WVC—Opioids in veterinary medicine: panacea and pandemonium

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Opioids are a large class of natural and synthetic compounds derived from the opium poppy.¹ They include pain medications legally prescribed to people and animals, such as morphine and fentanyl, as well as recreational versions—like heroin—that are illegal.²

The “black box” warnings opioids carry on their prescription labels point out the dangers and risks of dependency for humans. Although veterinarians prescribe opioids for animals, they should be mindful of the potential for drug diversion—abuse or illegal distribution—on the part of the pet owner.^3,4

“Our patients are not the addicts,” said Julie A.L. Adrian, DVM, associate professor in the Department of Pharmacy at the University of Hawaii, Hilo. “But at times, the owners may be, and [prescribed opiates] get diverted to people instead. So, we have to remember to prescribe to safe environments.”

While generally harmless when taken for a short time by the intended patient and via the prescription by a medical doctor, she added, “they produce euphoria or bliss in addition to pain relief, and they can be misused.”

How opioids work

Opiates work at the receptor level within the nervous system (limbic, thalamus, hypothalamus, striatum, midbrain, spinal cord), gastrointestinal and urinary tracts, and smooth muscle throughout the body.⁵ They modulate several central nervous system (CNS) receptor types:

• Mu receptors, found in pain-regulating regions of the brain: Opioids bound to these receptors may produce analgesia, euphoria, respiratory depression, hypothermia, miosis and physical dependence.^5,6
• Kappa receptors, found in deep layers of the cerebral cortex and spinal cord: Opioids bound to these may produce analgesia, sedation and miosis.^5,6
• Sigma receptors, found in the cerebral cortex, olfactory bulb, nuclei of mesencephalon, hypothalamus and Purkinje cells: Opioids bound to these receptors may produce dysphoria, hallucinations, cardiac/respiratory stimulation and mydriasis.^5,7
• Delta receptors, found in the limbic system: Opioids bound to these may blunt persistent pain and improve depressive emotional states.^5,8

Opioids work mostly on the mu receptors as analgesics, antitussives and sedating agents. But many of their mu effects, ranging from respiratory depression to emesis to constipation to physical dependence, are potentially dangerous. The secondary effects of opioids, including euphoria and confusion, bradycardia, hypotension, syncope and urinary retention, can be just as crippling.⁵

Dr. Adrian reminded the audience about the contradictory effects of opioids, which are generally species- or agent-dependent. For instance, opioids produce miosis in dogs and horses, and mydriasis in cats. Likewise, while opioids generally cause sedation and constipation, morphine produces excitement in horses, cattle and pigs, and defecation in dogs.⁵

Opioid classification and cautions

Opioids are controlled substances classified by the U.S. Drug Enforcement Administration (DEA) based on acceptable medical use and abuse or dependency potential⁵:

• Schedule I: no currently accepted medical use and high potential for abuse; includes heroin, lysergic acid diethylamide (LSD), marijuana and ecstasy.⁹
• Schedule II: high potential for abuse and dependency; includes cocaine, methamphetamine, hydromorphone, combination products containing less than 15 mg hydrocodone/dosage unit, oxycodone, fentanyl and meperidine.⁹
• Schedule III: moderate to low potential for physical and psychological dependence; includes compounds containing less than 90 mg codeine/dosage unit, ketamine, testosterone and anabolic steroids.⁹
• Schedule IV: low potential for abuse or dependency; includes tramadol, alprazolam, diazepam and zolpidem.⁹
• Schedule V: lower potential for abuse; includes preparations containing low quantities of certain narcotics and used mainly as antitussives and antidiarrheals.⁹

The schedule II drugs important in veterinary medicine include codeine, fentanyl, hydrocodone, hydromorphone and meperidine. These medications are potentially dangerous because they can cause profound sedation, respiratory depression and death, particularly when combined with other CNS depressants like benzodiazepines and alcohol. They can also induce neonatal opioid withdrawal syndrome.^10-14

Veterinarians should use extra caution when prescribing schedule II compounds for a pet that shares a household with children; in some cases, a single dose can kill a child who accidentally ingests one of these medications.

“Many of our patients live with children,” Dr. Adrian said. “So, we need to educate the owners that they need to keep these drugs in a safe place.”

Fentanyl, an opioid used extra-label in small animals, is typically dosed as a transdermal patch for painful pets. It should be used with caution in geriatric and otherwise debilitated patients, as it can cause CNS, respiratory and cardiac depression, as well as urinary retention and constipation. Fatal overdoses can result from increased drug release and rapid absorption in hyperthermic conditions caused by heating pads, warm baths and such. For households with children, this patch is probably too risky.¹¹

Hydrocodone bitartrate is a human-labeled opiate agonist used as an antitussive and analgesic for moderate pain in dogs. Immediate-release products are available in combination with homatropine, acetaminophen, ibuprofen and chlorpheniramine. Cautions include excessive sedation, vomiting and constipation, and it is contraindicated in patients taking monoamine oxidase inhibitors and those that are geriatric or have underlying conditions including Addison’s disease, hypothyroidism, renal insufficiency and respiratory disease.¹²

Hydromorphone, an opiate agonist used off-label in animals as a sedative, analgesic and preanesthetic agent, can cause vomiting, defecation, panting, sedation, and CNS, respiratory and cardiac depression in dogs. Cats may experience nausea, ataxia, hyperthermia, hyperesthesia and behavioral changes.¹³ Both hydromorphone and hydrocodone can produce rapid-release overdosage if tablets are crushed/chewed.

Codeine, an opioid used in cats and dogs to alleviate pain, coughing and diarrhea, causes sedation, constipation and respiratory depression. Cats may experience CNS excitement.¹⁰

Meperidine hydrochloride, a human-labeled opioid agonist, is used for analgesia but produces histamine release in cats, resulting in gastrointestinal effects and hypersalivation. For cats and other species, including humans, it carries most of the aforementioned opiate risks, contraindications and adverse effects. Both codeine and meperidine are subject to potentially lethal dosing errors due to confusion between milligrams and milliliters.¹⁴

Of the lower-schedule drugs, Dr. Adrian pointed out three that are commonly used by veterinarians. Buprenorphine hydrochloride, a schedule III opiate partial agonist that is particularly useful in cats, is an injectable or buccal analgesic. Often used as part of a short-term immobilization “cocktail,” it has fewer adverse effects but lower efficacy than morphine and hydromorphone. Its main risk is potentially fatal respiratory depression, and its effects are not completely reversible with naloxone.¹⁵

Butorphanol tartrate, a schedule IV opiate partial agonist, is used as a premedication, antitussive, antiemetic and analgesic in many species. Contraindicated in patients with liver disease, hypothyroidism, Addison’s disease, renal insufficiency and head trauma, it can trigger sedation, ataxia, anorexia and diarrhea in dogs and cats. A particularly effective analgesic in horses, butorphanol can decrease critical equine gut motility and cause excitement.¹⁷

Diphenoxylate hydrochloride, a schedule V opiate agonist used in fixed-dose combination with atropine sulfate, is an effective GI motility modifier and antitussive for dogs. It carries cautions for use with certain underlying diseases, and is contraindicated in several diarrheal conditions. Constipation, bloat and sedation are the chief adverse effects. Diphenoxylate must be dosed carefully in small dogs, and it should not be used in young kittens.¹⁷

Dr. Adrian closed by asking the veterinary audience which scheduled drugs—of those she covered in her lecture—they use most frequently in their patients. Buprenorphine (mainly in cats) was the No. 1 response, followed by a tie between butorphanol and hydromorphone.

References

1. Melemis SM. I want to change my life. How to overcome anxiety, depression and addiction. Toronto, Ontario: Modern Therapies; 2010.

2. Opioid overdose: commonly used terms. Centers for Disease Control and Prevention website. cdc.gov/drugoverdose/opioids/terms.html. Reviewed February 12, 2019. Accessed February 24, 2020.

3. Opioid resources for veterinarians. AVMA website: avma.org/resources/veterinarians-and-public-health/opioid-resources-veterinarians. Accessed February 24, 2020.

4. A guide to drug safety terms at FDA. U.S. Food and Drug Administration website. fda.gov/downloads/forconsumers/consumerupdates/ucm107976.pdf. Published November 2012. Accessed February 24, 2020.

5. Plumb DC. Pharmacology of narcotic (opiate) agonist analgesics. In: Plumb DC, ed. Plumb’s Veterinary Drug Handbook. 7th ed. Stockholm, WI: John Wiley & Sons; 2011:2417-2418.

6. Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology. 2013;115(6):1363-1381.

7. Hayashi T, Su TP. The sigma receptor: evolution of the concept in neuropsychopharmacology. Curr Neuropharmacol. 2005;3(4):267-280.

8. Pradhan AA, Before K, Nozaki C, et al. The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol Sci. 2011;32(10):581-590.

9. Drug scheduling. U.S. Drug Enforcement Administration website. dea.gov/druginfo/ds.shtml. Accessed February 24, 2020.

10. Plumb DC. Codeine. In: Plumb DC, ed. Plumb’s Veterinary Drug Handbook. 9th ed. Stockholm, WI: John Wiley & Sons; 2018:293-295.

11. Plumb DC. Fentanyl transdermal patch. In: Plumb DC, ed. Plumb’s Veterinary Drug Handbook. 9th ed. Stockholm, WI: John Wiley & Sons; 2018:481-485.

12. Plumb DC. Hydrocodone bitartrate. In: Plumb DC, ed. Plumb’s Veterinary Drug Handbook. 9th ed. Stockholm, WI: John Wiley & Sons; 2018:574-576.

13. Plumb DC. Hydromorphone. In: Plumb DC, ed. Plumb’s Veterinary Drug Handbook. 9th ed. Stockholm, WI: John Wiley & Sons; 2018:580-583.

14. Plumb DC. Meperidine HCL. In: Plumb DC, ed. Plumb’s Veterinary Drug Handbook. 9th ed. Stockholm, WI: John Wiley & Sons; 2018:752-755.

15. Plumb DC. Butorphanol tartrate. In: Plumb DC, ed. Plumb’s Veterinary Drug Handbook. 9th ed. Stockholm, WI: John Wiley & Sons; 2018:157-163.

16. Butorphanol tartrate injection. In: Drug facts and comparisons 2017. Philadelphia, PA: Wolters Kluwer Health; 2017.

17. Plumb DC. Diphenoxylate HCL + atropine sulfate. In: Plumb DC, ed. Plumb’s Veterinary Drug Handbook. 9th ed. Stockholm, WI: John Wiley & Sons; 2018:389-390.

Dr. Joan Capuzzi is a small animal veterinarian and journalist based in the Philadelphia area.