Opioids are drugs that have opiate-like activities and are the cornerstone of effective pain treatment. They have high efficacy and are remarkably safe and with the benefit of reversibility. Historically, opioids have been used since the 15th century; however, it was not until the 1960s that studies described the administration of a combination of fentanyl and droperidol, or morphine, meperidine and pentazocine for analgesia and sedation in the dog undergoing surgery.^1,2 In the early 1980s, studies showed that opioids could produce an inhalant anesthetic-sparing effect.³ However, it was not until the mid-1980s that postoperative analgesia in dogs after administration of different opioids gained some attention.⁴ Later on, epidural administration of morphine became a popular means of providing postoperative analgesia while reducing inhalant anesthetic requirements in dogs and cats.^5,6 In the 1990s, a "boom" of studies comparing different opioids for postoperative analgesia was observed. Multimodal and preemptive analgesia were incorporated as important concepts in veterinary medicine.^7,8 It was also in the 1990s that several studies were published about the safety and efficacy of opioid analgesics in cats.^7,9 These studies provided some crucial information that opioids could be administered safely in cats. The term "morphine-mania" was only a result of inappropriate dosage regimens. In the 2000s, appropriate dosage regimens and intervals of administration were better described in dogs and cats due to pharmacokinetic (PK) and pharmacodynamics (PD) studies including some "old" classic opioid agents when administered as new formulations.¹⁰ It was shown that their analgesic effects were dependent on the dose, route of administration, delivery system and species to which the drug is given.¹⁰

Recently, a long-acting transdermal formulation of fentanyl solution (Recuvyra) has been indicated for canine orthopedic and soft tissue surgery. In 2014, a new formulation of buprenorphine (Simbadol) has been licensed for subcutaneous administration in cats in the USA. It may provide postoperative analgesia for up to 3 days when administered every 24 h. It seems that long-sustained release formulations of opioids will be one of the subjects of extensive research in the upcoming years. This also may include studies on new opioid agents such as tapentadol, a drug with a dual mechanism of action (opioid and inhibition of noradrenaline reuptake). Tapentadol has shown superior analgesia and less adverse effects when compared with tramadol in humans; however, PK results have not been promising in dogs, poor availability was demonstrated.

It is impossible to predict the future of opioids in veterinary medicine, but it is reasonable to think that we may improve our knowledge in the subject by understanding, for example, opioid-induced individual variability. Some pharmacogenetic modulators of opioid therapy have been identified and may play a role in the pharmacokinetics of opioids analgesics, and consequently on their efficacy, or even triggering/altering drug interactions. Gender, age, genotype, and coat colour among others are becoming more important in translational research. The involvement of NMDA-receptors and toll-like receptor (TLR)-mediated glial activation in the development of neuropathic pain, and opioid-induced hyperalgesia/tolerance/side effects are current targets for cutting-edge research in opioid therapy. This lecture is an attempt to provide a historical journey on opioid analgesics. Their past, present and future clinical implications in small animal veterinary medicine is discussed.

References

1.  Short CE, Hoppingardner J, Bendick F, Greenwald W. Comparative responses of pentazocine & meperidine for control of postoperative pain in dogs. (A blind study). Vet Med Small Anim Clin. 1971;66:586.

2.  Soma LR, Shields DR. Neuroleptanalgesia produced by fentanyl and droperidol. J Am Vet Med Assoc. 1964;145:897–902.

3.  Murphy MR, Hug CC Jr. The anesthetic potency of fentanyl in terms of its reduction of enflurane MAC. Anesthesiology. 1982;57:485–488.

4.  Taylor PM, Houlton JE. Post-operative analgesia in the dog: a comparison of morphine, buprenorphine and pentazocine. J Small Anim Pract. 1984;25:437–451.

5.  Valverde A, Dyson DH, Cockshutt JR, McDonell WN, Valliant AE. Comparison of the hemodynamic effects of halothane alone and halothane combined with epidurally administered morphine for anesthesia in ventilated dogs. Am J Vet Res. 1991;52:505–509.

6.  Golder FJ, Pascoe PJ, Bailey CS, Ilkiw JE, Tripp LD. The effect of epidural morphine on the minimum alveolar concentration of isoflurane in cats. Vet Anaesth Analg. 1998;25:52–56.

7.  Lascelles BD, Cripps P, Mirchandani S, Waterman AE. Carprofen as an analgesic for postoperative pain in cats: dose titration and assessment of efficacy in comparison to pethidine hydrochloride. J Small Anim Pract. 1995;36:535–541.

8.  Kehlet H, Dahl JB. The value of "multimodal" or "balanced analgesia" in postoperative pain treatment. Anesth Analg. 1993;77:1048–1056.

9.  Slingsby LS, Waterman-Pearson AE. Comparison of pethidine, buprenorphine and ketoprofen for postoperative analgesia after ovariohysterectomy in the cat. Vet Rec. 1998;143:185–189.

10. Hofmeister EH, Egger CM. Transdermal fentanyl patches in small animals. J Am Anim Hosp Assoc. 2004;40:468–478.