordingly, pH decreased reaching the lowest level (pH 7.29) 15 mins after initiation of the propofol infusion. The analgesic effect of the present combination was not studied, but the absence of the palpebral and pedal reflexes suggested a surgical stage of anaesthesia. Therefore, propofol infusion in beagles pre-medicated with medetomidine proved to be a promising anaesthetic regimen but, if used clinically, oxygen-enriched inspired air should be used.     

The influence of atipamezole on the cardiovascular effects of detomidine in horses

The reversal of the cardiovascular effects of the α₂-adrenoceptor agonist detomidine by the α₂-antagonist atipamezole was studied. Nine horses were given detomidine 20 μg/kg iv. On a separate occasion they were given atipamezole 100 μg/kg iv 15 mins after the detomidine injection. Blood gas tensions were measured and clinical signs of sedation were also observed. Bradycardia and the frequency of heart blocks induced by detomidine were reduced after atipamezole and blood pressure decreased. These reversal effects of atipamezole were of short duration (a few minutes) at the dose level tested. Two of the nine horses exhibited premature depolarisations after administration of detomidine, but not after atipamezole injection. PaO₂ decreased and PaCO₂ increased slightly after detomidine injection, but the arterial pH was within reference values or slightly elevated. Administration of atipamezole did not alter these values. Base excess rose after detomidine, and it decreased more quickly towards the baseline level, when the horses were given detomidine alone. No clinical adverse effects were seen from the administration of atipamezole. Atipamezole may be beneficial, if detomidine-induced bradycardia needs to be reversed in horses.     

Sedative and cardiovascular effects of romifidine, alone and in combination with butorphanol, in the horse

The behavioural and sedative effects of intravenous (iv) romifidine (40 and 80 μg/kg bodyweight [bwt]) alone or in combination with iv butorphanol (50 μg/kg bwt) were investigated in four ponies and one Thoroughbred horse. Apparent sedation, as judged by the lowering of the head, and by the response to imposed touch, visual and sound stimuli was assessed. The combination with butorphanol reduced the animals' response to imposed stimuli when compared with the effect of the same dose of romifidine alone. Following the administration of romifidine/butorphanol combinations muzzle tremor was noted and some animals attempted to walk forward. In a separate series, the cardiopulmonary effects of iv romifidine (80 μg/kg bwt) alone, or in combination with butorphanol (50 μg/kg bwt) were investigated. Romifidine and the romifidine/butorphanol combination caused similar cardiovascular changes, these being bradycardia with heart block, and hypertension followed by hypotension. Romifidine caused a transient decrease in arterial oxygen tensions and arterial carbon dioxide tensions had increased significantly by the end of the 90 min recording period. Romifidine/butorphanol combinations produced significantly higher arterial carbon dioxide tensions during the first 15 mins after drug administration than did romifidine alone. Butorphanol at 50 μg/kg bwt iv reduced the response to imposed stimuli in horses sedated with romifidine. The combination produced no cardiovascular changes beyond those induced by romifidine alone, but did increase the degree of respiratory depression.     

The use of intraoperative fentanyl in spontaneously breathing dogs undergoing orthopaedic surgery

Nineteen dogs were assigned randomly to one of three groups. Animals in Group 1 were pre-medicated with acepromazine, 50 μg/kg bodyweight (bwt) intramuscularly (im) and received 10 ml of 0.9 per cent saline intravenously (iv) at the time of skin incision. Dogs in Group 2 were pre-medicated with acepromazine, 50 μg/kg bwt im, and received fentanyl 2 μg/kg bwt iv at skin incision. Dogs in Group 3 were pre-medicated with acepromazine, 50 μg/kg bwt and atropine, 30 to 40 μg/kg bwt, im and received fentanyl, 2 μg/kg bwt iv at skin incision. Pulse rate, mean arterial blood pressure, respiratory rate and end tidal carbon dioxide were measured before and after fentanyl or saline injection. Fentanyl caused a short-lived fall in arterial blood pressure that was significant in dogs premedicated with acepromazine, but not in dogs pre-medicated with acepromazine and atropine. A significant bradycardia was evident for 5 mins in both fentanyl treated groups. The effect on respiratory rate was most pronounced in Group 3, in which four of seven dogs required intermittent positive pressure ventilation (IPPV) for up to 14 mins. Two of six dogs in Group 2 required IPPV, whereas respiratory rate remained unaltered in the saline controls. The quality of anaesthesia was excellent in the fentanyl treated groups; however, caution is urged with the use of even low doses of fentanyl in spontaneously breathing dogs under halothane-nitrous oxide anaesthesia.     

An investigation into the use of propofol (Rapinovet®) in long-tailed macaques (Macaca fascicularis)

Propofol, an intravenous (iv) anaesthetic agent, was given to 12 long-tailed macaque monkeys (Macaca fascicularis) that were initially chemically restrained using ketamine hydrochloride. Anaesthesia was induced and maintained using incremental iv injections of propofol at various dose rates. Physiological parameters were monitored during anaesthesia. Five animals were allowed to recover from anaesthesia and their recovery was usually uneventful. At the dose levels investigated there was good muscle relaxation and analgesia and cardiovascular and respiratory functions were adequately maintained. A dose of 10 mg/kg bodyweight gave moderate surgical anaesthesia for between 20 and 40 mins.     

Antinociceptive actions of intravenous a2-adrenoceptor agonists in sheep

The antinociceptive activity of the intravenously administered alpha 2-adrenoceptor agonists, clonidine and xylazine, was measured in sheep using thermal and mechanical pressure threshold detection systems. Both drugs demonstrated clear antinociceptive activity for both forms of threshold stimuli and clonidine at 6 micrograms/kg i.v. was more potent and longer lasting than xylazine at 50 micrograms/kg i.v. The antinociceptive effects were reversed by idazoxan (0.1 mg/kg i.v.), but were not affected by naloxone at 0.2 mg/kg i.v. indicating that these effects were mediated by alpha 2-adrenoceptors.     

Buprenorphine in combination with naloxone at a ratio of 15:1 does not enhance antinociception from buprenorphine in healthy cats

Naloxone can enhance the antinociceptive/analgesic effects of buprenorphine in humans and rats. The antinociceptive effects of a patented 15:1 buprenorphine:naloxone combination was investigated in cats using a thermal and mechanical nociceptive model. Twelve cats received buprenorphine 10 μg/kg, naloxone 0.67 μg/kg or a buprenorphine-naloxone combination intramuscularly in a randomised cross over study. Using thermal and mechanical analgesiometry validated in the cat, pre-treatment baselines were measured. Following test drug administration, thresholds were studied for the next 24h. Naloxone did not enhance the thermal antinociceptive effect of buprenorphine. The results from this study are in agreement with previously published work showing that naloxone antagonises the effects of clinically analgesic doses of buprenorphine. Mechanical nociceptive thresholds were not affected by buprenorphine.     

Stimulation of growth hormone release in anesthetized and conscious pigs by synthetic human pancreatic growth hormone-releasing factor [hpGRF(1-29)-NH2]

Synthetic human pancreatic growth hormone (GH)-releasing factor containing 29 amino acids, hpGRF(1-29)-NH₂, was administered intravenously to halothane-anesthetized growing pigs at 0.19 and 0.93 μg/kg and to conscious growing pigs at 1, 4 and 8 μg/kg. In the anesthetized pigs, a dose-dependent elevation of plasma GH levels was observed within five minutes of injection. Growth hormone levels returned to baseline within 60 minutes at the low dose, but had not yet decreased to pretreatment values by 120 minutes at the high dose level. In contrast, although all doses increased GH levels in the conscious pigs, the large variability in response to the peptide resulted in only the high dose level causing a significantly increased GH release (P<0.05) during the 3-hour post-treatment period.     

A COMPARISON OF THE SEDATIVE EFFECTS OF MEDETOMIDINE AND XYLAZINE IN THE HORSE.

The sedative effects in horses of the new α₂-agonist medetomidine were compared with those of xylazine. Four ponies and one horse were treated on separate occasions with two doses of medetomidine (5 mμ/kg bodyweight and 10 μg/kg bodyweight) and with one dose of xylazine (1 μg/kg bodyweight) given by intravenous injection. Medetomidine at 10 μg/kg was similar to 1 mg/kg xylazine in sedative effect but produced greater and more prolonged ataxia. Ataxia was so severe following 10 μg/kg of medetomidine that one animal fell over during the study. Medetomidine (5 μg/kg) produced less sedation but a similar degree of ataxia to 1 mg/kg xylazine.     

Single‐ and multiple dose pharmacokinetics and multiple dose pharmacodynamics of oral ABT‐116 (a TRPV1 antagonist) in dogs

Six dogs were used to determine single and multiple oral dose pharmacokinetics of ABT‐116. Blood was collected for subsequent analysis prior to and at 15, 30 min and 1, 2, 4, 6, 12, 18, and 24 h after administration of a single 30 mg/kg dose of ABT‐116. Results showed a half‐life of 6.9 h, k_el of 0.1/h, AUC of 56.5 μg·h/mL, T_max of 3.7 h, and C_max of 3.8 μg/mL. Based on data from this initial phase, a dose of 10 mg/kg of ABT‐116 (no placebo control) was selected and administered to the same six dogs once daily for five consecutive days. Behavioral observations, heart rate, respiratory rate, temperature, thermal and mechanical (proximal and distal limb) nociceptive thresholds, and blood collection were performed prior to and 4, 8, and 16 h after drug administration each day. The majority of plasma concentrations were above the efficacious concentration (0.23 μg/mL previously determined for rodents) for analgesia during the 24‐h sampling period. Thermal and distal limb mechanical thresholds were increased at 4 and 8 h, and at 4, 8, and 16 h respectively, postdosing. Body temperature increased on the first day of dosing. Results suggest adequate exposure and antinociceptive effects of 10 mg/kg ABT‐116 following oral delivery in dogs.     

Cardiopulmonary effects of a two hour medetomidine infusion and its antagonism by atipamezole in horses and ponies

The cardiopulmonary effects of an intravenous (iv) medetomidine injection (5 μg/kg) followed 5 min later by its infusion at 3.5 μg/kg/h for 115 rnin were studied in 9 horses and ponies. Five minutes after the end of infusion 60 μg/kg atipamezole were given. Physiological data during infusion were compared with pre-sedation values. Stroke volume was reduced significantly 5 min after initial medetomidine injection. Cardiac index was reduced significantly and systemic vascular resistance increased significantly for the first 20 min, but returned towards pre-sedation values after this time. Arterial blood pressures were reduced significantly from 30 min until the end of the procedure (minimum MAP was 102.4 ± 9.61 mmHg). Mixed venous oxygen tension was reduced significantly during the infusion. Respiratory rate fell and PaCO₂- rose significantly from 40 min onward. Other variables showed no significant changes. The horses recovered rapidly after atipamezole was injected. Arterial blood pressures remained significantly lowered, but other cardiovascular variables returned towards pre-sedation values. It is concluded that the infusion of medetomidine at 3.5 μg/kg/h causes minimum cardiopulmonary depression once the effects of an initial 5 μg/kg injection have waned, and so could prove suitable as part of an anaesthetic technique in equidae.     

Neurophysiological assessment of the sedative and analgesic effects of a constant rate infusion of dexmedetomidine in the dog

The sedative and analgesic effects of continuous rate infusion (CRI) of dexmedetomidine (DEX) were investigated in Beagle dogs (n = 8) using auditory and somatosensory evoked potentials (AEPs and SEPs) recorded before, during and after a CRI of saline or DEX (1.0, 3.0, 5.0 μg/kg bolus, followed by 1.0, 3.0, 5.0 μg/kg/h CRI, respectively).The results showed a significant reduction in AEP at doses of 1.0 μg/kg/h and above and a significant reduction of the SEP at doses of 3.0 and 5.0 μg/kg/h. Neither the AEP nor the SEP was further reduced at 5.0 μg/kg/h when compared to 3.0 μg/kg/h, although a slower return towards baseline values was observed at 5.0 μg/kg/h. The mean plasma levels (±SEM) of DEX during infusion were 0.533 ± 0.053 ng/mL for the 1.0 μg/kg/h dose, 1.869 ± 0.063 ng/mL for the 3.0 μg/kg/h dose and 4.017 ± 0.385 for the 5.0 μg/kg/dose. It was concluded that in adult dogs, a CRI of DEX had a sedative and analgesic effect that could be described quantitatively using neurophysiological parameters. Sedation was achieved at lower plasma levels than required for analgesia, and DEX had a longer (but not larger) effect with infusion rates above 3.0 μg/kg/h.     

Use of naltrexone to antagonize high doses of remifentanil in cats: a dose-finding study

ObjectiveTo determine the dose of naltrexone necessary to fully antagonize a high dose of remifentanil in cats.Study designProspective experimental study.AnimalsSix healthy adult cats weighing 4.9 ± 0.7 kg.MethodsIn a first phase, remifentanil (200 μg kg^?1 followed by 60 μg kg^?1 minute^?1) was administered intravenously to two cats, causing an increase in locomotor activity. Naltrexone (100 μg kg^?1) was then administered intravenously every minute until the increase in locomotor activity had been reversed. In a second phase, six cats were used. Baseline thermal threshold was determined, naltrexone (600 μg kg^?1) was administered intravenously and 30 minutes later thermal threshold determination repeated. Remifentanil (200 μg kg^?1 followed by 60 μg kg^?1 minute^?1) was administered intravenously and thermal threshold determination repeated at 60, 120, 180, and/or 240 minutes after naltrexone administration. Thermal threshold determinations were started shortly after the start of the continuous rate infusion (CRI) of remifentanil and this CRI was discontinued immediately after thermal threshold determination. If an increase in thermal threshold was found, naltrexone administration was repeated at decreasing intervals in the next experiment (all cats were not used for all dosing intervals). Experiments were repeated until a naltrexone dosing interval was found that prevented increases in thermal threshold for 4 hours in all six cats.ResultsIn the first phase, both cats became severely dysphoric following remifentanil administration. A cumulative naltrexone dose of 300 μg kg^?1 was necessary to restore normal behavior in both cats. In the second phase, hourly administration of naltrexone (600 μg kg^?1) prevented increases in thermal threshold associated with hourly administration of remifentanil for 4 hours. Less frequent administration did not prevent increases in thermal threshold consistently.ConclusionsHourly administration of naltrexone (600 μg kg^?1) antagonizes the behavioral and antinociceptive effects of a high dose of remifentanil in cats.Clinical relevanceNaltrexone may be useful for the treatment of opioid overdose in cats.