Further development of equipment to measure nociceptive thresholds in large animals

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.     

An assessment of the peripheral antinociceptive potential of remoxipride, clonidine and fentanyl in sheep using the forelimb tourniquet

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 μg/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 μg/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.     

Development of a technique for continuous perineural blockade of the palmar nerves in the distal equine thoracic limb

Objective To develop a technique for placing continuous peripheral nerve block (CPNB) catheters adjacent to palmar nerves in horses and to evaluate the effect of low‐volume local anesthetic (LA) infusion on nociception in the distal equine thoracic limb. Study design In vitro and in vivo laboratory investigation. Study material and animals Forty‐two thoracic limbs from 22 equine cadavers and five horses. Methods Thoracic limb specimens were dissected to find landmarks for catheter insertion adjacent to medial and lateral palmar nerves. Based on the anatomy of the proximal metacarpus, a technique for placing palmar CPNB catheters was developed and the potential for catheter dislodgement studied in vitro by fluoroscopic visualization during passive carpal flexion and dye injection following simulated limb motion. The feasibility of CPNB catheter instrumentation in standing, sedated horses was tested in five animals, with ultrasound control. Electrical and mechanical stimulation thresholds and response latencies for hoof withdrawal responses (HWR) were determined following saline or LA infusion. Results Medial and lateral CPNB catheters were inserted percutaneously 2 and 4–5 cm, respectively, distal to the accessory carpal bone and advanced for ～7 and 10 cm, respectively, to place the tip just proximal to the communicating branch of the nerves. Catheters were placed correctly in 88% and 85% of cadaver limbs. In the standing horses, LA infusion not only increased HWR thresholds and latencies to noxious mechanical or electrical stimulation but also caused vasodilation and limb swelling over time. Conclusion The technique, developed in vitro, for placing and maintaining palmar CPNB catheters in the equine thoracic limb was successfully applied in vivo. Catheters were well tolerated but LA infusion may cause limb swelling, suggesting a need for further exploration of drug and infusion regimens. Clinical relevance Continuous perineural LA infusion along palmar nerves may develop into an effective analgesic technique in horses suffering from lower limb pain.     

Involvement of opioidergic and alpha2-adrenergic mechanisms in the central analgesic effects of non-steroidal anti-inflammatory drugs in sheep

The level within the central nervous system where non-steroidal anti-inflammatory drugs (NSAIDs) produce analgesia and the mechanisms by which they mediate this effect are still uncertain. This study assessed the central analgesic effects of ketoprofen, phenylbutazone, salicylic acid and tolfenamic acid in sheep implanted with indwelling intrathecal (i.t.) catheters and submitted to mechanical noxious stimulation. The sheep received i.t. cumulative concentrations (0.375-200 microM; 100 microL) as well as a single intravenous (i.v.) dose (3, 8, 10 and 2 mg/kg, respectively) of each NSAID. The sheep were also given i.t. naloxone (5.49 mM; 100 microL) and atipamezole (4.03 mM; 100 microL) prior to i.v. ketoprofen. None of the i.t. NSAIDs increased mechanical thresholds. Intravenously, only ketoprofen and tolfenamic acid raised the pain thresholds. The hypoalgesic effect of i.v. ketoprofen was prevented by i.t. naloxone or atipamezole. Although NSAIDs had no direct effect on the spinal cord, their analgesic action appeared to be spinally mediated.     

The effects of opioid and α2 adrenergic blockade on non-steroidal anti-inflammatory drug analgesia in 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 attpamezole (an α₂-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.     

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.     

Analgesic and anti-hyperalgesic effects of epidural morphine in an equine LPS-induced acute synovitis model

Epidural morphine is widely used in veterinary medicine, but there is no information about the anti-hyperalgesic and anti-inflammatory effects in acute inflammatory joint disease in horses. The analgesic, anti-hyperalgesic and anti-inflammatory effects of epidural morphine (100mg/animal or 0.17±0.02mg/kg) were therefore investigated in horses with acute synovitis. In a cross-over study, synovitis was induced in the talocrural joint by intra-articular lipopolysaccharide (LPS). The effect of epidural morphine was evaluated using physiological, kinematic and behavioural variables. Ranges of motion (ROM) of the metatarsophalangeal and talocrural joints were measured, clinical lameness scores and mechanical nociceptive thresholds (MNTs) were assessed and synovial fluid inflammatory markers were measured. The injection of LPS induced transient synovitis, resulting in clinical lameness, decreased ranges of motion in the talocrural and metatarsophalangeal joints, decreased limb loading at rest and increased composite pain scores. Epidural morphine resulted in a significant improvement in clinical lameness, increased ROM and improved loading of the LPS-injected limb at rest, with no effects on synovial fluid inflammatory markers. Morphine prevented a decrease in MNT and, hence, inhibited the development of hyperalgesia close to the dorsal aspect of inflamed talocrural joints. This study showed that epidural morphine provides analgesic and anti-hyperalgesic effects in horses with acute synovitis, without exerting peripheral anti-inflammatory effects.     

Use of a new finger-mounted device to compare mechanical nociceptive thresholds in cats given pethidine or no medication after castration

Mechanical nociceptive thresholds are regularly used to determine the efficacy of analgesic agents both experimentally and clinically in a variety of species. The 'pressure of palpation device' (PPD) was developed for use in cats and is a small battery operated device with a finger-mounted force sensing resistor (FSR, Interlink Electronics, Northumberland. UK). The PPD was used in a study assessing the analgesic efficacy of pethidine after castration in cats. Pethidine was demonstrated to prevent the development of post-operative scrotal hypersensitivity for up to 2 hours after castration, whereas cats given no analgesics showed marked hyperalgesia immediately after surgery. Visual Analogue Scale (VAS) pain scores after castration showed a similar analgesic effect of pethidine. These results suggest that the PPD could become a useful research tool to assess the effectiveness of analgesic agents in the cat.     

Centrally administered verapamil prevents the autonomic reaction to visceral pain in sheep

The significant role of voltage gated calcium channels (VGCC) L-type antagonists used concomitantly with opioids in attenuation of clinical pain has been confirmed. The aim of this study was to evaluate the effect of centrally administered verapamil on behavior and biochemical parameters in sheep that have undergone experimental duodenal distension (DD) and to determine whether verapamil exerts any anti-nociceptive effects under these conditions. The study was carried out using 24 mature crossbred ewes, each weighing 38-43 kg. Verapamil, a VGCC blocker, was administered through an intracerebroventricular cannula at the following doses: 0.25, 0.5, 1.0 and 2.0 mg in toto. Ten minutes later experimental DD was conducted by insertion and the distension of rubber balloon (containing 40 ml of warm water) inserted into sheep duodenum. After 5 min of mechanical DD the following reactions were then observed: the significant increase in behavioral pain responses, i.e. tachycardia, hyperventilation, inhibition of reticulo-ruminal contractions (70% approximately, during 15 min), an increase of plasma catecholamine concentration (over 7-fold increase of epinephrine during 2 h following DD, 2-times norepinephrine and ±80% increase of dopamine). Verapamil infusion administered 10 min prior to DD decreased intensity of visceral pain responses, such as: behavioral changes, tachycardia, hyperventilation, inhibition of the reticulo-rumen motility and efficiently prevented the appearance of catecholamine release. These data demonstrated that the development and persistence of duodenal hyperalgesia depends on the activation of Ca²⁺ ion flux leading to neurotransmitters release and modulation of membrane excitability. The observed antinociceptive action of VGCCs type-L blockers suggests that these channels play a crucial role in the modulation of acute visceral hyperalgesia in sheep.     

The anti-nociceptive efficacy of low dose intramuscular xylazine in lambs

The anti-nociceptive effects of 50 microg kg(-1)of intramuscular xylazine were examined in seven lambs of 4-6 weeks of age using an electrical nociceptive testing method. Lamb anti-nociception increased from an average baseline of 5.88+/-0.72 mA to an average peak value of 13.66+/-1.49 mA at 21 minutes (mean+/-SEM) after the dose, and remained above baseline for the duration of the experimental period (60 minutes). All values were significantly above baseline from 5 minutes post-xylazine administration onwards. These data were also compared with previously published data from adult sheep undergoing the same treatment. There were no differences in the analgesic response between the adult or lamb groups suggesting xylazine dose requirements scale with bodyweight and are unaffected by age over this range. These findings support the use of xylazine as an effective analgesic in sheep with comparable effects and consistent dosing requirements per unit body weight between adult sheep and lambs.     

Blood pressure response to tourniquet use in anesthetized horses

Blood pressure during anesthesia and surgery was compared for 2 groups of horses. Group A, consisting of 23 horses, had a tourniquet placed on the distal portion of a limb. The other group of 20 horses (group B) had surgery of comparable nature and duration as did group-A horses, but a tourniquet was not used. There was a statistical difference (P less than 0.05) in the peak systolic arterial blood pressure between the groups; group-A horses had a mean (+/- SEM) peak of 151 +/- 6 mm of Hg and group-B horses had a peak of 118 +/- 4 mm of Hg. In addition, group-A horses had immediate decrease in blood pressure, coincident with tourniquet deflation. The blood pressure decrease of 23 +/- 3 mm of Hg represented 16% of immediate predeflation blood pressure. Comparable blood pressure decrease was not observed at the end of surgery in group-B horses. Significant difference was not found when other factors that could affect blood pressure were considered. These factors included preanesthetic medication, anesthetic agents, mode of ventilation, pretourniquet inflation blood pressure, and duration of tourniquet inflation. Significant (P less than 0.05) difference in peak blood pressure was observed when the tourniquet was placed on the dependent, compared with the uppermost, limb, with changes more pronounced when the tourniquet was placed on the dependent limb. Tourniquet placement was associated with hypertension, and tourniquet deflation was associated with blood pressure decrease in these anesthetized horses.     

Comparison of 2 techniques for regional antibiotic delivery to the equine forelimb: intraosseous perfusion vs. intravenous perfusion

The purpose of this study was to compare the synovial fluid concentrations and pharmacokinetics of amikacin in the equine limb distal to the carpus following intraosseous and intravenous regional perfusion. The front limbs of 6 horses were randomly assigned to either intraosseous or intravenous perfusion. A tourniquet was placed distal to each carpus and the limb perfused with 500 mg of amikacin. Systemic blood samples and synovial fluid samples were collected over 70 min from the distal interphalangeal (DIP) joint, metacarpophalangeal joint, and digital flexor sheath. The tourniquet was removed following the 30 min sample collection. The mean peak amikacin concentration for the DIP joint was significantly higher with intravenous perfusion. There were no significant differences in time to peak concentration or elimination half-life between methods at each synovial structure. Each technique produced mean peak concentrations ranging from 5 to 50 times that of recommended peak serum concentrations for therapeutic efficacy.     

Evaluation of a Midhumeral Block of the Radial,Ulnar, Musculocutaneous and Median (RUMM Block) Nerves for Analgesia of the Distal Aspect of the Thoracic Limb in Dogs

Objective: To evaluate a technique for midhumeral peripheral nerve blockade in the dog. Study Design: Cadaveric technique development; in vivo placebo‐controlled, prospective crossover study. Animals: Canine cadavers (n=38) and 8 clinically healthy, adult hound dogs. Methods: A technique for peripheral block of the radial, ulnar, musculocutaneous, and median nerves (RUMM block) was evaluated using cadaver limbs. Eight purpose‐bred, research dogs were anesthetized; a RUMM block was performed on each thoracic limb. One limb from each dog randomly received 0.5% bupivacaine and the opposite limb was assigned to receive sterile saline solution as a control. After recovery from anesthesia, skin sensation at selected dermatomes was evaluated for 24 hours using a mechanical stimulus. Weight‐bearing, conscious proprioception, and withdrawal reflex were also evaluated. One month after initial testing, each dog was reanesthetized and each limb received the opposite treatment. Results: Sensory thresholds were significantly increased over baseline measurements when compared with control limbs for all nerves. Complete sensory block was achieved in radial (15/16), ulnar (3/16), musculocutaneous (8/16), and median (11/16) nerves, using a mechanical stimulus of analgesia. Complete simultaneous block of all nerves was only obtained in 1 of 16 limbs. Conclusion: RUMM block resulted in desensitization of the skin in the associated dermatomes for 4–10 hours. Complete sensory block of the dermatomes supplied by the radial nerve was most consistent. Clinical Relevance: RUMM block may be an effective technique to provide adjunctive analgesia for dogs undergoing surgery of the distal aspect of the thoracic limb.     

Effects of limb tourniquet ischemia on local and systemic acid-base and blood gases of cattle.

Effects of forelimb tourniquet ischemia of 90 minute duration were investigated in six bulls aged two to three years. Studies were also conducted up to 150 minutes after release of the tourniquet. Parameters investigated were pH, PCO2, PO2, oxygen saturation and HCO3. In systemic circulation no variations in different parameters were observed during 90 minutes of ischemia. However, significant increase in arterial and venous pH were observed after 30 and 45 minutes of the release of tourniquet, respectively. These increases were accompanied by an increase in HCO3. In the affected limb, ischemia resulted in severe acidosis with a significant increase in PCO2 and a nonsignificant decrease of HCO3. There was a significant fall in PO2 and oxygen saturation. After release of the tourniquet, limb venous pH increased significantly due to a significant fall in PCO2 and a nonsignificant increase in HCO3. A significant increase in the limb venous PO2 and oxygen saturation post tourniquet was observed up to the end of the experiments. There was evidence of very poor oxygen exchange and utilization up to 150 minutes after release of the tourniquet. These results demonstrated that tourniquet ischemia of 90 minutes duration of the limb of cattle may not be safe.     

An analgesic evaluation of isoxsuprine in horses

Isoxsuprine is used clinically to treat navicular disease and laminitis in horses. Although it is thought to increase digital and laminar blood flow, isoxsuprine's mechanism of action remains controversial, and analgesia has been suggested recently as such possible mechanism. This research investigated the analgesic potential of isoxsuprine in healthy horses submitted to a mechanical nociceptive test. Isoxsuprine (1.2 mg/kg), xylazine (1.1 mg/kg), distilled water : ethanol 95% (2 : 1, v/v, 20 ml) and saline (0.9%, 20 ml) were injected intravenously, and nociceptive thresholds were measured over 90 min. Only xylazine significantly increased nociceptive thresholds, confirming that alpha(2)-adrenoceptor agonists produce analgesia in horses. Our results do not support an analgesic mechanism of action for isoxsuprine in horses, suggesting that other mechanisms might account for the clinical efficacy of this drug or that mechanical nociceptive testing may not be sufficiently sensitive to demonstrate an analgesic effect for this drug.     

Effects of preoperative epidural administration of racemic ketamine for analgesia in sheep undergoing surgery

OBJECTIVE: To investigate the effects of preoperative epidural administration of racemic ketamine to provide analgesia in sheep undergoing experimental hind limb orthopedic surgery. ANIMALS: 12 adult sheep (weight range, 51.4 to 67.2 kg). PROCEDURE: Sheep were anesthetized with guaifenesin, thiopental, and isoflurane; after induction of anesthesia, sheep received a lumbosacral epidural injection of ketamine (1 mg/kg; n = 6) or saline (0.9% NaCl) solution (1 mL/7 kg; 6 [control group]). Respiratory and cardiovascular variables were recorded before and at intervals during and for 6 hours after anesthesia. During that 6-hour postoperative period, analgesia was evaluated subjectively with a numeric ranking scale that included assessments of comfort, posture, movement, and response to wound palpation; buprenorphine was administered when a score > 3 (maximum score, 10) was achieved. Rectal temperature, heart and respiratory rates, and lameness were evaluated daily for 2 weeks after surgery. RESULTS: At all evaluations, cardiovascular and respiratory variables were comparable between the 2 groups. Compared with control sheep, time to first administration of rescue analgesic was significantly longer and total dose of buprenorphine administered during the 6- hour postoperative period was significantly decreased for ketamine-treated sheep. During the second week following surgery, ketamine-treated sheep had significantly less lameness than control sheep. CONCLUSIONS AND CLINICAL RELEVANCE: In sheep undergoing hind limb surgery, preoperative epidural administration of ketamine appears to provide analgesia in the immediate postoperative period and has residual analgesic effects, which may contribute to more rapid return of normal function in surgically treated limbs.     

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.     

Epidural analgesia with a combination of bupivacaine and buprenorphine in rats

We determined the analgesic effects of epidural administration of either bupivacaine at 62.5, 125, 250, and 500 micrograms/kg; buprenorphine at 5 and 10 micrograms/kg; and the combination of bupivacaine at 125 micrograms/kg and buprenorphine at 5 or 10 micrograms/kg, using the tail flick (TF) and colorectal distension (CD) tests in rats and compared the results with those obtained using morphine at 100 micrograms/kg. In both the TF and CD tests, all doses of bupivacaine alone produced potent anti-nociceptive effects, although the effect rapidly diminished after 20-30 min of administration. The administration of buprenorphine at 10 and 5 micrograms/kg produced mild to moderate anti-nociceptive effects in both the TF and CD tests, and the effects were relatively constant throughout the 2-h experimental period. Combinations of 5 or 10 micrograms/kg of buprenorphine with 125 mg/kg of bupivacaine produced a significantly higher percentage of maximum possible analgesic effect (%MPE) than that of the calculated additive effect of each drug alone in the TF and CD tests. The analgesic effect of this combination was similar to that of morphine. Minimal ataxia was observed in rats administered this combination.     

Pharmacokinetics of ceftiofur in the metacarpophalangeal joint after standing intravenous regional limb perfusion in horses

This study investigated the pharmacokinetics of ceftiofur after intravenous regional limb perfusion (IVRLP). Six horses were involved in 3 IVRLP sessions. For each session, operators with varying clinical experience placed the tourniquet. A wide-rubber tourniquet was applied in the antebrachium as 2 g of ceftiofur in a total volume of 100 mL was injected into the cephalic vein. Plasma and metacarpophalangeal synovial fluid samples were obtained to evaluate perfusate leakage and synovial fluid concentrations of ceftiofur over 24 h. Overall, mean plasma concentrations were not significantly different before and after tourniquet removal. Mean synovial fluid ceftiofur concentrations were significantly higher 5 min and 8 h after tourniquet removal versus 24 h, after which values above the minimum inhibitory concentration (MIC) (1 μg/mL) were not detected. Concentrations above the MIC were detected in 72% and 50% of the horses at 5 min and 8 h, respectively. Overall, higher synovial fluid concentrations were obtained for the operator with the most recent clinical experience performing IVRLP.     

Pre-emptive epidural ketamine or S(+)-ketamine in post-incisional pain in dogs: a comparative study

OBJECTIVE: To compare the pre-emptive analgesic effects of epidural ketamine or S(+)-ketamine on post-incisional hyperalgesia. STUDY DESIGN: Prospective randomized study. ANIMALS: Twenty-four mongrel dogs (1-5 years, weighing 11.9+/-1.8 kg). METHODS: Dogs were anesthetized with propofol (5 mg/kg intravenously) and a lumbosacral epidural catheter was placed. Dogs were randomly allocated to 3 groups, each with 8 dogs. The control group (CG) was administered saline solution (0.3 mL/kg); the ketamine group (KG) ketamine (0.6 mg/kg); and the S(+)-ketamine group (SG) S(+)-ketamine (0.6 mg/kg). The final volume was adjusted to 0.3 mL/kg in all groups. Five minutes after the epidural injection a surgical incision was made in the common pad of the right hind limb and was immediately closed with simple interrupted nylon suture. Respiratory (RR) and heart (HR) rates, rectal temperature (T), sedation (S), lameness score, and mechanical nociceptive threshold by von Frey filaments were evaluated before the propofol anesthesia and at 15, 30, 45, 60, 75, and 90 minutes and then at 2, 4, 6, 8, 12, and 24 hours after epidural injection. RESULTS: There were no differences in RR, HR, T, or S between groups. Motor blockade of the hind limbs was observed during 20+/-3.6 minutes in KG and during 30.6+/-7.5 minutes in SG (mean+/-SD). Mechanical force applied to obtain an aversive response was higher from 45 minutes to 12 hours in KG and from 60 to 90 minutes in SG, when compared with CG. CONCLUSIONS: Pre-emptive epidural ketamine induced no alterations in RR and HR, and reduced post-incisional hyperalgesia for a longer time than did S(+) ketamine. CLINICAL RELEVANCE: Although anesthetic and analgesic potency of S(+) ketamine is twice that of ketamine, the racemic form is seemingly better for post-incisional hyperalgesia.