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The postoperative analgesia and sedation in cats given carprofen (4.0 mg/kg bodyweight by subcutaneous injection preoperatively) was compared to that in cats given pethidine (3.3 mg/kg bodyweight by intramuscular injection postoperatively) in a controlled, randomised, blinded, multicentre clinical trial. Further dosing with the particular analgesic was allowed if a cat was exhibiting unacceptable pain. In total, 57 carprofen cases and 59 pethidine cases were evaluated. Significantly fewer cats in the carprofen group required additional doses of analgesic, and mean pain scores were significantly lower from four hours after ovariohysterectomy, and at 18 to 24 hours after castration, compared to the pethidine group. In conclusion, carprofen provided as good a level of postoperative analgesia as pethidine, but of a longer duration (at least 24 hours) and was well tolerated. It thus provides an option for 'pre-emptive analgesia' in cats about to undergo surgery.

A modification of the intravenous regional anaesthesia technique was used to assess the peripheral antinociceptive effect of remoxipride, clonidine and fentanyl. Drugs administered intravenously via peripheral catheters were restricted to the distal limb and nociceptive threshold test site by prior inflation of a tourniquet proximal to both the catheter and a threshold-testing device. Lignocaine (1 mg/kg) induced peripheral antinociception during tourniquet inflation. Clonidine (6 micrograms/kg) only induced significant elevations in thresholds after tourniquet deflation. A low dose of remoxipride (2 mg/kg), which had no systemic antinociceptive effect, produced antinociception after its restriction to the periphery. Peripheral administration of saline and tourniquet-induced restriction of blood flow to the distal limb did not alter threshold values. Peripheral administration of fentanyl was used to test a further modification of the injection protocol designed to reduce the incidence of leakage into the systemic circulation. Fentanyl administration (11.2 micrograms/kg) failed to elicit an increase in thresholds when it was restricted to the distal limb test site. The contribution of a peripheral mechanism to the antinociception induced by systemic administration of a higher remoxipride dose (7.5 mg/kg) was investigated using an inflated tourniquet to exclude remoxipride from the periphery. Exclusion of remoxipride from the periphery reduced its antinociceptive effect, i.e. threshold values were lower than if remoxipride was allowed free access to the limb prior to tourniquet inflation. The technique described here was effective in demonstrating that the increase in noninflammatory nociceptive thresholds seen with clonidine and fentanyl is not peripherally mediated whilst that seen with remoxipride has a peripheral component.

ONE of the most gratifying developments in veterinary work in recent years has been the increased awareness among the profession of the need to provide effective pain relief following surgery. However, some veterinarians are still slightly reluctant to administer analgesics to cats routinely following surgery. This article aims to answer some questions and provide information which will encourage the routine use of analgesics in cats as well as dogs.

The aim of this study was to titrate the optimal dose of carprofen for single dose usage, for alleviating postoperative pain, under a double-blind and randomised protocol, using both negative and positive controls. Renal tolerance was assessed by screening plasma urea and creatinine. Pre- and postoperative assessment of pain and sedation was made using a dynamic and interactive visual analogue scoring system in 60 cats undergoing ovariohysterectomy. The cats were randomly assigned to one of six groups: (1) carprofen at 1.0 mg/kg subcutaneously (sc); (2) carprofen at 2.0 mg/kg sc; (3) carprofen at 4.0 mg/kg sc; (4) pethidine at 5.0 mg/kg intramuscularly (im), (5) pethidine at 10.0 mg/kg im: and (6) no analgesics (injection of saline). All injections were given postoperatively on tracheal extubation and administered in a double-blind manner. Assessments were made up to 20 hours post extubation. Prior to induction and at 20 hours post extubation, blood samples were taken for laboratory analysis of the urea and creatinine content to check for any adverse effect on renal function. Cats given pethidine did not appear more sedated than the groups receiving carprofen or saline. Cats receiving carprofen were in less pain postoperatively overall, with 4.0 mg/kg being the most effective dose rate (significantly better than the other doses of carprofen at four and eight hours post extubation). The highest dose of pethidine provided significantly better analgesia than the highest dose of carprofen up to two hours post extubation, but from two to 20 hours post extubation carprofen at 4.0 mg/kg provided significantly better analgesia than the pethidine. None of the analgesic regimens appeared to affect renal function adversely, as measured by urea and creatinine levels.

The antinociceptive potential of remoxipride was investigated in sheep and rats with concurrent motor function assessments. Previous studies of sheep given intravenous remoxipride have revealed increases in mechanical nociceptive thresholds. Here, further investigation in sheep demonstrated elevated thermal nociceptive thresholds with no effect on subjectively assessed sedation or motor impairment scores. However, in rats, the dose of remoxipride (100 mg/kg i.p.) required to produce nociceptive thresholds similar to those elicited by morphine (30 mg/kg i.p.), itself reduced rotarod performance. Medetomidine (200 micrograms/kg i.p.) evoked sedation without influencing rotarod performance or antinociception. The antinociceptive, motor deficit and cataleptogenic actions of remoxipride were similar to those induced by two other dopamine antagonists, haloperidol (5 mg/kg) and raclopride (16 mg/kg i.p). Tocainide (100 mg/kg i.p.) induced thermal antinociception with normal rotarod performance and no catalepsy suggesting that Na+ channel blockade by remoxipride is not responsible for the changes in nociceptive thresholds. This study emphasizes the importance of motor function assessment during acute antinociceptive testing.

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 micrograms/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.

Existing methods of assessing pain and analgesia in large animals leave much to be desired. Equipment capable of measuring pain thresholds to a gradually increasing mechanical stimulus was developed. The device was pneumatically powered and controlled by a computer. It was used to assess pain thresholds in sheep, thoroughbred horses and human volunteers. All three species had very similar thresholds, about 5 N. The distribution of thresholds in both healthy and lame sheep was normal; the mean threshold in lame sheep was slightly but significantly lower than that in healthy sheep. Injection of saline had no effect on thresholds over six hours, but the analgesic detomidine significantly raised thresholds in both sheep and horses. The device was able to differentiate analgesia and sedation however, as acepromazine did not raise the thresholds of either species. The equipment proved robust and simple to use.

The effects of osteochondral defect location and post-operative walking exercise on structural repair and recovery of joint function were examined in the midcarpal joints of ponies. Functional recovery was monitored by measuring ground reaction forces using a force plate. Structural repair was evaluated histologically and by measuring the total collagen and uronic acid content and relative proportions of Type I and II collagen in the repair tissue. Central defects tended to cause a more marked functional disturbance but were repaired with fibrocartilage rather than fibrous tissue in 3 out of 6 ponies while marginal defects were repaired almost exclusively with fibrous tissue. There was no significant difference between defect locations with regard to the biochemical measures evaluated. Exercise produced no beneficial effect on structural repair of the defects. Secondary 'kissing' lesions in the third carpal bones opposite the defects appeared grossly more severe in the exercised ponies which also showed a trend to more marked functional disturbance.

1. The intrathecal administration of xylazine (100 micrograms), via a chronic indwelling, cervical intrathecal catheter, produced a marked elevation of the mechanical nociceptive thresholds in the sheep. This antinociceptive effect was abolished by the prior intrathecal administration of the alpha 2-adrenoceptor antagonist, idazoxan. 2. The intrathecal administration of the selective alpha 2-antagonists, idazoxan (100 micrograms) and RX811059 (33 micrograms), significantly attenuated the antinociceptive activity of intravenous xylazine, with a 60-65% reduction in the area under the antinociceptive curve. The intrathecal administration of the antagonists alone had no significant effect on nociceptive thresholds. 3. Examination of the distribution of tritiated idazoxan (25 microCi in 100 microliters) indicated that the site of action of the drug was limited to the cervical spinal cord after intrathecal administration. 4. These studies demonstrate that a significant proportion of the antinociceptive effect of systemically administered xylazine is mediated by spinal alpha 2-adrenoceptors.

This study was undertaken to assess the analgesia provided by detomidine (20 μg kg −1 intravenously) in thoroughbred horses. Pain thresholds to a mechanical noxious stimulus were measured before and after a period of mild chronic pain in one foreleg. Detomidine was a good analgesic in control animals; their pain thresholds were significantly elevated for about 60 minutes. After injury, the injured leg had a significantly lower pain threshold and the intensity and duration of analgesia provided by detomidine were significantly reduced. The analgesia in the opposite (sound) leg was also reduced, indicating that there were both central and peripheral aspects to this increased sensitivity to painful stimuli. Detomidine deserves to be considered as a potent analgesic in the horse rather than a sedative with analgesic side effects.

The effects of thiopentone and propofol on oesophageal pressures were examined in 39 bitches. The dogs were premedicated with either atropine (n = 13), acepromazine maleate (n = 13) or a combination of atropine and acepromazine. Anaesthesia was induced with either thiopentone (15 dogs) or propofol (24 dogs), both given intravenously. Immediately following the induction of anaesthesia, gastric pressure and lower oesophageal sphincter pressure (LOSP) were measured and oesophageal barrier pressure determined. There were no significant differences attributable to the premedication regimens used but both LOSP and barrier pressure were significantly lower in the dogs anaesthetised with propofol compared to the animals given thiopentone (LOSP 12-2 ± 4-2 cm H2O propofol group versus 26-8 ± 6-5 cm H2O thiopentone group).

Fifty dogs were investigated in order to correlate the length and position of the lower oesophageal sphincter (LOS) with external measurements. Various external measurements were taken while the dogs were anaesthetised and positioned in lateral recumbency. An oesophageal tube was then introduced into the oesophagus and thoracic radiographs were taken. The 'real internal length of the oesophagus' was calculated as the length from the lower jaw incisor tooth to the position of the oesophageal tube at the costal border of the diaphragm. A highly significant linear correlation was found between this internal length and the external length from lower jaw incisor tooth to the anterior border of the head of the 10th rib. Using oesophageal manometry, the length and position of the LOS was also studied in 25 clinically normal bitches. The mean length of the LOS was found to be 4.6 +/- 0.92 cm. The position of the LOS was a mean of 4.4 +/- 1.69 cm cranial to the costal border of the diaphragm. The findings of this study indicate that the external measurements can be used to position catheters for accurate oesophageal manometry in the dog.

The effect of metoclopramide (0.4 mg/kg, IM) on lower oesophageal sphincter pressure (LOSP) and barrier pressure (BrP) were studied manometrically (non-perfused with strain gauge pressure transducer) in 30 dogs undergoing ovariohysterectomy. Premedication (45–50 min prior to anaesthesia) consisted of either acepromazine (0.1 mg/kg, IM) plus 1 mg/kg (IM) pethidine (ACP + P) or their combination with metoclopramide which was given 5–7 min either before or after the other drugs. Studies of continuous tracings taken for 1 min at 10 min interval during surgery have suggested that if metoclopramide is given prior to ACP + P it can restore BrP to a significantly (Unpaired “t” test) higher level than when it is given subsequently or not used at all. It seemed that if the effect of ACP+P on the LOS initiated by metoclopramide is incapable of maintaining or restoring BrP. It has also been suggested that metoclopramide is unable to maintain a significantly higher level of LOSP in anaesthetized dogs irrespective of the time of its administration. However, if it is used before ACP+P it lowers the risk of gastro-oesophageal reflux (GOR) by maintaining a better barrier pressure.

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.

A comparison of the analgesic potency of the alpha 2-adrenoceptor agonist, xylazine, in control healthy sheep and sheep suffering chronic pain from footrot, indicated that the analgesic effectiveness of xylazine was significantly reduced in the animals experiencing chronic pain. This was measured by recording the threshold to a mechanically applied pressure stimulus. Furthermore, when the condition was apparently resolved, by conventional treatment over a period of 2 to 3 weeks, the decreased analgesic effectiveness of the alpha 2-agonist was still apparent although the animals were clinically cured of the footrot.

Summary The urinary excretion of pethidine and its major metabolite, norpethidine, was investigated in four male dogs given pethidine as a postoperative analgesic. The urinary excretion of pethidine in the first 4 h after drug administration was low at 1·9% of the administered dose. The percentage of the drug excreted as norpethidine was also low at 3·7% but there was a great deal of individual variation. Urinary excretion, therefore, appears to be a minor route in the clearance of pethidine in the dog.

Summary The influence of repeated intra-articular injections of sodium hyaluronate and polysulphated glycosaminoglycan on the repair of full-thickness osteochondral defects was examined in the midcarpal joints of ponies. The study showed no significant difference between treated and control groups with regard to total collagen content, uronic acid content or the relative proportions of Type I and Type II collagen in the repair tissue, indicating that the drugs did not affect the biochemical composition of the repair tissue 11 weeks after defect induction.

Plasma cortisol, prolactin and vasopressin concentrations were measured by radioimmunoassay in blood samples from control and lame sheep. The lame sheep were all suffering from naturally occurring clinical cases of footrot and showed all the behavioural characteristics of chronic pain; they were scored for impairment of gait and pathology of the foot and divided into mild and severely lame groups. The severely lame sheep had increased plasma prolactin and decreased plasma cortisol concentrations. Plasma vasopressin was variable and showed no consistent changes with lameness. The relationships between plasma cortisol, prolactin and vasopressin may be a useful index in the assessment of animals experiencing chronic pain, when taken in conjunction with other measurements.

A device capable of testing the nociceptive threshold to mechanical stimuli has been developed for use in horses. It was operated by compressed gas and was designed so that the part attached to the horse was semi disposable. The stimulus was applied via a 2mm diameter blunt ended pin and had a number of safety features incorporated in the design to ensure that the maximum force applied was 27 newtons. The device has been used to assess the response to detomidine in a group of thoroughbreds and has proved reliable and robust in use.

Systemic administration of remoxipride, a dopamine (D2) antagonist, to sheep has previously been shown to generate an antinociceptive action without producing a significant motor impairment. The present study examined whether a spinal locus of action was responsible for this action of remoxipride. Remoxipride (17.7 mg) administered intrathecally via chronically indwelling catheters produced a greatly variable but significant (p0.05) increase in nociceptive thresholds as judged by a focused mechanical stimulus (blunt pin) applied to the forelimb of four sheep. However, this dose of remoxipride induced a marked forelimb motor impairment as judged by a subjective visual analogue scoring system. Conversely, intrathecal xylazine (100 and 200 microg), an alpha-adrenergic agonist with antinociceptive properties, did not produce forelimb weakness although the higher dose (200 microg) produced significant sedation. In vitro autoradiography was performed on cervical spinal cord sections taken from sheep. Remoxipride displaced [3H] YM-09151-2, a selective D2 antagonist, from densely-labelled areas in the superficial layer of the dorsal horn, lamina X and ventral horn. Even though there are possible anatomical substrates within the spinal cord for both an antinociceptive and motor disturbance action of remoxipride, the behavioural data suggest that the spinal cord is unlikely to be the primary site of antinociceptive action for systemically-administered doses of remoxipride.

The development of central hypersensitivity as a result of a routine surgical procedure, midline ovariohysterectomy, was investigated in rats using the paw pressure test (PPT) and tail-flick latency (TFL) tests of spinal reflex activity. In addition, the modulating effect of pre-emptive versus post-operative administration of pethidine (a short-acting pure mu-opioid agonist) on the development of central hypersensitivity was studied. Initial experiments indicated that pethidine (15 mg/kg, i.m.) gave sub-maximal increases in thresholds for 60 min, and also that the administration of an anaesthetic did not unduly prolong the action of pethidine. Subsequently, 24 female Wistar rats were allocated to 1 of 4 treatment protocols: (1) anaesthesia without analgesics; (2) anaesthesia and surgery (midline ovariohysterectomy) without analgesics; (3) anaesthesia and surgery with pre-operative administration of pethidine; (4) anaesthesia and surgery with post-operative administration of pethidine. Thirty-five minutes after the end of anaesthesia thermal and mechanical nociceptive thresholds were measured at stepwise increasing intervals for 480 min. Changes were expressed as percentage changes from baseline (PPT) or deviation from expected values (TFL). Area under the threshold versus time response curves (AUCs) were also calculated for the following time sectors: 30-90, 90-150, 150-270, 270-390 and 390-510 min post-anaesthetic. Results of the TFL testing did not indicate the development of any significant hyperalgesia in any groups, but the results of the PPT did. In the time sectors 150-270 and 270-390 min post-anaesthetic, the AUCs in rats subjected to anaesthesia and surgery with either post-operative administration of pethidine or surgery with no analgesic drug administration, were significantly lower than the AUCs in rats given analgesics pre-operatively or those subjected to general anaesthesia alone (P < 0.01), Mann-Whitney). In summary, it appears that pethidine, in this protocol, prevented the development of surgically induced hyperalgesia when it was given pre-emptively.

Threshold responses to a mechanical pressure test were measured in two groups of adult female sheep taken from 27 flocks in north Devon. The first group consisted of 470 healthy sheep and the second of 139 sheep suffering from obvious lameness, clinically diagnosed as foot rot. The lame sheep were assessed for the severity of the lesion and the level of lameness and assigned a score. In flocks with sheep with a severe degree of lameness, the sheep had a significantly lower threshold to a mechanical nociceptive stimulus than their matched sound controls and their thresholds remained low when tested three months later, after the apparent resolution of the foot rot lesion. In flocks where the lame sheep were less severely affected there was no difference in the threshold responses to a mechanical stimulus between the sound and lame sheep.

The analgesic effects of the non-steroidal anti-inflammatory drugs (NSAIDs) flunixin and dipyrone were assessed in healthy sheep with no pre-existing inflammation, and in sheep with a chronic inflammatory lesion, using a mechanical noxious stimulus. Saline and dexamethasone were given as controls. Blood taken from healthy sheep after NSAID administration was assayed for thromboxane B2 (TxB2) to compare the ability of these drugs to inhibit cyclo-oxygenase. Both flunixin and dipyrone produced a small but statistically significant rise in pain thresholds (18% and 21% of maximum possible effect respectively) in the healthy sheep which peaked at 30 min and had returned to pre-drug values by 2-3 h. In the lame sheep a similar effect occurred but the response was smaller, much more variable and tended to be prolonged. Saline and dexamethasone had no effect on thresholds over 6 h in either group of sheep. The rise in thresholds was prevented by pre-treatment with naloxone (an opioid antagonist) or atipamezole (an alpha 2-adrenergic antagonist) in the healthy sheep. Naloxone and atipamezole had no effect on thresholds when given alone to healthy sheep. Both NSAIDs inhibited the production of TxB2 to a similar extent. These results indicate that central mechanisms may be involved in NSAID analgesia.

The effect of body position on lower oesophageal sphincter pressure (LOSP), gastric pressure and barrier pressure (BrP) was investigated in 40 dogs anaesthetised for neutering procedures. The dogs were placed in lateral recumbency followed by dorsal recumbency (group 1) or vice versa (group 2). LOSP decreased significantly in the animals which were positioned initially in lateral recumbency, when they were then placed in dorsal recumbency, while those initially positioned in dorsal recumbency showed no significant change in their LOSP or BrP when their position was altered to lateral recumbency. When the data from both groups were pooled, LOSP and BrP were significantly lower when the dogs were in dorsal compared to lateral recumbency (P < 0.05).

Plasma cortisol concentrations were measured in two groups of sheep taken from 29 flocks in north Devon. The first group were healthy adult females and the second group were adult females suffering from footrot in one forefoot. These sheep were assessed for the severity of the lesion and the level of lameness and assigned a score. The plasma cortisol concentration was significantly higher in the lame sheep than in the healthy sheep and remained so for up to three months after the apparent resolution of the clinical lesion. There was no correlation between the severity of the footrot and the concentration of plasma cortisol.

Cyanogen bromide was used to solubilise and specifically fragment purified equine Type I and II collagen and equine articular surface repair tissue. The resultant peptides were separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and quantified by densitometric scanning. Measurement of the relative amounts of the peptides alpha 2(I) CB3, 5 and alpha 1(II)CB10 provided an accurate method of establishing the ratio of Type I to Type II collagen in mixtures of purified equine collagens. The method was sensitive to 6% Type II collagen when the band areas were corrected for peptide molecular weight and the number of chains in the parent tropocollagen molecule which contain that particular peptide. Use of this technique showed that repair tissue in full thickness osteochondral defects in the dorso-distal margins of the intermediate carpal bones of ponies did not contain detectable amounts of Type II collagen 11 weeks after defect induction.

Fifty DSH cats were studied radiographically and a highly significant linear correlation was found between the length of the oesophagus measured to the diaphragmatic line on the radiographs and the externally measured distance from the lower jaw incisor teeth to the anterior border of the head of 10th rib. A subsequent manometric study utilizing this correlation in 40 cats suggests that the functional lower oesophageal sphincter (LOS) is situated almost at the level of the diaphragm in the cat. Significant differences were found between the length of the LOS in cats anaesthetized with ketamine compared to alphaxalone-alphadolone or xylazine-ketamine-atropine. The mean lengths of the LOS was 1.42 ± 0.3 cm. The findings of this study indicate that external measurements can be used to position catheters for accurate oesophageal manometry in the cat.

Plasma adrenaline ( AN ) and noradrenaline ( NA ) concentrations were measured by high performance liquid chromatography with electrochemical detection in blood samples from control and lame sheep. The lame sheep suffered from naturally occurring foot rot and showed behavioural characteristics normally associated with chronic pain. The lame sheep were scored both for impairment of gait and pathology of the foot and divided into mild and severely affected groups. Both the mildly and severely lame group showed a significant increase in plasma AD and plasma NA which tended to persist even after clinical resolution of the condition. The measurement of plasma AD and NA may provide information which can be used to assess animals experiencing chronic pain, when taken in conjunction with other parameters, such as nociceptive thresholds and plasma hormone levels.

This paper describes a relatively simple and noninvasive method for the chronic implantation of intrathecal catheters in the sheep. The technique has been carried out on 17 occasions in nine sheep, with 60% of attempted catheterizations producing a correctly positioned, functional catheter. The placement and integrity of the catheters were confirmed by radiography using a contrast medium. Correctly placed catheters have been maintained for up to 16 months without problems.

The plasma concentration of pethidine was measured in 16 horses, after its administration intravenously (i.v.) at a dose rate of 1 mg/kg bodyweight (bwt). In eight animals studied before surgery, the plasma levels of the drug decreased in a bi-exponential manner with a distributive half life of 3 mins and an elimination half life of 57.7 mins. Total body clearance was 17.7 ml/kg bwt/min. The remaining horses were investigated immediately after a period of anaesthesia and surgery and in these animals the drug exhibited smaller volumes of distribution (V1 cand Vdarea) and a significantly lower clearance rate of 12.8 ml/kg bwt/min in these animals. Correlation between the plasma concentration of pethidine and information published previously on the duration of action of the agent in the horses suggests that plasma levels of approximately 0.4 microgram/ml are required to produce analgesia in this species.

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.

Waterman, A.E. & Kalthum, W. The effect of clinical hepatic disease on the distribution and elimination of pethidine administered post-operatively to dogs. J. vet. Pharmacol. Therap. 13, 137–147. The pharmacokinetics of pethidine were investigated in dogs suffering from portosystemic vascular shunts and hepatic parenchymal disease. The drug was administered post-operatively at a dose rate of 2.0 mg/kg either intravenously or intramuscularly. When the drug was given intravenously to dogs suffering from intrahepatic shunts, the elimination half life was 75.5 ± 4.2 min and the clearance rate was 29.0 ± 2.3 ml/kg min. When the drug was given intramuscularly its rate of absorption was very slow (57.9 ± 6.1 min) and the time taken to reach the maximum plasma concentration was long at 26.7 ± 6.4 min. The elimination half-life for the intramuscularly administered drug was also very slow at 108.0 ± 13 min, reflecting the reduced ability of these dogs to metabolize and eliminate pethidine. These findings suggest that caution should be exercised in the administration of pethidine to dogs suffering from hepatic dysfunction. In particular, the slower rate of absorption should be remembered in judging whether or not maximum effects have been achieved and the longer elimination half-life indicates the need to extend the intervals between repeat doses of this analgesic. A. E. Waterman, Department of Veterinary Surgery, University of Bristol, Langford House, Langford, Bristol BS18 7DU, UK.

The assessment of analgesia in conscious unrestrained farm animals presents particular problems. In order to provide a reliable nociceptive stimulus, two devices have been constructed, one that provides a threshold reading for a ramped thermal stimulus of the pinna of the ear and another that measures a threshold reading for a pressure stimulus to the foreleg. Both devices allow the rapid termination of the stimulus once a reaction has occurred and allow repeated readings without causing tissue damage. Examples of the analgesic action of α 2 -adrenoceptor agonists and opioids measured by using the two pieces of apparatus are shown.

Summary The plasma concentration-time profiles of pethidine following a single bolus dose by intravenous injection in normal dogs and in dogs in the immediate postoperative period can be fitted into a biexponential equation, Cp = Ae -at + Be -βt . The rate of distribution was significantly reduced when a comparatively higher dose rate (3.5 mg/kg) was used in normal dogs but no other differences were seen in the rest of the kinetic parameters. On the other hand using the same dose rate (2 mg/kg) the kinetic constants of both ∝ and β phases in normal and post-surgical dogs were not significantly different, with their respective β half-lives of 36.59 ± 5.98 min and 52.54 ± 11.94 min. However, the distribution volumes and the total body clearance were markedly reduced in surgical as compared to normal dogs. Thus there were differences between the pharmacokinetics of pethidine in normal when compared to dogs undergoing surgical manipulations.

Arterial blood samples were collected under sedation, from the femoral artery of 35 dogs suffering from laryngeal paralysis. Pre-operatively, the dogs showed a moderate degree of arterial hypoxaemia (mean PaO2 77 mmHg), with the worst affected clinically showing the most severe hypoxia. Following corrective surgery there was a significant improvement in PaO2 tensions (90 mmHg). A group of 20 control dogs were also sedated and sampled. Their mean arterial oxygen tension was 91 mmHg, indicating that the pre-operative hypoxaemia found in the dogs with laryngeal paralysis was not the result of sedation.

Xylazine and clonidine, given intravenously, cause an increase in airway pressure in the anaesthetized, ventilated sheep. This increase was dose dependent and was not mediated by histamine, nor was it blocked by the alpha 1-adrenoceptor antagonist prazosin. However, the increase was abolished by the alpha 2-adrenoceptor antagonist, idazoxan. When the alpha 2-adrenoceptor agonists were administered into the cerebrospinal fluid by injection into the cisterna magna there was no increase in airway pressure, although a similar dose given peripherally still produced an effect. These findings would indicate that the increase in airway pressure seen in these sheep, following administration of xylazine and clonidine, was mediated by peripherally located alpha 2-adrenoceptors.

Disturbances of fluid and electrolyte balance may occur in the horse as a consequence of many disease processes. Disorders may be classified into 3 main categories, primary water loss, mixed water and electrolyte depletion and acid base disturbances. This paper reviews the changes which occur with each type of disorder and discusses methods of diagnosis and assessment of such imbalances. The principles of treatment are described and the management of fluid replacement therapy in 3 of the disorders, mainly acute intestinal obstruction, inability to drink and diarrohea is discussed.

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.

The plasma concentration of pethidine was measured after it had been administered intramuscularly to fully conscious dogs, and to dogs in the postoperative period and during general anaesthesia. The absorption of the drug was erratic except in the anaesthetised animals and the plasma concentrations of the drug were also higher in this group. Correlation of plasma concentrations of the drug with its analgesic activity revealed a 'critical' concentration of pethidine of 0.4 micrograms/ml for complete analgesia; useful though not complete analgesia was achieved with concentrations above 0.2 micrograms/ml. These concentrations were maintained for 90 minutes after the administration of the drug at a dose of 2.0 mg/kg and for 120 minutes after a dose of 3.5 mg/kg.

The effects of intravenous injections of ketamine in sheep on the cardiovascular and respiratory systems are compared with the effects of intracerebroventricular injections of the same drug and also with the effects of intravenous barbiturate and steroid anaesthetics. Intravenously administered ketamine caused an initial fall in arterial blood pressure the extent of which was dose dependent. This depression was short lived and was occasionally followed by a mild pressor phase. Intracerebroventricular injection of the drug provoked only a mild transient rise in mean arterial blood pressure. The intravenous injection of ketamine gave a brief period of respiratory depression which was mirrored in the PaO2 and PaCO2 levels followed by a period of respiratory stimulation with elevated PaO2, levels. The comparison of the three injection anaesthetics showed that the blood gas tensions with ketamine showed there was a brief period of respiratory depression similar to that seen with the steroid anaesthetic but that the barbiturate caused a much longer depression. The blood gas tensions following the steroid anaesthetic soon returned to normal while the tensions following ketamine indicated an elevated PaO2, after the initial depression. The blood gas tensions following intracerebro-ventricular injection of ketamine were difficult to evaluate due to the variable period of apnoea which followed the injection.