Effects of meperidine or saline on thermal, mechanical and electrical nociceptive thresholds in cats

Transcription

1 Veterinary Anaesthesia and Analgesia, 2008, 35, doi: /j x SHORT COMMUNICATION Effects of meperidine or saline on thermal, mechanical and electrical nociceptive thresholds in cats Valerie M Millette* BSc, Paulo VM Steagall DVM, MSc, Tanya Duke-Novakovski* BVet Med, DVA, Diplomate ACVA, Diplomate ECVAA & Alex J Livingston* BSc, BVetMed, PhD, Diplomate ECVPT *Department of Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada Department of Veterinary Surgery and Anesthesiology, Faculdade de Medicina Veterinária e Zootecnia, Universidade Estadual Paulista, UNESP, Botucatu, São Paulo, Brazil Correspondence: Paulo Vinicius Mortensen Steagall, Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI , USA. psteagall@svm.vetmed.wisc.edu Abstract Objective To measure cutaneous electrical nociceptive thresholds in relation to known thermal and mechanical stimulation for nociceptive threshold detection in cats. Study design Prospective, blinded, randomized crossover study with 1-week washout interval. Animals Eight adult cats [bodyweight 5.1 ± 1.8 kg (mean + SD)]. Methods Mechanical nociceptive thresholds were tested using a step-wise manual inflation of a modified blood pressure bladder attached to the cat s thoracic limb. Thermal nociceptive thresholds were measured by increasing the temperature of a probe placed on the thorax. The electrical nociceptive threshold was tested using an escalating current from a constant current generator passed between electrodes placed on the thoracic region. A positive response (threshold) was recorded when cats displayed any or all of the following behaviors: leg shake, head turn, avoidance, or vocalization. Four baseline readings were performed before intramuscular injection of meperidine (5 mg kg )1 ) or an equal volume of saline. Threshold recordings with each modality were made at 15, 30, 45, 60, 90, and 120 minutes post-injection. Data were analyzed using ANOVA and paired t-tests (significance at p < 0.05). Results There were no significant changes in thermal, mechanical, or electrical thresholds after saline. Thermal thresholds increased at minutes (p < 0.01) and mechanical threshold increased at 30 and 45 minutes after meperidine (p < 0.05). Maximum thermal threshold was +4.1 ± 0.3 C above baseline at 15 minutes while maximum mechanical threshold was 296 ± 265 mmhg above baseline at 30 minutes after meperidine. Electrical thresholds following meperidine were not significantly different than baseline (p > 0.05). Thermal and electrical thresholds after meperidine were significantly higher than saline at 30 and 45 minutes (p < 0.05), and at 120 minutes (p < 0.05), respectively. Mechanical thresholds were significantly higher than saline treatment at 30 minutes (p 0.05). Conclusion and clinical relevance Electrical stimulation did not detect meperidine analgesia whereas both thermal and mechanical thresholds changed after meperidine administration in cats. Keywords analgesia, cat, electrical, mechanical, thermal, thresholds. 543

2 Introduction A reliable method to objectively assess nociceptive threshold is required to study the efficacy of analgesic drugs. Ideally, more than one method should be used to measure nociceptive thresholds in laboratory settings to more accurately reflect clinical pain, as various types of noxious stimuli cause pain in clinical settings (Steagall et al. 2008). A method for detecting thermal and mechanical thresholds in cats has been developed and used under laboratory conditions (Dixon et al. 2002, 2007). The devices were used to assess and compare the onset, magnitude and duration of effect of several opioids. Data using these devices have since been applied to clinical settings, enhancing clinical management of pain in cats (Steagall et al. 2006). The aim of this study was to evaluate the sensitivity of an electrical testing device to detect nociceptive thresholds, and to compare it to the known thermal and mechanical devices in cats. Contributing information about nociceptive thresholds from a third type of stimulus could be important for our understanding of clinical pain in cats. Materials and methods This study was approved by the University of Saskatchewan Committee for Animal Care (protocol number ). Animals Eight healthy adult cats (two intact females, six neutered males) were used in this study ranging in weight from 2.6 to 8.2 kg (5.1 ± 1.8 kg). Their ages ranged from 2.3 to 7.7 years (4.49 ± 1.7 years). During testing, cats were housed individually in cages equipped with a bed and a litter tray. They were fed dry and wet food and water was available ad libitum. All cats had been well handled and familiarized with the testing procedure prior to the study. Testing devices Each device had a pre-determined cut-off point at which the nociceptive stimulus would be turned off automatically to avoid tissue trauma (Dixon et al. 2002, 2007). Prior to opioid or saline administration, four measurements were made at 15-minute intervals and their mean value taken as the control threshold. Thermal threshold Thermal thresholds were measured by applying a thermal stimulus to elicit nociception (Dixon et al. 2002). A probe containing a heater element and temperature sensor was held against the shaved thorax using an elasticized band and a pressure bladder. The bladder was inflated manually to 100 mmhg to ensure consistent contact between the probe and the skin. When activated, the probe heated at 0.6 C second )1, with an automatic cutoff at 55 C, if not terminated earlier. For each test, the probe was activated and then switched off as soon as the cat reacted; this was usually a skin flick, jumping forward, a turn to bite the band, or vocalization. At the point of reaction, the probe temperature was recorded as the thermal threshold. Mechanical threshold Mechanical thresholds were measured by applying a mild mechanical stimulus to elicit nociception (Dixon et al. 2007). A plastic bracelet was taped around a shaved thoracic limb. Three long brass pins tipped with ball-bearings were mounted in a triangle perpendicular to the skin surface, with a stiff rubber backing. The pins were pressed against the craniolateral surface of the leg by manual inflation of a modified blood pressure bladder positioned directly behind the pins. The volume in the bladder was increased at a rate of 1.5 ml second )1 until the cat reacted. The cats behavioral reactions to the mechanical stimulus were taken as the end point threshold (picking up and shaking the leg, turning the head towards the bracelet, licking or biting the bracelet, and vocalization). The cut-off pressure was 850 mmhg. Electrical threshold Nociceptive threshold assessment was obtained using an electrical stimulus produced by a constant current unit generator (CCG) and a Grass stimulator (Model CCU1 Constant Current Unit; Astro-Med Inc, West Warwick, RI, USA). The CCG was set to deliver a constant current despite changes in skin resistance between individuals and body position. The CCG was set to continuously deliver stimuli with duration of 1 ms and 1 ms delay between pulses. Two electrodes placed 2 cm apart in a plastic handle were vertically held against a shaved area of the mid-thorax. The current was manually increased at 544 Ó 2008 The Authors. Journal compilation Ó 2008 Association of Veterinary Anaesthetists, 35,

3 a rate of 1 ma second )1 until the cat displayed behavioral signs of pain (attempting to look at, lick or bite at the electrodes, vocalizing, jumping forward). The current at which the cat reacted was recorded in ma. A maximum current level of 5 ma (cut-off) was used based on preliminary trials. Pilot study Each cat s response to the various stimuli was studied and recorded several weeks before the study began. A sham test was conducted by testing untreated cats several times with the electrical device powered off. Two electrodes were placed and held against the skin by one observer, while the other observer pretended to manually increase the current with the equipment. To test repeatability of the measurement the electrical threshold device was set to deliver the same constant current to be used for the study, and each untreated cat s electrical nociceptive thresholds were collected every 15 minutes over 2 hours, and were analyzed using one-way ANOVA to observe repeatability The parameters used were those which showed a consistent pain effect when applied to the experimenters. If the cat showed no response to the stimulus, the test was terminated when a maximum current level of 5 ma had been achieved. Observations were made to detect any skin damage at the site of the electrical stimulus. Drug treatment After baseline readings were taken, an injection of 5mgkg )1 of meperidine or an equal volume of saline was administered intramuscularly (IM) into the pelvic limbs (Dixon et al. 2002). The observer was unaware which treatment had been administered. Threshold recordings were made at 15, 30, 45, 60, 90, and 120 minutes post-injection in a two period cross-over study with a 1-week washout period between treatments. The three nociceptive techniques were applied to each cat during each session in a randomized order. Data within each treatment group were analyzed for changes with time by using one-way repeatedmeasures ANOVA followed by Dunnett s test. The treatment thresholds were compared using paired t-tests (Graph pad Prism software, version 4.00; Graphpad Software Inc., San Diego, CA, USA). A value of p 0.05 was regarded as statistically significant. Results The electrical threshold was repeatable using oneway ANOVA during the pilot study (p > 0.05 data not shown). No skin damage occurred at either thermal or mechanical testing sites. Although the electrical stimulator caused slight focal reddening of the skin on two of six cats, it was well tolerated in all animals. Two cats were not used to test the electrical stimulus, as during the pilot study, one did not respond to the stimulus even at the cut-off current, and the other did not tolerate even minimal stimulation. Thresholds Skin temperature did not change after the administration of saline (p > 0.05), but increased at 15 minutes (p < 0.05) after meperidine administration (Table 1). There were no significant changes in thermal, mechanical, or electrical thresholds with time after the saline treatment (p > 0.05). The thermal threshold increased at minutes after meperidine treatment (p < 0.01). The maximum increase in thermal threshold was 4.17 ± 0.3 C from baseline at 15 minutes. Mechanical threshold increased at 30 and 45 minutes after meperidine was administered (p < 0.05) achieving a maximum increase above baseline of 296 ± 265 mmhg at 30 minutes. The electrical threshold was not significantly different with time from baseline threshold with meperidine treatment (p > 0.05) (Table 1). Thermal and electrical thresholds after meperidine treatment were significantly higher compared with saline treatment at 30 and 45 minutes (p < 0.05), and at 120 minutes (p < 0.05), respectively (Table 1). Mechanical thresholds after meperidine were significantly higher compared with saline treatment at 30 minutes (p 0.05) (Table 1). Behavioral changes No behavioral changes were observed after saline treatment. One cat hyper-salivated for the first 30 minutes after meperidine. One obese cat became vocal, hyper-responsive, excited and dysphoric after <10 minutes after meperidine, and showed signs of fear, anxiety, and disorientation. The effects of the opioid were reversed with 0.05 mg kg )1 of naloxone IM. The meperidine-related data from this cat were not included in the statistical analysis. For this reason, electrical thresholds from only five cats were Ó 2008 The Authors. Journal compilation Ó 2008 Association of Veterinary Anaesthetists, 35,

4 Table 1 Mean ± SD for skin temperature, thermal, mechanical and electrical thresholds after intramuscular administration of meperidine (5 mg kg )1 ) or an equal volume of saline Treatment Baseline 15 minutes 30 minutes 45 minutes 60 minutes 90 minutes 120 minutes Skin temperature ( C) Thermal threshold ( C) Mechanical threshold (mmhg) Electrical threshold (ma) Saline 37.9 ± ± ± ± ± ± ± 1.1 Meperidine 37.9 ± ± 0.7* 38.4 ± ± ± ± ± 0.8 Saline 42.6 ± ± ± ± ± ± ± 2.1 Meperidine 43.0 ± ± 1.4* 46.7 ± 1.2* 46.2 ± 2.0* 45.9 ± 1.0* 44.8 ± ± 1.8 Saline 185 ± ± ± ± ± ± ± 74 Meperidine 211 ± ± ± 304* 349 ± 142* 435 ± ± ± 89 Saline 1.1 ± ± ± ± ± ± ± 0.3 Meperidine 1.2 ± ± ± ± ± ± ± 1.3 *Significantly increased after meperidine (p < 0.05) compared with baseline; significantly higher after meperidine (p < 0.05) compared with saline. included in the statistical analysis. Based on these events, the doses of meperidine and saline administered were reduced to 75% of the total dose for another obese cat used in this study. When this cat was excluded from the statistical analysis, changes in thresholds were only related to time and not treatment. For this reason, this cat was included in the overall results. Discussion The sensation of pain involves more than one type of nociceptor; therefore, studies using more than one type of nociceptive stimulus present more information relevant to clinical pain and analgesia (Steagall et al. 2008). The present study confirms the original reports that the mechanical and thermal threshold devices were well tolerated by the cats (Dixon et al. 2002, 2007; Steagall et al. 2007). This study, in accordance with a previous study by Steagall et al. (2007), reports that the mechanical device was not as useful as the thermal device at detecting nociceptive thresholds as it was designed to elicit a different type and degree of noxious stimulus. The sensitivity of a third device, a cutaneous electrical stimulator, was evaluated for detecting the electrical nociceptive thresholds in cats. It was hypothesized that the electrical stimulation would cause minimal tissue trauma, the data would be quantifiable and repeatable, and that an opioid analgesic effect would be detected similar to the thermal and mechanical devices. In this study, the cutaneous electrical stimulator did not detect meperidine analgesia. However, Duke et al. (1994) used this device to detect the analgesic effects of fentanyl and medetomidine administered by the epidural route in cats. Electrical stimulation is not a natural pain sensation, and skin sensation contains a vibration-mechanical component which is not triggered using an electrical stimulator, therefore the nociceptive sensitivity to noxious stimuli provided by the CCG may be more dependent on anatomical location and nociceptor density (Duke et al. 1994). Duke et al. (1994) fixed the electrodes on the limbs of cats, using electrocardiogram patches and a different constant current, whereas in the present study the electrodes were manually held against the thorax. The electrical threshold was statistically significantly higher after meperidine compared with saline at 120 minutes and this was probably attributable to one cat whose threshold was 3.3 ma (Table 1) and probably not as a result of an overall decrease in response to electrical stimulation. When the mean of the rest of the group was substituted for this reading at 120 minutes, the electrical threshold was not statistically significant at this time (p > 0.05). No pattern of analgesic effect of the drug was observed using electrical stimulation. Mechanical thresholds after meperidine were significantly higher compared with saline treatment at only 30 minutes. This was probably a result of a large standard deviation due to a large variation in the individual response. This could preclude the ability to reject the null hypothesis that differences between groups did not occur. Meperidine was chosen for this study because it has been well studied and its analgesic effects are documented in cats (Booth & Rankin 1954; Dixon et al. 2002). An obese cat used in the study experienced side effects including severe excitement, 546 Ó 2008 The Authors. Journal compilation Ó 2008 Association of Veterinary Anaesthetists, 35,

5 dysphoria, and anxiety when treated with meperidine. Obesity increases the percentage of fat tissue over the lean mass, increasing the volume of distribution for lipophilic drugs into tissues that are not metabolically active (Casati & Putzu 2005). In our clinical experience, obese animals are routinely medicated with only 75% of the calculated dose for opioid drugs to avoid excitement associated with overdosing, thus the second obese cat used in the study received 75% of the dose of saline and meperidine to avoid any further drug complications. Other known adverse effects of meperidine and other opioids were observed in this study including profuse salivation in one cat, as well as hyperthermia in another cat (Booth & Rankin 1954). The mean skin temperature of the cats increased significantly within 15 minutes of injection with meperidine. This was most probably significant because one cat had an increase in skin temperature of 1.6 C; thereby distorting the mean and standard deviation. In this study, the ambient temperature did not vary; therefore, the increase in skin temperature was attributed to administration of the drug. Conclusion This study showed that the electrical stimulus was not as useful as the thermal and mechanical devices at detecting the analgesic effect of meperidine in cats. References Booth N, Rankin A (1954) Evaluation of meperidine hydrochloride in the cat. Vet Med 49, Casati A, Putzu M (2005) Anesthesia in the obese patient: pharmacokinetic considerations. J Clin Anesth 7, Dixon MJ, Robertson SA, Taylor PM (2002) A thermal threshold testing device for evaluation of analgesics in cats. Res Vet Sci 72, Dixon MJ, Taylor PM, Steagall PVM et al. (2007) Development of a pressure nociceptive threshold testing device for evaluation of analgesics in cats. Res Vet Sci 82, Duke T, Cox AM, Remedios AM et al. (1994) The analgesic effects of placing fentanyl or medetomidine in the lumbosacral epidural space of cats. Vet Surg 23, Steagall PVM, Carnicelli P, Taylor PM et al. (2006) Effects of subcutaneous methadone, morphine, buprenorphine or saline on thermal and pressure thresholds in cats. J Vet Pharmacol Ther 29, Steagall PVM, Taylor PM, Brondani JT et al. (2007) Effects of buprenorphine, carprofen and saline on thermal and mechanical nociceptive thresholds in cats. Vet Anaesth Analg 34, Steagall PVM, Taylor PM, Brondani JT et al. (2008) Antinociceptive effects of tramadol and acepromazine in cats. J Feline Med Surg 10, Received 22 August 2007; accepted 16 December Ó 2008 The Authors. Journal compilation Ó 2008 Association of Veterinary Anaesthetists, 35,