Opioids are the cornerstone of effective acute pain management in small animal veterinary medicine. They have high efficacy, are remarkably safe, and with the benefit of reversibility. These drugs bind to opioid receptors located in the central and peripheral nervous system and decrease the release of excitatory neurotransmitters and hyperpolarize the neuronal membrane thereby reducing the pain from nociceptive stimulus without interfering with proprioception.

In the perioperative period, opioids are administered to produce analgesia and sedation as part of premedication and perioperative multimodal analgesic protocols. Infusion and epidural administration of opioids have been used to provide perioperative analgesia; these two drug delivery methods may decrease inhalant anesthetic requirements during surgery and in some cases, improve cardiorespiratory function due to volatile anesthetic-sparing effects.

In general, opioid-induced adverse effects are not clinically relevant or may be easily treated when pain relief is a priority. This lecture aims to provide an overview of the present use of opioid analgesics and their impact in canine and feline practice. It highlights the current knowledge, misconceptions, and controversies pertaining to the various routes of administration.

Current Knowledge, Misconceptions, and Controversies: The Routes of Administration

Traditional Routes of Administration

Opioids have been traditionally administered by the intravenous (IV), intramuscular (IM) or subcutaneous (SC) route of administration or as constant rate infusions (CRIs). Pharmacokinetic-pharmacodynamic (PK-PD) studies have shown that the route of administration may influence the onset, magnitude and duration of analgesic effects. Historically, IV administration of opioids has always been considered advantageous because of its rapid onset and prompt pain relief when compared with the IM or SC route. In addition, opioids may provide inhalant-anesthetic sparing effects, analgesia and stable anesthesia when administered as an infusion. On the other hand, the SC route was considered to be less painful at injection than other routes when an IV catheter is not in place, particularly in cats. However, this route may not provide adequate analgesia depending on the opioid, dosage regimens, and its formulation. SC administration of hydromorphone or buprenorphine (0.3 mg/mL) provided less analgesia with greater variability when compared with the IM or IV routes in cats.¹

This can become confusing considering the launching of a FDA-approved high-concentrated formulation of buprenorphine (1.8 mg/mL; Simbadol®). This drug provides up to 24 hours of postoperative analgesia in cats after one SC dose which may be administered for up to 3 consecutive days. Simbadol® or other sustained release formulations should not be confused with other brands using lower concentrations (0.3 mg/mL) of buprenorphine.

Transdermal

Long-sustained release formulations of opioids provide "hands-off" analgesia, eliminates costs associated with injections, and always the patient to reside at home. Transdermal patches of fentanyl have been used to provide postoperative pain relief for up to 72–96 hours. Significant variation in analgesic effect has been observed between dogs and cats, and the former species will usually have higher bioavailability after fentanyl patch placement than the latter.^2,3

Transdermal patches are typically safe when applied and discarded in an appropriate manner. However, accidental ingestion or exposure to the patch has been described resulting in serious adverse effects and potentially death. Veterinarians should be aware of complications, liability issues, off-label administration and adverse effects with the use of fentanyl patches.

The effects of a non-FDA-approved fentanyl patch is not to be confused with a long-acting transdermal solution (Recuvyra®), which is FDA-approved in the United States and in various countries for treatment of perioperative pain. In order to avoid accidental exposure or abuse, the manufacturer of Recuvyra® has developed a program called the Risk Minimization and Action Plan (RiskMAP). It restricts its distribution to those who are certified by this training program. The drug is applied to the skin 2–4 hours before surgery and may provide analgesia after single application for up to 4 days post-administration. Common opioid-induced adverse effects associated with this formulation (sedation, reduced food intake bradycardia and hypothermia) may be observed and reversed with naloxone. The safety and efficacy of Recuvyra® in cats is undetermined and administration is not recommended.

Epidural (Extradural)

Epidural administered opioids relieve somatic and visceral pain by blocking nociceptive impulses without interfering with sensory and motor function or the sympathetic nervous system. Morphine produces analgesia 30 to 40 minutes after epidural administration and may last for 12–24 hours. In addition, they can be administered with or without local anesthetics to reduce inhalant anesthetic requirements during surgery. Extradural administration of morphine via "splash" (topical) or soaked in gelatin foam appears to be another effective, simple, and safe means to deliver opioids during spinal surgery. Preservative-free morphine must be used and dosage regimens have to be respected to avoid neurotoxicity and adverse effects. Urinary retention, vomiting, nausea, and pruritus are not common, but are potential adverse effects seen in dogs and cats receiving epidural morphine. Gentle bladder expression is recommended after epidural administration of morphine and before patient extubation in clinical cases. The use of buprenorphine epidurally reduces the incidence of urinary retention dramatically while still providing analgesia. Epidural administration of opioids provides adequate analgesia for acute pain management especially when used as part of a multimodal analgesia protocol.

Intra-Articular

A significant increase in µ-opioid receptors in both articular and peri-articular tissues occurs after joint inflammation.⁴ Intra-articular administration of morphine provides minimal to no adverse effects after aseptic administration, however, there is still some controversy if it provides significant analgesia after specific arthroscopic procedures. Besides these conflicting results, the technique is routinely used as part of a multimodal approach to pain management for knee and elbow surgery.

Buccal (Oral Transmucosal)

The buccal route (sublingual or oral transmucosal, OTM) is a non-invasive and pain-free means of administering opioids. This is particularly of interest in cats since minimal physical restraint is required for administration. OTM administration bypasses the first-pass gastrointestinal clearance after opioid administration and allows higher bioavailability when compared with the oral route. OTM administration of buprenorphine and methadone has shown to provide analgesia in cats, but not as effective as the IV and IM route.^5,6 In addition, buprenorphine has also been reported to produce analgesia in dogs after OTM administration, but the study design has been criticized and the high dose (0.12 mg/kg OTM) required would be cost-prohibitive. At this point, this route is not recommended in canine patients. In the clinical setting, the authors prescribe OTM buprenorphine or methadone to feline patients for late postoperative analgesia along with nonsteroidal anti-inflammatories.

Oral

Oral administration of opioids has shown low bioavailability, large individual variability, erratic gastrointestinal absorption and limited analgesic effect particularly in dogs. Different metabolic and elimination pathways occur in dogs when compared to humans which explains why bioavailability and analgesic efficacy of these drugs are dramatically different between these species. Oral administration of codeine, oxycodone and hydrocodone are not recommended for the treatment of pain in dogs or cats. Tramadol use has been controversial in dogs. Originally, significant opioid M1 metabolite (O-desmethyltramadol) concentrations were reported in dogs, however, these results were not accurate due to cross-reactivity with other metabolites.⁷ Recent trials have indicated that oral administration of tramadol does not produce significant concentrations of the opioid M1 metabolite (O-desmethyltramadol) in dogs which are required to produce an opioid effect in other species.⁸ Therefore, tramadol should not be used as a "stand-alone" therapy for the treatment of pain in dogs due to the limited evidence to support it as an effective reliable analgesic agent. Cats produce the opioid M1 metabolite and analgesia has been reported after oral and parenteral administration of tramadol in this species.⁹ The drug might be useful in the treatment of chronic painful conditions (osteoarthritis) in this species.

References

1.  Steagall PV, Pelligand L, Giordano T, et al. Pharmacokinetic and pharmacodynamic modelling of intravenous, intramuscular and subcutaneous buprenorphine in conscious cats. Vet Anaesth Analg. 2013;40(1):83–95.

2.  Kyles AE, Papich M, Hardie EM. Disposition of transdermally administered fentanyl in dogs. Am J Vet Res. 1996;57(5):715–719.

3.  Lee DD, Papich MG, Hardie EM. Comparison of pharmacokinetics of fentanyl after intravenous and transdermal administration in cats. Am J Vet Res. 2000;61(6):672–677.

4.  Keates HL, Cramond T, Smith MT. Intraarticular and periarticular opioid binding in inflamed tissue in experimental canine arthritis. Anesth Analg. 1999;89(2):409–415.

5.  Ferreira TH, Rezende ML, Mama KR, Hudachek SF, Aguiar AJ. Plasma concentrations and behavioral, antinociceptive, and physiologic effects of methadone after intravenous and oral transmucosal administration in cats. Am J Vet Res. 2011;72(6):764–771.

6.  Robertson SA, Lascelles BD, Taylor PM, Sear JW. PK-PD modeling of buprenorphine in cats: intravenous and oral transmucosal administration. J Vet Pharmacol Ther. 2005;28(5):453–460.

7.  KuKanich B, Papich MG. Pharmacokinetics of tramadol and the metabolite O-desmethyltramadol in dogs. J Vet Pharmacol Ther. 2004;27(4):239–246.

8.  Kukanich B, Papich MG. Pharmacokinetics and antinociceptive effects of oral tramadol hydrochloride administration in Greyhounds. Am J Vet Res. 2011;72(2):256–262.

9.  Pypendop BH, Siao KT, Ilkiw JE. Effects of tramadol hydrochloride on the thermal threshold in cats. Am J Vet Res. 2009;70(12):1465–1470.