Ignacio A. Gómez de Segura

Efficacy of tolfenamic acid and meloxicam in the control of postoperative pain following ovariohysterectomy in the cat

OBJECTIVE The hypothesis was that Visual Analog Scale (VAS) scores would be lower, and mechanical wound thresholds (MWT) higher, in cats receiving tolfenamic acid compared to those receiving placebo in the postoperative period following elective ovariohysterectomy. ANIMALS Sixty-nine client-owned cats. METHODS A prospective, randomized, blinded and placebo-controlled study was performed in cats which underwent ovariohysterectomy following preoperative tolfenamic acid, meloxicam, or placebo. A second dose of the same analgesic was administered 24 hours postoperatively. Assessments were made 1-hour before induction and 1, 2, 4, 6, 22, and 25 hours postoperatively. Pain was assessed by a blinded observer using Numerical Rating (NRS) and VAS scales. The MWT were measured using a force-measuring device. Group comparison was performed by using one-way anova and chi-squared test for qualitative and quantitative data, respectively, and a mixed model for repeated measurements (p < 0.05). RESULTS Sixty-five cats were included in the study. There were no differences between groups at baseline. There was a treatment effect on the NRS scores at 6, 22 and 25 hours. The meloxicam group was less painful than controls at 6 and 22 hours; both treatment groups were less painful than controls at 25 hours. There were no differences between groups in VAS for pain or sedation. The number of animals receiving rescue analgesia did not differ between groups. There was a treatment effect on MWT; thresholds in both treatment groups were significantly higher than that observed in controls at all time points. CONCLUSIONS Preoperative tolfenamic acid or meloxicam reduced wound sensitivity following ovariohysterectomy in the cat. CLINICAL RELEVANCE Tolfenamic acid and meloxicam administered preoperatively provided a similar analgesic effect in the postoperative period lasting 24 hours. Mechanical thresholds may be a better way of evaluating postoperative analgesia provided by nonsteroidal anti-inflammatory drugs in cats.OBJECTIVE The hypothesis was that Visual Analog Scale (VAS) scores would be lower, and mechanical wound thresholds (MWT) higher, in cats receiving tolfenamic acid compared to those receiving placebo in the postoperative period following elective ovariohysterectomy. ANIMALS Sixty-nine client-owned cats. METHODS A prospective, randomized, blinded and placebo-controlled study was performed in cats which underwent ovariohysterectomy following preoperative tolfenamic acid, meloxicam, or placebo. A second dose of the same analgesic was administered 24 hours postoperatively. Assessments were made 1-hour before induction and 1, 2, 4, 6, 22, and 25 hours postoperatively. Pain was assessed by a blinded observer using Numerical Rating (NRS) and VAS scales. The MWT were measured using a force-measuring device. Group comparison was performed by using one-way ANOVA and chi-squared test for qualitative and quantitative data, respectively, and a mixed model for repeated measurements (p < 0.05). RESULTS Sixty-five cats were included in the study. There were no differences between groups at baseline. There was a treatment effect on the NRS scores at 6, 22 and 25 hours. The meloxicam group was less painful than controls at 6 and 22 hours; both treatment groups were less painful than controls at 25 hours. There were no differences between groups in VAS for pain or sedation. The number of animals receiving rescue analgesia did not differ between groups. There was a treatment effect on MWT; thresholds in both treatment groups were significantly higher than that observed in controls at all time points. CONCLUSIONS Preoperative tolfenamic acid or meloxicam reduced wound sensitivity following ovariohysterectomy in the cat. CLINICAL RELEVANCE Tolfenamic acid and meloxicam administered preoperatively provided a similar analgesic effect in the postoperative period lasting 24 hours. Mechanical thresholds may be a better way of evaluating postoperative analgesia provided by nonsteroidal anti-inflammatory drugs in cats.

Antinociceptive and motor-blocking action of epidurally administered IQB-9302 and bupivacaine in the dog.

Background and Objectives The aim of this study was to compare the antinociceptive and motor-blocking effects of epidurally administered IQB-9302 (C18 H26N2O. HCl) and bupivacaine in the dog. Methods Twelve adult female Beagle dogs were used. Each animal received 3 concentrations (0.25%, 0.50%, and 0.75%) of either IQB-9302 (n = 6) or bupivacaine (n = 6) by means of a chronic epidural catheter. The nocifensive and motor-blocking status were determined at regular intervals before (baseline) and after drug administration. Results Epidurally administered IQB-9302 caused a more potent nocifensive and motor-blocking action than bupivacaine. The duration of complete nocifensive block was the longest with IQB-9302, whereas the duration of dermatome nocifensive block was similar for both drugs. The nocifensive to motor block ratio was significantly higher with IQB-9302. Conclusions IQB-9302 produced an anesthetic action similar to that of bupivacaine, although the former drug induced a slightly more potent nocifensive block. Nocifensive and motor block duration are very similar with IQB-9302, whereas bupivacaine induces a more prolonged motor block without nocifensive block.

Reduction of the minimum alveolar concentration of isoflurane in dogs using a constant rate of infusion of lidocaine–ketamine in combination with either morphine or fentanyl

The objective of this study was to determine the effects of a constant rate of infusion of lidocaine and ketamine in combination with either morphine or fentanyl on the minimum alveolar concentration of isoflurane (MAC(ISO)) during ovariohysterectomy in dogs. Female dogs (n=44) were premedicated with acepromazine and midazolam. Anaesthesia was induced with propofol and maintained with isoflurane. Dogs received ketamine (0.6 mg/kg/h) and lidocaine (3 mg/kg/h) together with morphine (0.24 mg/kg/h; MLK) or fentanyl (0.0036 mg/kg/h; FLK). The control group received Ringers lactate solution. A skin incision was used as the noxious stimulus. The MAC(ISO) value was obtained with Dixons up-and-down method. MAC(ISO) was 0.7±0.0 vol.% in the control group, 0.3±0.0 vol.% in the MLK group (45% MAC reduction) and 0.0±0.0 vol.% in the FLK group (97% MAC reduction). A combination of fentanyl with lidocaine and ketamine decreased the MAC(ISO) in dogs; this decrease was more pronounced than that produced by morphine, lidocaine and ketamine.

Aspirin synergistically potentiates isoflurane minimum alveolar concentration reduction produced by morphine in the rat.

Background The combination of opioids and nonsteroidal antiinflammatory drugs is more analgesic than the summed effect of each drug administered separately. This synergism has been used to obtain analgesia in the postoperative period at doses at which side effects are minimal. The aim of this study is to evaluate the analgesic interaction between aspirin and morphine in the rat during isoflurane anesthesia. The reduction in minimum alveolar concentration of isoflurane (MACISO) was used as an objective measure of the analgesic potency of individual drugs and their use in combination. Methods Thirty‐seven male Wistar rats were anesthetized with isoflurane in oxygen, and the MACISO was determined before and after the intravenous administration of aspirin and morphine. Rats were administered morphine alone (1, 3, and 10 mg/kg) or morphine (1 and 3 mg/kg) and aspirin (30 mg/kg). The MACISO was determined from alveolar gas samples at the time of tail clamp. The duration of MACISO reduction was recorded. Results Aspirin did not have an effect on MACISO, (average, 1.35 +/− 0.1%), whereas the combination of morphine (1 and 3 mg/kg) and aspirin (30 mg/kg) produced a reduction in the dose of morphine needed to produce the same degree of MACISO reduction. Actual MACISO+drug data were as follows: 1 mg/kg morphine, 1.17 +/− 0.14%; 3 mg/kg morphine, 0.98 +/− 0.15%; 1 mg/kg morphine plus aspirin, 0.90 +/− 0.04%; 10 mg/kg morphine, 0.63 +/− 0.13%; and 3 mg/kg morphine plus aspirin, 0.64 +/− 0.06%. Conclusions The synergistic effects of aspirin and morphine allow a clinically significant reduction in the requirements of isoflurane and isoflurane plus morphine, and these drug combinations may decrease the side effects associated with the use of single higher, equianalgesic doses of these drugs.

Opioid Tolerance Blunts the Reduction in the Sevoflurane Minimum Alveolar Concentration Produced by Remifentanil in the Rat

Background:Acute opioid tolerance is a known entity leading to reduced analgesic efficacy of these drugs in the postoperative period. However, the development of acute opioid tolerance in the very short term, i.e., during the intraoperative period when opioids are being administered, has not been reported. Therefore, the aim of this study was to determine if acute opioid tolerance could develop and limit the opioid-induced reduction in the minimum alveolar concentration (MAC) for inhalant anesthetics. Methods:Male Wistar rats were randomly allocated to receive two doses of remifentanil (120 and 240 &mgr;g · kg−1 · h−1) under sevoflurane anesthesia, and the sevoflurane MAC was determined before and at two time intervals afterwards. In a second experiment, the low dose of remifentanil was increased once an acute opioid tolerance effect was observed. The sevoflurane MAC was determined from alveolar gas samples at the time of tail clamp. Results:A remifentanil constant rate of infusion dose-dependently reduced the sevoflurane MAC from 2.4 to 1.8 ± 0.2 vol% and from 2.3 ± 0.3 vol% to 1.5 ± 0.3 vol%, at the low and high doses, respectively. However, 90 min later, when the sevoflurane MAC was redetermined, the observed reduction was blunted to nearly 50% of the previous sevoflurane MAC values. When this acute opioid tolerance effect was observed with the low dose, the sevoflurane MAC reduction originally achieved could be reattained by doubling the dose; i.e., giving the high dose. Conclusions:Remifentanil efficacy in reducing the sevoflurane MAC diminishes within a short term, suggesting that increased opioid doses may be required to maintain intraoperative analgesia during sevoflurane anesthesia.

Effects of Naloxone on Opioid-induced Hyperalgesia and Tolerance to Remifentanil under Sevoflurane Anesthesia in Rats

Background:Opioid antagonists at ultra-low doses have been used with opioid agonists to prevent or limit opioid tolerance. The aim of this study was to evaluate whether an ultra-low dose of naloxone combined with remifentanil could block opioid-induced hyperalgesia and tolerance under sevoflurane anesthesia in rats. Methods:Male adult Wistar rats were allocated into one of four treatment groups (n = 7), receiving remifentanil (4 µg·kg−1·min−1) combined with naloxone (0.17 ng·kg−1·min−1), remifentanil alone, naloxone alone, or saline. Animals were evaluated for mechanical nociceptive thresholds (von Frey) and subsequently anesthetized with sevoflurane to determine the baseline minimum alveolar concentration (MAC). Next, treatments were administered, and the MAC was redetermined twice during the infusion. The experiment was performed three times on nonconsecutive days (0, 2, and 4). Hyperalgesia was considered to be a decrease in mechanical thresholds, whereas opioid tolerance was considered to be a decrease in sevoflurane MAC reduction by remifentanil. Results:Remifentanil produced a significant decrease in mechanical thresholds compared with baseline values at days 2 and 4 (mean ± SD, 30.7 ± 5.5, 22.1 ± 6.4, and 20.7 ± 3.7g at days 0, 2, and 4, respectively) and an increase in MAC baseline values (2.5 ± 0.3, 3.0 ± 0.3, and 3.1 ± 0.3 vol% at days 0, 2, and 4, respectively). Both effects were blocked by naloxone coadministration. However, both remifentanil-treated groups (with or without naloxone) developed opioid tolerance determined by their decrease in MAC reduction. Conclusions:An ultra-low dose of naloxone blocked remifentanil-induced hyperalgesia but did not change opioid tolerance under inhalant anesthesia. Moreover, the MAC increase associated with hyperalgesia was also blocked by naloxone.

Analgesic and motor-blocking action of epidurally administered levobupivacaine or bupivacaine in the conscious dog

OBJECTIVE To compare the analgesic and motor-blocking effects of epidurally administered levobupivacaine and bupivacaine in the conscious dog. STUDY DESIGN Prospective, randomized, cross-over study. ANIMALS Six adult female Beagle dogs. METHODS Each animal received three doses of levobupivacaine or bupivacaine (0.5, 1.0 and 1.5 mg kg(-1); concentrations 0.25%, 0.50%, and 0.75%, respectively) in a total volume of 0.2 mL kg(-1) by means of a chronically implanted epidural catheter. Onset, duration (through pinch response in the sacral, lumbar and toe areas) and degree of analgesia and motor-blocking status was determined with a scoring system and at regular intervals over 8.5 hours before (baseline) and after drug administration. RESULTS Epidurally administered levobupivacaine and bupivacaine had a similar dose-dependent analgesic action with no significant differences in onset (range: 5-8 minutes), duration (bupivacaine: 42 +/- 28, 135 +/- 68 and 265 +/- 68 minutes, and levobupivacaine: 28 +/- 33, 79 +/- 55 and 292 +/- 133 minutes; 0.25%, 0.50%, and 0.75%, respectively) or maximum degree of analgesia. However, levobupivacaine tended to produce a shorter duration of motor block than bupivacaine and the difference in the motor to nociceptive blockade times was significant at the highest dose. CONCLUSION Epidural levobupivacaine produced an analgesic action similar to that of bupivacaine. CLINICAL RELEVANCE Epidural levobupivacaine is suitable for clinical use in dogs, mostly at the highest dose if a high degree of analgesia is required.

Reduction of the sevoflurane minimum alveolar concentration induced by methadone, tramadol, butorphanol and morphine in rats.

This study aimed to estimate the reduction in the minimum alveolar concentration (MAC) of sevoflurane induced by low and high doses of methadone (5 and 10 mg/kg), tramadol (25 and 50 mg/kg), butorphanol (5 and 10 mg/kg) or morphine (5 and 10 mg/kg) in the rat. A control group received normal saline. Sixty-three adult male Sprague-Dawley rats were anaesthetized with sevoflurane (n = 7 per group). Sevoflurane MAC was then determined before and after intraperitoneal administration of the opioids or saline. The duration of the sevoflurane MAC reduction and basic cardiovascular and respiratory measurements were also recorded. The baseline MAC was 2.5 (0.3) vol%. Methadone, tramadol and morphine reduced the sevoflurane MAC (low dose: 31 ± 10, 38 ± 15 and 30 ± 13% respectively; high dose: 100 ± 0, 83 ± 17 and 77 ± 25%, respectively) in a dose-dependent manner. The low and high doses of butorphanol reduced the sevoflurane MAC to a similar extent (33 ± 7 and 31 ± 4%, low and high doses, respectively). Two rats developed apnoea following administration of high-dose butorphanol and methadone. These anaesthetic-sparing effects are clinically relevant and may reduce the adverse effects associated with higher doses of inhalational anaesthetics.

Growth hormone plus high protein diet promotes adaptation after massive bowel resection in aged rats

OBJECTIVE To determine whether GH improves adaptation following massive bowel resection in the aged rat fed on a high protein-content diet. MATERIAL AND METHODS Seventy-seven male Wistar rats aged 22+/-1 months underwent 80% bowel resection or laparotomy (sham-operation). They were randomly placed into one of eight groups, treated with either growth hormone (1mg/kg/day) or saline, and fed a liquid diet containing either a high or a normal protein content. Intestinal tissue and blood samples were taken seven days after surgery and analysed to measure intestinal mucosal proliferation and mucosal height, as well as plasma levels of IGF-1 and somatostatin. RESULTS Resection of the small bowel in aged rats remarkably increased villous height and crypt proliferation. Growth hormone did not potentiate the increase in mucosal height and crypt proliferation observed after intestinal resection in aged rats fed a normal protein content diet, but did in those receiving a high-protein diet. Plasma levels of IGF-1 and somatostatin were not modified by surgery or treatment. CONCLUSION Growth hormone may increase the adaptation of intestinal mucosa in aged rats undergoing massive intestinal resection, but requires an adequate nutritional support with increased amounts of high quality protein.

Ketamine and remifentanil interactions on the sevoflurane minimum alveolar concentration and acute opioid tolerance in the rat.

BACKGROUND: Ketamine is used at low doses for its analgesic and antihyperalgesic properties when combined with opioids but also when opioid-induced hyperalgesia and tolerance appear. In this study we determined the interaction of ketamine and remifentanil on the minimum alveolar concentration (MAC) of sevoflurane in rats and to determine whether ketamine may block acute opioid tolerance (AOT). METHODS: Male Wistar rats were anesthetized with sevoflurane, and the MAC was determined before and after ketamine administration (10, 20, 40, and 80 mg kg−1 or saline) alone or combined with remifentanil (120 and 240 &mgr;g kg−1 h−1, low and high doses, respectively). One additional group received the lowest ketamine dose after starting a remifentanil infusion. Finally, naloxone was administered to determine the potential action of ketamine on opioid receptors. MAC was determined from intratracheal gas samples, and tail clamping was used as a supramaximal stimulus. End-tidal anesthetic concentrations were assayed using a side stream gas analyzer. Statistical analysis was performed with an analysis of variance. RESULTS: Ketamine and remifentanil dose-dependently reduced the MAC. Adding the low dose of remifentanil to ketamine did not improve the MAC reduction, whereas the high dose of remifentanil enhanced ketamine reduction in a subadditive fashion. Nevertheless, ketamine was unable to block the development of AOT to remifentanil at either dose. Finally, naloxone blocked the MAC reduction produced by ketamine. CONCLUSIONS: A subadditive effect between ketamine and remifentanil was found on the sevoflurane MAC reduction rats. In addition, ketamine was unable to block AOT. The clinical relevance of these findings should be elucidated in future studies to reduce anesthetic requirements.