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Introduction
Post-operative pain hinders recovery, slows wound healing, causes immunosuppression, impairs homeostasis and metabolism, and increases tissues catabolism (Bufalari et al., 2007). The increase in circulatory catecholamine is responsible for electrolytic, hemodynamic, and neuroendocrine changes (Desborough, 2005). Most anaesthetic drugs do not eliminate the neuronal processes involved with pain (Duarte and Saraiva, 2005), thus, opioid pre-emptive analgesia can play an important role in preventing central sensitization (Wordliczek et al., 2002) and reduce the magnitude and duration of post-operative pain.
Unilateral mastectomy is the treatment of choice for mammary tumours in bitches (Stratmann et al., 2008) and it consists of complete surgical removal of one mammary gland chain, adjacent tissues, and lymph nodes. This technique results in an extremely painful post-operative period (Lana et al., 2007). Preemptive analgesic treatment in these patients can be challenging due to surgical manipulation and aggression on different tissues, and the advanced age of bitches usually affected by mammary tumours (Papich, 2000).
Methadone is a mu (μ), delta (δ), and kappa (κ) opioid receptors agonist; N-methyl-D-aspartate (NMDA) antagonist; and 5-hydroxytryptamine (5-HT) and norepinephrine reuptake inhibitor, with similar potency to morphine (1:1). Tramadol is a weak μ receptor agonist and 5-HT and noradrenaline reuptake inhibitor, with ten times lower potency than morphine (1:10). These drugs act on different stages of the nociceptive pathway, with proven efficacy and few side effects in dogs (Pereira et al., 2001; Pereira et al., 2013).
These analgesics are presented as appropriate therapeutic options in the prevention and control of post-operative pain derived from aggressive surgical procedures in dogs (Mastrocinque and Fantoni, 2003; Pereira et al., 2013; Teixeira et al., 2013; Cardozo et al., 2014). However, due to the importance of NMDA receptors on central sensitization pathophysiology (Sarrau et al., 2007), we hypothesize that methadone could provide acceptable analgesia, maintain cardiorespiratory physiology, and lead to less anesthetic consumption than tramadol. Thus, the aim of this study was to compare the efficacy of pre-emptive methadone or tramadol analgesia on post-operative pain control, anaesthetic/analgesic consumption and intra-operative cardiorespiratory effects in bitches subjected to therapeutic ovariohysterectomy and unilateral mastectomy.
Material and Methods
Ethical considerations
This study was approved by the Ethics Committee on the Use of Animals (CEUA) of the UNESP- Univ. Estadual Paulista (protocol no. 9189/2012). Dog owners were required to sign an informed consent agreement and commit to provide the recommended post-operative care. The animals were hospitalized for 2 days, closely monitored, and re-assessed every 5 days until suture removal at 10 days post-surgery. Patients were discharged following complete clinical recovery.
Experimental design
To reach a 75% statistical power (Based on pilot study results and calculated with Minitab 16® software), this study analysed 48 bitches (n=48) of various breeds that were admitted for unilateral mastectomy as treatment for mammary tumours. The inclusion criteria were: The American Society of Anesthesiologists (ASA) Physical Status ASA I and II; normal values for complete blood count, alanine aminotransferase, blood urea nitrogen, creatinine, and total plasma proteins; absence of hypertension, arrhythmogenic cardiomyopathy, dilated congestive heart failure, history of endocrine disorders; and no analgesic or anti-inflammatory treatment for at least two weeks prior to the surgical procedure. A prospective randomized blinded clinical trial was used. Food and water were removed 12 and 2 hours prior to surgery, respectively.
Prior to initial manipulation and drugs administration (time 0), heart (HR) and respiratory rates (RR) were determined by thoracic auscultation. The right cephalic vein was cannulated with a 20-gauge catheter for saline solution infusion at 10 mL/kg/h and 30 mg/kg cephalothin (IV) administration (ABL-Antibióticos do Brasil, Cosmópolis, Brazil). The dogs were randomly (raffle) distributed into two experimental groups (n = 24): the TRA group received 5 mg/kg tramadol (Cristalia Laboratories, Itapira, Brazil) and the MET group 0.5 mg/kg methadone (Cristalia Laboratories, Itapira, Brazil) intramuscularly (IM), diluted in saline to a final volume of 0.1 mL/kg. The anaesthetist was unaware of which premedication had been administered.
Ten minutes later (Giorgi et al 2010; Slingsby et al., 2015), anaesthesia was induced by intravenous (IV) administration of 2 mg/kg propofol boluses (Cristalia Laboratories, Itapira, Brazil), repeated every 60 seconds until loss of palpebral reflex. The total propofol induction dose (PID) was recorded. The animals were intubated with an appropriate (in size) orotracheal tube and anaesthesia maintained with isoflurane in oxygen (FiO2 = 1.0; 100 mL/kg/min) via a circle breathing circuit with spontaneous ventilation. The anaesthetist adjusted the vaporizer to maintain an adequate surgical anaesthesia plane based on standardized anaesthesia parameters: rostroventral rotation of the eye, absence of palpebral and pupillary reflex, and maintenance of mean arterial pressure (MAP > 60 mmHg). A 22-gauge catheter was inserted in the caudal auricular artery for invasive blood pressure measurement.
After anaesthetic stabilization (time 10 m), the following parameters were evaluated using a multiparametric monitor (DX2023®, Dixtal Biomedical Industry Ltd, São Paulo, Brazil): HR, RR, MAP, oxyhemoglobin saturation (SpO2), end-tidal isoflurane concentration (EtISO), and carbon dioxide pressure (EtCO2). Subsequently, and at least 20 minutes after analgesics administration (time 20 m), the OVH procedure was initiated and unilateral mastectomy performed by the same experienced surgical team. The same parameters were then recorded every 10 minutes (time 20 to 110m), until the end of the surgical procedure. Electrocardiographic and physical parameters (temperature, capillary refill time, mucous membrane colour) were continuously monitored during anaesthesia and anaesthetic intercurrences recorded and treated accordingly.
Once the surgical procedure was over, isoflurane anaesthesia was discontinued and extubation was made after laryngeal reflex recovery. Animals were placed in individual recovery cages where post-operative pain was rated by a trained evaluator (blinded for analgesic treatment) according to the University of Melbourne Pain Scale (Firth and Haldane, 1999) and recorded for 12 hours: every 30 minutes during the first 4 hours after extubation and then every hour for the subsequent 8 hours. If the pain score was equal or greater than 12, rescue analgesia with 0.5 mg/kg methadone IV was given. Pain evaluation continued in all patients (data were not included in pain score after rescue) and if it was subsequently determined that clinical analgesia was needed, 2 mg/kg lidocaine (Cristalia Laboratories, Itapira, Brazil) IV was administered, followed by continuous infusion of 0.01 mg/kg/min ketamine for at least one hour (Ceva Animal Health, Paulínia, Brazil). Post-operative analgesics consumption (PAC) was calculated based on the number of applications required by each patient. At the end of the 12-hour pain evaluation period, 4 mg/kg tramadol and 0.2 mg/kg meloxicam IM (Cristalia Laboratories, Itapira, Brazil) were administered to all animals. Patients were discharged on the next day and recommendations given on the medications to be used.
Statistical analyses
Minitab 16 software (Minitab Inc. State College, USA) was used for statistical analysis. For cardiorespiratory parameters, normality of residuals and homoscedasticity of variances were previously tested (Shapiro test, variance test) and real or transformed data compared between groups by repeated measures ANOVA and Tukey's hoc-test. Anaesthesia complications between groups were compared by Chi-square test. EtISO, pain score, and analgesic consumption were compared by Kruskal-Wallis test and Dunns hoc-test. Rescue analgesia in time was compared by Kaplan Meier survival test (p<0.05).
Results
Age; body weight; and anaesthetic, surgical, and extubation time (Table 1) were similar (p>0.05) between groups. Anaesthetic complications that required intervention, such as clinical cardiorespiratory depression and cardiac arrhythmias (sinus bradycardia and atrioventricular block), were observed in 19% (9/48) of the bitches. There was no significant relationship (p>0.05) between these complications and the analgesic drugs used (Table 1). Animals that required treatment for these complications were removed from cardiovascular evaluation and all interventions were successful.
Table 1 Mean ± SD of clinical parameters of bitches pre-medicated with methadone (MET) or tramadol (TRA) prior to ovariohysterectomy and unilateral mastectomy.
HR remained within reference values throughout the experimental period, with no significant difference between times or treatments (p>0.05), except at 10 minutes of evaluation (HR>120 beats/min), when tachycardia was present in the TRA group (p= 0.03) (Figure 1a). MAP was significantly higher (p=0.02) in the MET group during minutes 10, 70, 90 and 100 (Figure 1b).
Figure 1 Mean ± SD of (a) Heart rate (HR beats/min) and (b) Mean arterial pressure (MAP mmHg) of bitches pre-medicated with methadone (MET) or tramadol (TRA) prior to ovariohysterectomy and unilateral mastectomy. *Significant difference between groups (p<0.05).
No significant difference (p>0.05) was observed in SpO2 between groups at any given time. The RR was similar between the groups, although the baseline value (0 min) was significantly greater (p=0.04) than the subsequent times in both groups (Figure 2a). EtCO2 was significantly higher (p=0.04) in MET than TRA at 20, 40, 50, 60, 70, and 80 minutes (Figure 2b). PID was significantly lower (p<0.001) in MET (5.4±1.1 mg/kg) than in TRA group (6.9±1.2 mg/kg) (Figure 3a); however, no significant difference (p>0.05) in EtISO was observed between groups (Figure 3b).
Figure 2 Mean ± SD of (a) Respiratory rate (RR breaths/min) and (b) end-tidal carbon dioxide pressure (EtCO2 mmHg) of bitches pre-medicated with methadone (MET) or tramadol (TRA) prior to ovariohysterectomy and unilateral mastectomy. *Significant difference between groups (p<0.05).
Figure 3 Median ± IQR of (a) Propofol induction dose (mg/kg) and (b) end-tidal isoflurane concentration (EtISO %) of bitches pre-medicated with methadone (MET) or tramadol (TRA) prior to ovariohysterectomy and unilateral mastectomy. *Significant difference between groups (p < 0.05).
Post-operative rescue analgesia requirements were significantly lower (p=0.04) in MET (6/24 animals) than in TRA (13/24 animals) (Figure 4a). Pain intensity was significantly greater (p=0.04) during the first hour in the TRA and decreased significantly (p<0.01) in both groups after 7 hours (Figure 4b). PAC was significantly lower (p<0.01) in MET (0.4 ± 0.3 applications) than in TRA (1.25 ± 0.7 applications).
Figure 4 Kaplan Meier survival curves for (a) rescue analgesia need and (b) median ± IQR of pain score according to the University of Melbourne Pain Scale within the first 12 hours following ovariohysterectomy and unilateral mastectomy in bitches pre-medicated with methadone (MET) or tramadol (TRA). *Significant difference between groups. °Significant difference from the initial times (p<0.05).
Discussion
Pre-emptive methadone administration resulted in superior post-operative pain control than tramadol; however, it was not sufficient as solo analgesia in bitches submitted to OVH and mastectomy. Methadone resulted in fewer rescue analgesia requirements, less post-operatory analgesic consumption, and better post-operative pain scores than pre-emptive tramadol. The findings from this study corroborate the results of Cardozo et al. (2014) who compared tramadol to two different doses of methadone (0.5 - 0.7 mg/kg) in dogs subjected to orthopaedic surgery. This effect may be attributed to the wide action of methadone on the nociceptive pathway, giving it superior anti-nociceptive potency and duration (Gourlay et al. 1982; Sarrau et al., 2007) thus leading to a more effective block of central sensitization (Dyson, 2008; Gottschalk et al., 2011).
The propofol sparring effect observed in the MET group (20%) has been described for other opioids (Short and Bufalari 1999; Covey-Crump and Murison 2008; Kaur et al., 2013) and for the methadone/dexmedetomidine association (Canfrán et al., 2016) and can be attributed to the strong sedative effect of methadone on dogs (Monteiro et al., 2009), which was not observed when tramadol was used. However, the sedation in these animals was not evaluated and is a limiting factor in the present study. In contrast, isoflurane requirements were similar in both groups corroborating the results by Leibetseder et al. (2006) and Guedes et al. (2005) in dogs undergoing surgical procedures.
The two analgesics examined in this study resulted in different cardiovascular effects. The HR was significantly higher and MAP lower in the TRA group compared to the MET group at time 10 (anaesthetic stabilization) and the values were considered outside normal clinical ranges (MAP < 65 mmHg and HR > 120 bpm) concluding that animals experienced clinical hypotension and reflex tachycardia. This could be due to the higher PID used in this group (6.9±1.2 mg/kg) as propofol causes a dose-dependent hypotensive effect (Branson, 2007) in addition to the hypotensive effect related to the high doses of tramadol (≥ 5 mg/kg) administered, causing an increased release of nitric oxide in the vascular endothelium (Raimundo et al., 2008; Monteiro et al., 2009). On the other hand, the MET group exhibited significantly higher MAP at certain times (10, 70, 90, 100 minutes) and lower HR (non-significant 10 to 50 minutes) than the TRA group. However, these parameters are considered to be within the expected ranges and are in agreement with Pereira et al. (2013) and Cardozo et al. (2014). The cardiovascular effects of methadone are attributed to elevated blood arginine-vasopressin levels that increase peripheral vascular resistance and, consequently, MAP elevation and reflexive HR decrease (Hellebrekers et al., 1989; Maiante et al., 2008). Nevertheless, the lack of a significant difference in HR between groups after surgical manipulation (20 minutes) can be explained by the incomplete block of noxious stimuli, which enables the release of catecholamine (Desborough, 2005; Leibetseder et al., 2006).
Due to institutional limitations, blood gas analysis was not performed and thus, EtCO2 and SpO2 measurements were used to estimate ventilation and oxygenation (Grosenbaugh and Muir, 1998). Clinical hypercapnia (EtCO2 > 45 mmHg) was present in the MET group for most of the study period. This alteration reflects respiratory depression, a common dose-dependent side effect of pure agonist opioids that can be exacerbated by anaesthetics (Papich, 2000). Pereira et al. (2013) did not observe changes in the respiratory parameters of dogs that received methadone, probably due to the lower dose used (0.3 mg/kg). Although EtCO2 was significantly higher in MET group, the expected physiological variation in RR was not observed, similarly to the results reported by Leibetseder et al. (2006).
The drugs used in this study had no effect on the prevalence of anaesthetic complications. Credie et al. (2010) reported bradycardia, sinus arrest, and ventricular escape rhythm when methadone was used, corroborating with cardiac depression and arrhythmias observed in the present study. However, studies using tramadol have reported no clinical complications (Mastrocinque and Fantoni, 2003; Monteiro et al., 2009) and the different results observed in this study were probably due to the high intensity of the surgical pain stimuli, which promotes the release of catecholamine (Desborough, 2005).
It can be concluded that methadone was more effective than tramadol in pre-emptive analgesia but not completely adequate on controlling pain in bitches subjected to unilateral mastectomy and OVH. Furthermore, methadone reduces propofol induction dose and analgesic consumption, while maintaining adequate blood pressure. These properties render methadone a good drug for multimodal anaesthesia in this type of procedures; however, it should be associated to others analgesic drugs for better post-operative pain management. Methadone alone can lead to significant clinical hypercapnia, thus special ventilation care is advised.
Conflicts of interest
None of the authors has any financial or personal relationship with other people or organization that could inappropriately influence or bias the content of this article.
Acknowledgments
The authors would like to thank the National Council for Scientific and Technological Development (CNPq), the Coordination for the Improvement of Personnel of Superior Level (CAPES), and the Research Support Foundation of the State of São Paulo (FAPESP) for the financial support; Mr Leandro N Coutinho, Ms Marina B S Brito, Ms Aracelle Alves, Ms Tathiana F Motheo, Ms Beatrice Macente, Ms Raquel R Gutierrez, and Ms Adriana Rossi for the help provided
