Perioperative analgesic efficacy of constant rate infused tramadol hydrochloride as an adjunct to postoperative ketoprofen in ovariohysterectomized bitches

The recognition of animal pain as a medical entity and ethical problem has attracted increasing scientific attention (Arkhtardanesh et al., 2014). Pain is a subjective expression of neural impulses induced by a stimulus with a capacity to potentially damage tissues of the body. Surgical procedures are known to evoke certain degrees of acute pain (Firth and Haldane, 1999) depending on the extent of tissue trauma. Ovariohysterectomy is known to elicit a moderate to severe degree of acute pain (Firth and Haldane, 1999).
        
Effective postoperative pain management is an essential component in the provision of quality care in patients (Dolin et al., 2002). It is ethically wrong to allow patients undergo postoperative pain without adequate pharmacological interventions (Stegman, 2001; Ferrell, 2005; Gunningberg and Idvall, 2007). Furthermore, unrelieved pain threatens the normal homeostasis and may cause both physiological and psychological negative effects. These negative effects include increased cardiac output and respiration, increased cortisol production and sustained hyperglycaemia, increased metabolic rate, reduced feeding and body weight, delayed wound healing and increased risk of developing chronic pain (Middleton, 2003; Gordon et al., 2005; Polomano et al., 2008; Kulkarni et al., 2015).  Moreover, unrelieved pain also results in delusory anxiety, fear, distress and depression (Ferrell, 2005; Kehlet et al., 2006). These measurable effects constitute the markers used to assess the level of pain and the effectiveness of analgesic interventions.
        
Opioids are the most potent and effective analgesics used in the treatment of acute and chronic pain in humans and animals (Quang-Cantagrel et al., 2000). Tramadol hydrochloride is a commonly used opioid-like analgesic in recent times and is effective for the treatment of moderate and severe degree of pain (Scott and Perry, 2000). Its strong efficacy is attributed to its dual mechanism of action (an opioid receptor agonist, and a norepinephrine and serotonin reuptake inhibitor) (Wagner et al., 2002). Ketoprofen on the other hand, is a non steroidal anti-inflammatory drug used to relieve short- and long-term post operative pain, inflam- mation and swelling after spaying, and other procedures (Lees et al., 2004).
        
The combination of different classes of analgesic also termed ‘balanced or multimodal analgesia’ can increase the safety and prolong duration of pharmacological analgesia (Lemke et al., 2002; Perez et al., 2014). In this regard, combination of opioids and NSAIDs has been used and proven efficacious in both experimental and clinical trials. A combination of tramadol and ketoprofen administered intramuscularly has been shown to be useful in the management of acute and chronic musculoskeletal pain, suggesting a possible synergism between the two drugs (Miranda et al., 2009; Martins et al., 2010; Miranda et al., 2012). A combination of ketoprofen and tramadol administered by constant rate infusion (CRI) proved efficacious in the management of laparotomy-induced pain (Ugwu et al., 2016). A combination of constant rate infused tramadol and postoperative ketoprofen has also been reported to prevent postoperative pain in laparotomized dogs (Ugwu et al., 2017). However, the effectiveness of constant rate infused tramadol on severe degree of acute pain has not been previously studied. Since ovariohysterectomy is known to elicit a severe degree of acute pain, the study was thus designed to ascertain the efficacy of a combination of constant rate infused tramadol hydrochloride and postoperative ketoprofen in ovariohysterectomized bitches.

Fifteen adult female dogs (mean body weight 5.19±0.51; mean age 1.20±0.9 years) undergoing routine ovariohysterectomy (OVH) in the Small Animal Hospital were recruited for this study. Only dogs with no concurrent medication for fourteen days prior to the procedure were recruited. Owners gave informed consent for the use of these drugs. Food and water were withheld from all dogs for twelve and two hours pre-operatively, respectively.
        
Dogs were randomly assigned to one of three groups (n=5) as follows: group1 (tramadol hydrochloride at 1.0mg/kg/hr, CRI), group 2 (tramadol hydrochloride at 2.0mg/kg/hr, CRI) or group 3 (normal saline infusion). These infusions commenced thirty minutes prior to the procedure. CRIs were administered by gravity flow using intravenous fluid bags. The left cephalic vein of each dog was catheterized with 21 G needle for administration of fluids. Prior to these infusions, dogs in groups 1 and 2 received a loading dose of 5.0mg/kg tramadol hydrochloride (Tramadol HCL®; IDA, Netherlands).
        
OVH was performed under general anaesthesia. Dogs were premedicated with 1% atropine sulphate (Pauco Atropine®; Pauco Pharmaceutical, Nigeria) at 0.02mg/kg, IM and 2% xylazine hydrochloride (XYLM2®; VMD, Belgium) at 1.0mg/kg, IM. Anaesthesia was induced five minutes after premedication with 5% ketamine hydrochloride (Ketamine®; Laborate Pharmaceutical, India) at 20mg/kg, IM and maintained with ketamine hydrochloride (10mg/kg, IM). Mid ventral OVH was performed on all dogs by a single trained veterinary surgeon using standard procedure. Mean duration of OVH was 52.67 ± 1.97 minutes.
        
Heart and respiratory rates, and rectal temperature were obtained one hour pre- (baseline value) and at twenty-minute interval for 200 minutes intra- and postoperatively. The dogs were subjectively assessed for pain at 1, 4, 24, 48, 72, 96, 120, 144 and 168 hours postoperatively using the University of Melbourne pain scale (UMPS; Firth and Haldane, 1999). The total pain score per dog was the sum of the behavioural and physiologic parameter scores. Pain was subjectively assessed by two independent observers blind to the treatments. Body weight was also obtained.
        
By cephalic venipuncture, blood samples were collected for determination of blood glucose and serum cortisol levels pre-, intra- and at 1, 4 and 24 hours postoperative. Blood glucose was determined using a glucometer kit (Accuchek®; Roche, Germany). The serum harvested after centrifugation for cortisol assay was frozen at -4°C until use. Cortisol concentration was determined using ELISA kit (Accudiag®; Diagnostic Automation/Cortez Diagnostics Inc, USA).
        
 Ketoprofen (Ketonal®5%, 5mg/kg, SC; Lek Pharm, Slovenia) was given at 1 hour post-OVH after pain assessment and on days 2 and 3 post-OVH to dogs in all the three groups. 5% gentamicin sulphate (5mg/kg, IM) was also given to all the dogs for three days postoperative. Skin sutures were removed on postoperative day 7.
        
Parametric data (vital parameters, blood glucose, serum cortisol and body weight) were subjected to One-way analysis of variance (ANOVA) using SPSS version 20. Pain scores were analyzed using Kruskal Wallis non-parametric test and presented as mean with standard error. Differences were considered to be significant if p≤0.05.

In the present study, constant rate infused tramadol Hcl (CRI T-HCL) was administered pre-emptively (thirty minutes prior to ovariohysterectomy) as previous studies have shown that the timing of analgesic intervention plays an important role in the development of postoperative pain (Gassel et al., 2005; Gilberto et al., 2002).
        
The intra- and one-hour postoperative pain assessments were used to evaluate the analgesic potency of CRI T-HCl alone. There was no significant difference in the mean heart rate and rectal temperature in all the groups. Mean respiratory rate of group 3 was significantly lower (p<0.05) than the tramadol-treated groups groups at 60, 80, 140, 160 and 180 minutes, showing that tramadol has minimal effect on respiration as reported by Hui-Chen et al., 2014. This finding also agrees with previous studies which reported that tramadol has little or no side effect on cardiovascular and respiratory functions (Quang-Cantagrel 2000; Larisa et al., 2010; Cagnardi et al., 2011; Marina et al., 2014; Ugwu et al., 2017).
        
Mean blood glucose and mean serum cortisol levels of group 3 dogs were significantly higher (p<0.05) than those of groups 1 and 2 intra- and at one hour postoperative (Fig 1 and 2). The increased glucose levels and cortisol concentration observed in the control group is regarded as a response to pain and stress (Saha et al., 2005; Ugwu et al., 2017). This observation suggests that CRI T-HCl was effective at preventing intra-and early postoperative pain. An ideal analgesic should be able to prevent postoperative pain especially at the first one hour following surgery (Hosking and Welchew, 1985). In response to pain and stress, cortisol increases blood glucose levels through the process of gluconeogenesis (Bishop et al., 2005). Further, xylazine has been reported to cause transient hyperglycaemia in patients (Saha et al., 2005).
 

 

        
Postoperatively, these pain assessment parameters (blood glucose, serum cortisol and UMPS score (Fig 3) were found to significantly decrease in the control group at 4 hours compared to their 1-hour values. These findings suggest the strong potency of ketoprofen as an analgesic. Ketoprofen is known to have analgesic activities against moderate to severe degree of acute and chronic pain. It is suggested that ketoprofen, a cyclo-oxygenase 1 and 2 inhibitor, blocks the formation of prostaglandins which is important in pain and inflammatory pathways (Lees et al., 2004). The administration of ketoprofen in the tramadol-treated groups caused no significant decrease in the values of pain assessment parameters when compared to their 1-hour postoperative values. This may be due to the fact that the effect of tramadol with a short half life (4-6 hours) was already waning at this period. Nevertheless, the finding supports claim of possible synergism between tramadol and ketoprofen (Miranda et al., 2009; Martins et al., 2010; Miranda et al., 2012; Ugwu et al., 2016; 2017). The absence of need for rescue analgesia in the control group observed in this study especially during the intraoperative period maybe as a result of the extra-analgesia offered by the anaesthetics regimen used.
 

        
Significant differences (p>0.05) were not recorded in the mean body weight through out the study period.

The findings of this study proved the perioperative analgesic efficacy of constant rate infused tramadol hydrochloride at the doses used for the management of ovariohysterectomy-induced pain. Findings also suggest that CRI T-HCl at 2mg/kg/hr was superior to 1mg/kg/hr especially as an adjunct to ketoprofen.

Authors wish to thank the administrators of Veterinary Teaching Hospital, Nsukka, for facilitating this study.