Tramadol peridural comparativamente à morfina para analgesia pós-operatória em cadelas submetidas à ovariosalpingohisterectomia

acb Acta Cirúrgica Brasileira Acta Cir. Bras. 0102-8650 1678-2674 Sociedade Brasileira para o Desenvolvimento da Pesquisa em Cirurgia São Paulo, SP, Brazil OBJETIVO: Comparar o efeito analgésico pós-operatório do tramadol em relação à morfina quando utilizados por via peridural em cadelas submetidas à ovariosalpingohisterectomia (OSH). MÉTODOS: Dezesseis cadelas foram aleatoriamente distribuídas em dois tratamentos, com oito animais em cada, tratadas com morfina (0,1mg kg-1, M) e tramadol (2mg kg-1, T). A medicação pré-anestésica foi feita por via intravenosa (iv) com acepromazina (0,05mg kg-1), seguindo-se indução e manutenção anestésicas com propofol (4mg kg-1 iv) e isofluorano, respectivamente. O grau de analgesia foi avaliado uma, três, seis e 12 horas após o término da cirurgia, com escala descritiva numérica, que incluiu a observação de alterações fisiológicas e comportamentais. Animais com escore > 06 foram tratados com morfina (0,5mg kg-1). A concentração sérica de cortisol foi mensurada antes da sedação (basal), ao término da cirurgia (T0), 1 (T1), 6 (T6) e 12 (T12) horas após a cirurgia. RESULTADOS: Os escores de dor e a concentração sérica de cortisol não diferiram entre os tratamentos. Analgesia de resgate foi necessária em um cão do tratamento T. CONCLUSÃO: A administração peridural de morfina e de tramadol resulta em analgesia adequada e de longa duração em cadelas submetidas à ovariosalpingohisterectomia. 6 - ORIGINAL ARTICLE ANESTHESIA A comparison of extradural tramadol and extradural morphine for postoperative analgesia in female dogs undergoing ovariohysterectomy1 Tramadol peridural comparativamente à morfina para analgesia pós-operatória em cadelas submetidas à ovariosalpingohisterectomia Celso Sawaya NevesI; Juliana Andrea Osório BalanII; Diego Roberto PereiraII; Helaine StevaninIII; Renata Navarro CassuIV IFellow Master degree, Postgraduate Program in Animal Science, UNOESTE, Presidente Prudente-SP, Brazil. Acquisition of data, helped with technical procedures, collection and processing of study informations, manuscript writing IIGraduate student, Faculty of Veterinary Medicine, UNOESTE, Presidente Prudente-SP, Brazil. Helped with technical procedures, collection and processing of study informations IIIFull Professor, Department of Veterinary Surgery and Anestesiology, Scholl of Veterinary Medicine, UNOESTE, Presidente Prudente-SP, Brazil. Responsible for surgical procedures IVPhD, Full Professor, Department of Veterinary Surgery and Anestesiology, Scholl of Veterinary Medicine, UNOESTE, Presidente Prudente-SP, Brazil. Mentor. Responsible for intelectual, scientific content and statistical analysis of the study, critical revision Correspondence ABSTRACT PURPOSE: To compare the postoperative analgesic effects of the extradural tramadol or morphine in female dogs undergoing ovariohysterectomy. METHODS: Sixteen female dogs were randomly assigned to two groups of eight animals each and received morphine (0.1mg kg-1 M group) or tramadol (2mg kg-1 T group). The pre-anesthetic medication was intravenously (iv) acepromazine (0.05mg kg-1). Anesthesia was induced with propofol (4mg kg-1iv) and maintained with isoflurane. The degree of analgesia was evaluated using a numerical rating scale that included physiologic and behavior variables. Dogs were scored at one, three, six and 12 hours after surgery by one blinded observer. Dogs were treated with morphine (0.5mg kg-1) if their scores were >6. Serum cortisol was measured before the pre-anesthetic medication was administered (basal), at the time of the ovarian pedicle clamping (T0), and at 1 (T1), 6 (T6) and 12 (T12) hours postoperative. RESULTS: The pain score did not differ between morphine and tramadol treatments. Rescue analgesia was administered to one dog in the T treatment group. Serum cortisol did not differ between treatments. CONCLUSION: The extradural administration of morphine or tramadol is a safe and effective method of inducing analgesia in female dogs undergoing ovariohyterectomy. Key words: Analgesics, Opioid. Tramadol. Morphine. Analgesia. Ovary. Hysterectomy. Dogs. RESUMO OBJETIVO: Comparar o efeito analgésico pós-operatório do tramadol em relação à morfina quando utilizados por via peridural em cadelas submetidas à ovariosalpingohisterectomia (OSH). MÉTODOS: Dezesseis cadelas foram aleatoriamente distribuídas em dois tratamentos, com oito animais em cada, tratadas com morfina (0,1mg kg-1, M) e tramadol (2mg kg-1, T). A medicação pré-anestésica foi feita por via intravenosa (iv) com acepromazina (0,05mg kg-1), seguindo-se indução e manutenção anestésicas com propofol (4mg kg-1 iv) e isofluorano, respectivamente. O grau de analgesia foi avaliado uma, três, seis e 12 horas após o término da cirurgia, com escala descritiva numérica, que incluiu a observação de alterações fisiológicas e comportamentais. Animais com escore > 06 foram tratados com morfina (0,5mg kg-1). A concentração sérica de cortisol foi mensurada antes da sedação (basal), ao término da cirurgia (T0), 1 (T1), 6 (T6) e 12 (T12) horas após a cirurgia. RESULTADOS: Os escores de dor e a concentração sérica de cortisol não diferiram entre os tratamentos. Analgesia de resgate foi necessária em um cão do tratamento T. CONCLUSÃO: A administração peridural de morfina e de tramadol resulta em analgesia adequada e de longa duração em cadelas submetidas à ovariosalpingohisterectomia. Descritores: Analgésicos Opióides. Tramadol. Morfina. Analgesia. Ovário. Histerectomia. Cães. Introduction Several studies have shown satisfactory results following extradural (ED) opioid administration for postoperative pain relief1-3. The analgesia associated with ED administration of opioids is reportedly of longer duration and higher potency when compared with systemic administration of the same drugs2,4. Additionally, the incidence of adverse effects, such as respiratory depression, bradycardia, vomiting, and urinary retention, is lower after ED administration when compared with parenteral administration5,6. Thus, many opioid drugs have been investigated for ED administration both in humans7-9 and dogs1-3,10. Tramadol is a synthetic codeine analog which is a weak µ-receptor agonist11. It also inhibits neuronal reuptake of norepinephrine and 5-hydroxytryptamine12. The analgesic effects of ED tramadol have been evaluated in human studies7,13-16, which have suggested that it is as effective as morphine for moderate pain management. Although the use of tramadol has become increasingly popular for postoperative pain control in companion animals, only a few studies have evaluated its effects by extradural route in dogs10,17. The purpose of this study was to compare postoperative analgesia of tramadol and morphine following extradural administration for ovariohysterectomy in dogs. Methods This study was approved by the Institutional Animal Research Ethical Committee (protocol number 107/06), and permission for the participation of each dog was obtained from the owner. Sixteen healthy adult, crossbreed, female dogs, which weighed 4.5 to 26kg (11±12kg) were evaluated. Animals undergoing elective ovariohysterectomy were selected for this study using a physical examination and laboratory tests (complete blood cell count, urea, creatinine, alanine aminotransferase and aspartate aminotransferase). After withdrawal of food and water for 12 and 3 hours, respectively, the animals underwent the same anesthesia protocol. All dogs were sedated with 0.05mg kg-1 of acepromazine maleate (Acepran 0.2%, Univet, Sao Paulo, Brazil) administered intravenously (IV). Fifteen minutes after sedation, anesthesia was induced with 4 to 5mg kg-1 (IV) of propofol (Propovan, Cristalia, Itapira, Brazil). The trachea was intubated, and anesthesia was maintained with isoflurane under spontaneous ventilation using a partial rebreathing system (Samurai III, Takaoka, Sao Paulo, Brazil) with an oxygen flow of 1L-1min-1. Ringer's solution (10mL kg-1 h-1) was infused IV using a peristaltic infusion pump (LifeMed, Fars 600, Sao Paulo, Brazil) throughout the surgical procedure. All dogs were prepared for ED analgesia: hair in the lumbosacral area was clipped, and the dogs were placed in sternal recumbency. Each was randomly assigned to receive 2mg kg-1 of tramadol (Tramadon, Cristalia, Itapira, Brazil) (T, n=8) and 0.1mg kg-1 of morphine (Tramadon, Cristalia, Itapira, Brazil) (M, n=8) by the extradural route. In both treatments, the drugs were diluted with a saline solution to produce a total volume of 0.25mL kg-1. Extradural injection was performed at the lumbosacral (L7-S1) space. Correct spinal needle placement was confirmed by a lack of resistance to injection3. The opioids were injected over a 2 minutes period. All animals underwent routine ovariohysterectomy through a 2 -to 3- cm midline incision by the same experienced surgeon. During the anesthetic procedure, end tidal carbon dioxide (PEtCO2), inspired carbon dioxide, expired and inspired isoflurane concentration (%), arterial oxygen saturation of hemoglobin (SpO2%) and heart rate (HH) were measured with a capnograph, pulse oximeter and gas analyzer continuously (VAMOS plus, Dräger, SP, Brazil. ). The end-tidal concentration of isoflurane was adjusted on the basis of arterial pressure and heart rate changes as well as using the conventional signs of anesthesia. Systolic arterial blood pressure (SABP) was measured by noninvasive method using a Doppler ultrasonic (Doppler 841-A, Parks Medical Electronics, Las Vegas, EUA). During the first 12 hours postoperative, the animals underwent a blind evaluation of the analgesia degree using a numerical pain scale18, with postoperative measurements at 1, 3, 6 and 12 hours. Pain scores were assigned, and the maximum possible scores obtained was 20 (Table 1). Scores of 0 to 5 indicated mild pain, scores of 6 to 9 indicated moderate pain, and scores of more than 10 indicated severe pain. Additional analgesia was given (intramuscular morphine at 0.5 mg kg-1) to dogs that scored 6 or more. Venous blood samples were collected from the jugular vein to measure of cortisol before the pre-anesthetic medication was administered (basal), at the time of the ovarian pedicle clamping (T0), and at 1 (T1), 6 (T6) and 12 (T12) hours post-ovariohysterectomy. Serum samples were stored at -70C and analyzed within 12 months after collection. Cortisol levels were quantified using a solid-phase radioimmunoassay (Coat-A-Count Cortisol - DPC, California, USA). Duration of surgery and time to endotracheal extubation were recorded as well as the occurrence of adverse effects such as nausea, vomiting, tremors, excitement and drooling. Data were recorded as mean±SD. The data analyzed using an analysis of variance with the F test followed by Tukey's test using Graphpad software. Differences between treatments at each time point, differences in time for each treatment, and the interaction between treatment and time were investigated. A P-value less than 0.05 was considered significant. Results There were no differences (P>0.05) between the groups in terms of mean age (24 and 20 months for the T and M groups, respectively), body weight (16±8 and 15.6±7 kg for the T and M groups, respectively), surgical time (40±3 and 39±2 minutes for the T and M groups, respectively) and extubation time (5±3, 4.5±2 minutes for the T and M groups, respectively). The median pain score did not significantly differ between the tramadol and morphine treatments at any time point (Figure 1). One dog in the T group required additional analgesia within 6 hours postoperative. Rescue analgesia was not required by any of the dogs who received morphine. Serum cortisol concentrations did not significantly differ between treatment groups or times (Figure 2). Undesirable side effects were not observed in any of the dogs. Discussion The current study confirms previous reports in humans7,16 and dogs, which have shown similar postoperative analgesia profiles following extradural administration of tramadol or morphine. In both groups, the postoperative pain score was low, and the median values were less than six at 12 hours postoperative, which implies that both regimens provide adequate analgesia for dogs undergoing ovariohysterectomy. The effects of ED morphine have been well documented in dogs. Several studies have reported the high analgesic efficacy and long duration of action of ED morphine2,5,19,20. Nevertheless, a few published studies have described the analgesic properties and the efficacy of extradural tramadol in dogs10,17. Pharmacokinetic and pharmacodynamic studies in humans have demonstrated that the analgesic effects of tramadol result mainly from the actions of the (+) M1 enantiomer21,22. According to Vettorato et al.10, the pharmacokinetic parameters of intravenous tramadol are equivalent to those produced by extradural tramadol. The rapid and effective production of M1 was observed after both routes of administration. Immediately after tramadol injection, M1 attained concentrations >10ng/mL for a period of eight hours. In humans, this value is considered the lowest concentration associated with therapeutic efficacy20. Although this concentration has not been evaluated in dogs, the results of this study and those previously reported10,17 demonstrate that tramadol provides satisfactory analgesia during the early postoperative period. In the present study, rescue analgesia was not required for any dogs given ED morphine; this was likely because of the long duration of drug action. The duration of action of extradural morphine in dogs undergoing ovariohysterectomy is at least 16 hours2. Regarding tramadol treatment, one dog received additional analgesia at six hours postoperative, while the other dogs in this group did not require rescue analgesia, which is in agreement with other studies10,17. Vettorato et al.10 have demonstrated that dogs undergoing surgical repair of ruptured cranial cruciate ligaments and treated with ED tramadol do not require rescue analgesia within the first 8 hours of extubation. Almeida et al.17 have reported long-lasting postoperative analgesia in dogs undergoing orquiectomy. The authors observed similar analgesic effects with ED tramadol/lidocaine and morphine/lidocaine and no dog required rescue analgesia during the first 24 hours postoperative. Pain recognition and assessment in animals is challenging because of their inability to communicate, the complexity of pain perception and variation in behavioral responses. Different pain scoring systems have been developed to assess the efficacy of analgesic techniques. Several investigators have reported the use of a variety of scales (visual analog, numerical rating, simple descriptive and composite) developed and correlated specifically for dog1,23,24. The pain scoring system employed in the current study has been previously described for pain quantification in dogs17, 18,23. In addition, only one observer scored all dogs to avoid interobserver variability in the subjective evaluation. Other attempts to gather objective data regarding pain and analgesics have included the evaluation of stress-related hormones and metabolites. Previous studies have shown satisfactory agreement between pain score and plasma catecholamine and serum cortisol levels25-27. In the current study, both tramadol and morphine were effective at preventing the postoperative stress response, using serum cortisol as a guideline. In both treatments groups, serum cortisol did not exceed the reference range (0.96 to 6.81 mg/dl) at any evaluated time point. In humans, extradural administration of opioids has been shown to have favorable effects on metabolites and hormonal variables in the immediate postoperative period28. Previous studies have reported that dogs receiving ED morphine29 or ED methadone3 have lower postoperative serum cortisol levels than those receiving the same analgesic by IV administration. In addition to their analgesic effects, both treatments provided satisfactory post-anesthetic recovery. No adverse effects were observed in the current study, which is in agreement with previous results reported in dogs2,10,17. Conclusions The extradural tramadol provides an analgesic effect similar to extradural morphine in dogs undergoing ovariohysterectomy. Additionally, both treatments inhibit the stress response and do not induce adverse effects, resulting in a safe option for analgesia in female dogs. Correspondence: Renata Navarro Cassu Depto Cirurgia e Anestesiologia Faculdade Medicina Veterinária e Ciência Animal - UNOESTE 19067-175 Presidente Prudente - SP Brasil Tel. : [phone] [e-mail], [e-mail] Received: November 22, 2011 Review: January 20, 2012 Accepted: February 22, 2012 Conflict of interest: none Financial source: none 1 Research performed at Veterinary Hospital, Department of Veterinary Surgery and Anestesiology, Faculty of Veterinary Medicine, Western Sao Paulo University, Presidente Prudente-SP, Brazil. 1. Smith LJ, Yu JK. A comparison of epidural buprenorphine with epidural morphine for postoperative analgesia following stifle surgery in dogs. Vet Anaesth Analg. 2001;28:87-96. A comparison of epidural buprenorphine with epidural morphine for postoperative analgesia following stifle surgery in dogs Vet Anaesth Analg 2001 87 96 28 Smith LJ Yu JK 2. Troncy E, Junot S, Keroack S, Sammut V, Pibarot P, Genevois JP, Cuvelliez S. Results of preemptive epidural administration of morphine with or without bupivacaine in dogs and cats undergoing surgery: 265 cases (1997-1999). J Am Vet Med Assoc. 2002;221:666-72. Results of preemptive epidural administration of morphine with or without bupivacaine in dogs and cats undergoing surgery: 265 cases (1997-1999) J Am Vet Med Assoc. 2002 666 72 221 Troncy E Junot S Keroack S Sammut V Pibarot P Genevois JP Cuvelliez S. 3. Leibetseder EN, Mosing M, Jones RS. A comparison of extradural and intravenous methadone on intraoperative isoflurane and postoperative analgesia requirements in dogs. Vet Anaesth Analg. 2006;33:128-36. A comparison of extradural and intravenous methadone on intraoperative isoflurane and postoperative analgesia requirements in dogs Vet Anaesth Analg. 2006 128 36 33 Leibetseder EN Mosing M Jones RS 4. Torske KE, Dyson DH. Epidural analgesia and anesthesia. Vet Clin North Am: Small Anim Pract. 2000; 30:860-3. Epidural analgesia and anesthesia Vet Clin North Am 2000 860 3 30 Torske KE Dyson DH 5. Valverde A, Dyson DH, McDonell WN. Epidural morphine reduces halothane MAC in the dog. Can J Anaesth. 1989;36:629-32. Epidural morphine reduces halothane MAC in the dog Can J Anaesth 1989 629 32 36 Valverde A Dyson DH McDonell WN 6. Chaney MA. Side effects of intrathecal and epidural opioids. Can J Anaesth. 1995;42:891-903. Side effects of intrathecal and epidural opioids Can J Anaesth 1995 891 903 42 Chaney MA 7. Ozcengiz D, Gunduz M, Ozbek H, Isik G. Comparison of caudal morphine and tramadol for postoperative pain control in children undergoing inguinal herniorrhaphy. Paediatr Anaesth. 2001;11:459-64. Comparison of caudal morphine and tramadol for postoperative pain control in children undergoing inguinal herniorrhaphy Paediatr Anaesth 2001 459 64 11 Ozcengiz D Gunduz M Ozbek H Isik G. 8. Aribogan A, Doruk N, Aribogan A, Akin S, Balcioglu O. Patient-controlled epidural analgesia after major urologic surgeries. A comparison of tramadol with or without bupivacaine. Urol Int. 2003; 71:168-75. Patient-controlled epidural analgesia after major urologic surgeries: A comparison of tramadol with or without bupivacaine Urol Int 2003 168 75 71 Aribogan A Doruk N Aribogan A Akin S Balcioglu O. 9. Axelsson K, Johanzon E, Essving P, Weckström J, Ekbäck G. Postoperative extradural analgesia with morphine and ropivacaine. A double-blind comparison between placebo and ropivacaine 10 mg/h or 16 mg/h. Acta Anaesthesiol Scand. 2005;49(8):1191-9. Postoperative extradural analgesia with morphine and ropivacaine: A double-blind comparison between placebo and ropivacaine 10 mg/h or 16 mg/h Acta Anaesthesiol Scand 2005 1191 9 8 49 Axelsson K Johanzon E Essving P Weckström J Ekbäck G. 10. Vettorato E, Zonca A, Isola M, Villa R, Gallo M, Ravasio G, Beccaglia M, Montesissa C, Cagnardi P. Pharmacokinetics and efficacy of intravenous and extradural tramadol in dogs. Vet J. 2010;183:310-5. Pharmacokinetics and efficacy of intravenous and extradural tramadol in dogs Vet J 2010 310 5 183 Vettorato E Zonca A Isola M Villa R Gallo M Ravasio G Beccaglia M Montesissa C Cagnardi P. 11. Scott LJ, Perry CM. Tramadol: a review of its use in perioperative pain. Drugs. 2000;60:139-76. Tramadol: a review of its use in perioperative pain Drugs 2000 139 76 60 Scott LJ Perry CM 12. Dayer P, Collart L, Desmeules J. The pharmacology of tramadol. Drugs. 1994;47(Suppl 1):3-7. The pharmacology of tramadol Drugs 1994 3 7 47 Dayer P Collart L Desmeules J. 13. Baraka A, Jabbour S, Ghabash M, Nader A, Khoury G, Sibai A. A comparison of epidural tramadol and epidural morphine for postoperative analgesia. Can J Anesth. 1993;40:308-13. A comparison of epidural tramadol and epidural morphine for postoperative analgesia Can J Anesth 1993 308 13 40 Baraka A Jabbour S Ghabash M Nader A Khoury G Sibai A. 14. Delilkan AE, Vijayan R. Epidural tramadol for postoperative pain relief. Anaesthesia. 1993;48:328-31. Epidural tramadol for postoperative pain relief Anaesthesia 1993 328 31 48 Delilkan AE Vijayan R. 15. Prosser DP, Davis A, Booker PD, Murray A. Caudal tramadol for postoperative analgesia in paediatric hypospadias surgery. Br J Anaesth. 1997;79:293-6. Caudal tramadol for postoperative analgesia in paediatric hypospadias surgery Br J Anaesth 1997 293 6 79 Prosser DP Davis A Booker PD Murray A. 16. Sayyid SS, Maroun MA, Sleimn D, Sfeir M, Baraka A. Epidural tramadol for postoperative pain after cesarean section. Can J Anesth. 1999;46:731-5. Epidural tramadol for postoperative pain after cesarean section Can J Anesth 1999 731 5 46 Sayyid SS Maroun MA Sleimn D Sfeir M Baraka A. 17. Almeida RM, Scobar A, Maguilnik S. Comparison of analgesia provided by lidocaine, lidocaine-morphine or lidocaine-tramadol delivered epidurally in dogs following orchiectomy. Vet Anaesth Analg. 2010;37:542-9. Comparison of analgesia provided by lidocaine, lidocaine-morphine or lidocaine-tramadol delivered epidurally in dogs following orchiectomy Vet Anaesth Analg 2010 542 9 37 Almeida RM Scobar A Maguilnik S. 18. Pibarot P, Dupuis J, Grisneaux E, Cuvelliez S, Planté J, Beauregard G, Bonneau NH, Bouffard J, Blais D. Comparison of ketoprofen, oxymorphone, and butorphanol in the treatment of postoperative pain in dogs. J Am Vet Med Assoc. 1997;211(4):438-44. Comparison of ketoprofen, oxymorphone, and butorphanol in the treatment of postoperative pain in dogs J Am Vet Med Assoc 1997 438 44 4 211 Pibarot P Dupuis J Grisneaux E Cuvelliez S Planté J Beauregard G Bonneau NH Bouffard J Blais D. 19. Kona-Boun JJ, Cuvelliez S, Troncy E. Evaluation of epidural administration of morphine or morphine and bupivacaine for postoperative analgesia after premedication with an opioid analgesic and orthopedic surgery in dogs. J Am Vet Med Assoc. 2006;229(7):1103-12. Evaluation of epidural administration of morphine or morphine and bupivacaine for postoperative analgesia after premedication with an opioid analgesic and orthopedic surgery in dogs J Am Vet Med Assoc 2006 1103 12 7 229 Kona-Boun JJ Cuvelliez S Troncy E. 20. Pekcan Z, Koc B. The post-operative analgesic effects of epidurally administered morphine and transdermal fentanyl patch after ovariohysterectomy in dogs. Vet Anaesth Analg. 2010;37(6):557-65. The post-operative analgesic effects of epidurally administered morphine and transdermal fentanyl patch after ovariohysterectomy in dogs Vet Anaesth Analg 2010 557 65 6 37 Pekcan Z Koc B. 21. Lehmann KA, Kratzenberg U, Schroeder-Bark B, Horrichs-Haermeyer G. Postoperative patient-controlled analgesia with tramadol: analgesic efficacy and minimum effective concentrations. Clin J Pain. 1990;6:212-20. Postoperative patient-controlled analgesia with tramadol: analgesic efficacy and minimum effective concentrations Clin J Pain 1990 212 20 6 Lehmann KA Kratzenberg U Schroeder-Bark B Horrichs-Haermeyer G. 22. Poulsen L, Arendt-Nielsen L, Brosen K, Sindrup SH. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther. 1996;60:636-44. The hypoalgesic effect of tramadol in relation to CYP2D6 Clin Pharmacol Ther 1996 636 44 60 Poulsen L Arendt-Nielsen L Brosen K Sindrup SH 23. Conzemius, MG, Brockman DJ, King LG, Perkowski SZ. Analgesia in dogs after intercostal thoracotomy: a clinical trial comparing intravenous buprenorphine and interpleural bupivacaine. Vet Surg. 1994;23:291-8. Analgesia in dogs after intercostal thoracotomy: a clinical trial comparing intravenous buprenorphine and interpleural bupivacaine Vet Surg 1994 291 8 23 Conzemius MG Brockman DJ King LG Perkowski SZ 24. Buback JL, Boothe HW, Carroll GL, Green RW. Comparison of three methods for relief of pain after ear canal ablation in dogs. Vet Surg. 1996;25(5):380-5. Comparison of three methods for relief of pain after ear canal ablation in dogs Vet Surg 1996 380 5 5 25 Buback JL Boothe HW Carroll GL Green RW 25. Sunshine A, Olson NZ, Zighelboim I, De Castro A. Ketoprofen, acetaminophen plus oxycodone, and acetaminophen in the relief of postoperative pain. Clin Pharmacol Ther. 1993;54:546-55. Ketoprofen, acetaminophen plus oxycodone, and acetaminophen in the relief of postoperative pain Clin Pharmacol Ther 1993 546 55 54 Sunshine A Olson NZ Zighelboim I De Castro A. 26. Mastrocinque S, Fantoni DT. A comparison of preoperative tramadol and morphine for the control of early postoperative pain in bitches submitted to ovariohisterectomy. Vet Anaesth Analg. 2003;30:220-8. A comparison of preoperative tramadol and morphine for the control of early postoperative pain in bitches submitted to ovariohisterectomy Vet Anaesth Analg 2003 220 8 30 Mastrocinque S Fantoni DT. 27. Martins T, Kahvegian MA, Noel-Morgan J, Leon-Román MA, Otsuki DA, Fantoni DT. Comparison of the effects of tramadol, codeine, and ketoprofen alone or in combination on postoperative pain and on concentrations of blood glucose, serum cortisol, and serum interleukin-6 in dogs undergoing maxillectomy or mandibulectomy. Am J Vet Res. 2010;71:1019-26. Comparison of the effects of tramadol, codeine, and ketoprofen alone or in combination on postoperative pain and on concentrations of blood glucose, serum cortisol, and serum interleukin-6 in dogs undergoing maxillectomy or mandibulectomy Am J Vet Res 2010 1019 26 71 Martins T Kahvegian MA Noel-Morgan J Leon-Román MA Otsuki DA Fantoni DT. 28. Hosoda R, Hattori M, Shimada Y. Favorable effects of epidural analgesia on hemodynamics, oxygenation and metabolic variables in the immediate post-anesthetic period. Acta Anaesthesiol Scand. 1993;37:469-74. Favorable effects of epidural analgesia on hemodynamics, oxygenation and metabolic variables in the immediate post-anesthetic period Acta Anaesthesiol Scand 1993 469 74 37 Hosoda R Hattori M Shimada Y. 29. Popilskis S, Kohn DF, Laurent L, Danilo P. Efficacy of epidural morphine versus intravenous morphine for post-thoractotomy pain in dogs. J Vet Anaesth. 1993;20:21-5. Efficacy of epidural morphine versus intravenous morphine for post-thoractotomy pain in dogs J Vet Anaesth 1993 21 5 20 Popilskis S Kohn DF Laurent L Danilo P.