This study compared the cardiovascular response to surgery and postoperative pain between an opioid-free protocol and two opioid-based protocols in cats undergoing elective ovariohysterectomy. Cats were randomly allocated into three intramuscular premedication treatments: DEX (dexmedetomidine 7 µg/kg, n = 12), DEXMET (dexmedetomidine 7 µg/kg + methadone 0.3 mg/kg, n = 13) and DEXMOR (dexmedetomidine 7 µg/kg + morphine 0.3 mg/kg, n = 14). Preoperatively, all cats received meloxicam 0.1 mg/kg, subcutaneously. Anesthesia was induced with propofol and maintained with sevoflurane. Heart rate (HR) and systolic arterial pressure (SAP) were measured intraoperatively. Pain was assessed before premedication (Baseline) and postoperatively for 6 hours using the Glasgow Composite Measure Pain Scale - Feline (CMPS-F) and Feline Grimace Scale (FGS). Rescue analgesia was given for CMPS-F scores ≥ 5. In all groups, HR and SAP increased intraoperatively, but tachycardia (HR >
200 beats/min) or hypertension (SAP >
180 mmHg) did not occur. Postoperative CMPS-F scores were lower in DEXMET than in DEX
FGS scores in DEX and DEXMOR were higher than in DEXMET. Rescue analgesia was administered to 50%, 23% and 29% cats in groups DEX, DEXMET and DEXMOR, respectively (p >
0.05). The odds ratio (95% confidence interval) of receiving postoperative rescue analgesia within 6 hours for opioid-free versus opioid-based techniques was 2.86 (0.76-11.43). All protocols allowed surgery to be performed without an exacerbated cardiovascular response. Incorporating methadone or morphine in the protocol decreased the odds of requiring postoperative rescue analgesia.