Introduction

Opioid analgesics have been used in dogs and cats undergoing surgical procedures for several reasons: a) improvement in intraoperative analgesia; b) decrease in anesthetic requirement for maintenance of anesthesia; c) reduction of the neuroendocrine response to surgical stimulus; d) to attain greater hemodynamic stability; and postoperative pain control.

Under clinical conditions, opioids are commonly given as premedication combined with sedative drugs. These drugs are also administered intraoperatively as intermittent boluses or as constant rate infusion. Finally, opioids are also administered after surgery for postoperative pain control. Regardless of the timing of administration, there are important differences in the pharmacological properties of opioids between dogs and cats. Good understanding of these differences is crucial to take advantage of the desirable properties of opioids.

Classification of Opioid Receptors

There are two opioid receptors that present the greatest clinical relevance: mu (µ) and kappa (κ). Full agonists at µ receptors are the most effective analgesics, but are associated with greater intensity of adverse effects. Full µ agonists include morphine, methadone, oxymorphone, hydromorphone, fentanyl, remifentanil and pethidine. Partial µ agonists (e.g., buprenorphine) and κ receptor agonists (e.g., butorphanol, nalbuphine) are less effective than full µ agonists and are thought to present lower incidence of adverse effects. In a clinical scenario, full µ agonists are the opioids of choice for severe pain control. Partial µ agonists and κ agonists are indicated for mild to moderate pain.¹

Effects of Opioids on the Minimum Alveolar Concentration (MAC)

The MAC is the minimum alveolar concentration of an anesthetic that produces immobility in 50% of subjects submitted to supramaximal noxious stimulus. It is a measure of potency of inhalation anesthetics and is quantified as vol %. Values of MAC differ among anesthetics (halothane, isoflurane, sevoflurane) and also between different species.² Drugs that induce central nervous system depression and/or analgesia decrease MAC. However, the reduction in MAC for certain drugs can be considerably different from one species to another.

Full µ-agonists greatly reduce MAC in dogs, this effect being dose-related. Morphine at cumulative doses of 0.5, 2.0 and 7.0 mg/kg reduced the MAC of enflurane by 17%, 32% and 63%.³ Remifentanil at constant rate infusions of 0.15, 0.30, 0.60 and 0.90 µg/kg/min reduced isoflurane MAC by 43%, 59%, 66% and 71%.⁴ Methadone at 0.5 and 1.0 mg/kg reduced isoflurane MAC by 35% and 48%.⁵ It is expected that all full µ opioid agonists can reduce the MAC of inhalation anesthetics to as much as 70%, although the dose for this purpose may not be used clinically for all opioids. The effect of opioids on the MAC of cats is not as pronounced as in dogs. Morphine doses of 0.1 and 1.0 mg/kg reduced the MAC of enflurane by 12% and 28%.⁶ Remifentanil at constant rate infusions of 0.25, 0.50 and 1.0 µg/kg/min reduced the isoflurane MAC by 23%, 30% and 26%.⁷ Thus, the maximum expected decrease on the MAC provided by full µ opioid agonists in cats is 30%, which is different to the 70% MAC reduction observed in dogs.

Effects of Opioids on the Cardiovascular System

Inhalation anesthetics cause dose-dependent cardiovascular depression.¹ Therefore, the reduction in MAC provided by opioids is expected to result in greater hemodynamic stability. Nevertheless, improvement in cardiovascular function may not be observed in dogs despite substantial decreases in MAC. In enflurane-anesthetized dogs, cardiac output and oxygen delivery were not improved despite a 65% decrease in enflurane MAC.⁸ In the same study, significant improvement in cardiac output and oxygen delivery were only observed when atropine was given to prevent fentanyl-induced bradycardia. Therefore, severe bradycardia induced by full µ opioid agonists may impair any hemodynamic improvement that might be expected as a result of the decrease in MAC. Cardiac output and oxygen delivery are not measured in routine anesthetic procedures. In clinical practice, arterial blood pressure is the main cardiovascular variable monitored. Because blood pressure may be influenced by cardiac output, the anesthetist should consider to administer an anticholinergic in dogs that develop bradycardia concurrently with hypotension. Conversely, if a dog develop opioid-induced bradycardia during isoflurane or sevoflurane anesthesia, but blood pressure is normal, treatment of sinus bradycardia with an anticholinergic is not mandatory.

Cats are less likely to develop bradycardia following opioid administration. In fact, heart rate and blood pressure increased in isoflurane-anesthetized cats administered remifentanil or alfentanil.^7,9 Furthermore, cardiac output, oxygen delivery and stroke volume were higher during alfentanil-isoflurane anesthesia compared with isoflurane alone.⁹ The improvement in hemodynamics appeared to be associated with concurrent increases in plasma catecholamines.

Final Considerations

Clinical effects of opioids are different in dogs and cats anesthetized with inhalation anesthetics. In dogs, high doses of full µ opioid agonists result in decreases of as much as 70% on the MAC. If bradycardia and hypotension occur, an anticholinergic should be administered with the aim of normalizing heart rate. The reduction in MAC by full µ opioid agonists in cats is much lower than in dogs and the maximum expected decreases in MAC are approximately 30%. Compared with dogs, cats are less likely to develop bradycardia and hypotension following opioid administration.

References

1.  KuKanich B, Wiese AJ. Opioids. In: Grimm KA, Lamont LA, Tranquilli WJ, Greene SA, Robertson SA, eds. Veterinary Anesthesia and Analgesia. Ames: Wiley Blackwell; 2015:207–226.

2.  Steffey EP, Mama KR, Brosnan RJ. Inhalation anesthetics. In: Grimm KA, Lamont LA, Tranquilli WJ, Greene SA, Robertson SA, eds. Veterinary Anesthesia and Analgesia. Ames: Wiley Blackwell; 2015:297–331.

3.  Murphy MR, Hug CC Jr. The enflurane sparing effect of morphine, butorphanol, and nalbuphine. Anesthesiology. 1982;57(6):489–492.

4.  Monteiro ER, Teixeira-Neto FJ, Campagnol D, Alvaides RK, Garofalo NA, Matsubara LM. Effects of remifentanil on the minimum alveolar concentration of isoflurane in dogs. Am J Vet Res. 2010;71(2):150–156.

5.  Credie RG, Teixeira Neto FJ, Ferreira TH, Aguiar AJ, Restitutti FC, Corrente JE. Effects of methadone on the minimum alveolar concentration of isoflurane in dogs. Vet Anaesth Analg. 2010;37(3):240–249.

6.  Ilkiw JE, Pascoe PJ, Tripp LD. Effects of morphine, butorphanol, buprenorphine, and U50488H on the minimum alveolar concentration of isoflurane in cats. Am J Vet Res. 2002;63(8):1198–1202.

7.  Ferreira TH, Aguiar AJ, Valverde A, Neto FJ, Steagall PV, Soares JH. Effect of remifentanil hydrochloride administered via constant rate infusion on the minimum alveolar concentration of isoflurane in cats. Am J Vet Res. 2009;70(5):581–588.

8.  Ilkiw JE, Pascoe PJ, Haskins SC, Patz JD, Jaffe R. The cardiovascular sparing effect of fentanyl and atropine, administered to enflurane anesthetized dogs. Can J Vet Res. 1994;58(4):248–253.

9.  Pascoe PJ, Ilkiw JE, Fisher LD. Cardiovascular effects of equipotent isoflurane and alfentanil/isoflurane minimum alveolar concentration multiple in cats. Am J Vet Res. 1997;58(11):1267–1273.