Opioids in Veterinary Anesthesia

Opioids have been used for thousands of years and they continue to be foundational for surgical and traumatic pain management. The last 10 years or so have seen the onset of dueling, but somewhat related, opioid crises: the human opioid abuse epidemic and recurring shortages of opioid analgesics. These societal and clinical pressures have forced veterinary practitioners to think creatively about analgesia for conditions involving acute pain, including increased use of multimodal analgesia and locoregional anesthetic techniques. In addition, as various injectable opioids become intermittently unavailable, veterinarians have had to be flexible about which opioids they employ to prevent and relieve suffering. This short article will highlight some of the clinical differences amongst the various injectable opioids.


All mu agonist opioids bind to mu receptors throughout the central nervous system, which are in especially high concentrations in areas of the brain that mediate descending antinociceptive pathways, including the periaqueductal grey matter and rostroventral medulla. In the spinal cord, mu opioid receptors are found in the superficial laminae of the dorsal horn, which processes painful sensory input. Finally, mu opioid receptors are also located in the periphery on free nerve endings and immune cells.


Opioids bind to the receptor and activate inhibitory G proteins, which, in turn, decrease calcium entry & cAMP formation and increase potassium efflux. This intracellular cascade results in hyperpolarization and decreased neurotransmitter release.

Mu opioid receptors are G-protein coupled receptors; binding of a ligand causes a conformational change that initiates intracellular molecular cascades resulting in hyperpolarization of neurons and decreased neurotransmitter release. In August 2020, the FDA approved a new injectable opioid, oliceridine, that purportedly favors G-protein mediated signaling over beta-arrestin pathways to provide analgesia with a reduced side effect profile. My guess is that this drug will be too expensive for veterinarians to use any time soon.


All full mu agonist opioids present a linear dose-response curve in regard to analgesic efficacy. However, escalating doses of opioids can be limited by side effects and, practically speaking, expense. The side effects of full mu agonist opioids generally are manifested by the CNS, respiratory, thermoregulatory, and GI systems, with some relatively minor cardiovascular effects, mostly consisting of bradycardia.



Named after the Greek god of sleep, Morpheus, morphine was first isolated from opium in the early 1800s. Widespread medical use had to wait until the hypodermic needle was invented in the mid-1800s.

Morphine

The prototypical full mu agonist opioid to which all others are compared. Sedation is a useful side effect that reliably occurs in dogs. As with all opioids, cats and horses may respond with increased motor activity and excitement, especially if they are not painful to begin with or higher doses are used. When morphine is given IM to non-painful dogs, about 75% will vomit and show signs of nausea. Intravenous boluses of morphine can lead to histamine release and resulting vasodilation, though this can be minimized by giving the drug slowly over a period of a few minutes or as an infusion.


Hydromorphone

About 5 times as potent as morphine, hydromorphone causes less vomiting in dogs and produces similar sedation at equipotent doses. Of all the full mu agonist opioids, hydromorphone has been most closely associated with post-anesthetic hyperthermia in cats. Hydromorphone minimally increases plasma histamine levels, to levels that are clinically insignificant.


Oxymorphone

Currently use is minimal in veterinary medicine since it is so similar to hydromorphone but many times more expensive.


Methadone

Has some associated cultural baggage but is actually a really lovely full mu agonist opioid that also is an NMDA antagonist and serotonin reuptake inhibitor. This pharmacological profile makes it attractive for patients with severe pre-existing or chronic pain states. Vomiting tends to be minimal and sedation can be slightly less profound than equivalent doses of morphine or hydromorphone. It is equipotent to morphine (i.e. recommended doses are similar). The major drawback to methadone is that it is relatively expensive.


Meperidine

Also commonly known as demerol and pethidine, this is a short-acting full mu agonist opioid that has activity at multiple receptor systems. In fact, meperidine was originally synthesized as an anticholinergic agent and the active metabolite, normeperidine, has been implicated in the development of seizures and serotonin syndrome. It is not commonly used in the US in veterinary patients.



Fentanyl is about 100 times as potent as morphine.

Fentanyl

A highly potent and very lipophilic full mu agonist opioid with a short duration. Because it is so lipophilic, vomiting is prevented because it can quickly cross the BBB and knock out the vomiting center. The short duration means that it is best administered by IV infusion and that it can be titrated up and down with relative ease. Fentanyl can be administered IM but duration of action may be as short as 30 minutes. Fentanyl is more expensive than morphine and hydromorphone but less so than methadone. Costs of continuous infusion (syringe/fluid pumps, extension sets, ongoing monitoring) must also be considered.


Sufentanil and Alfentanil

Fentanyl derivatives that produce similar clinical effects, though potencies and onset times vary.


Remifentanil

An interesting fentanyl derivative that undergoes extrahepatic metabolism by plasma esterases. This results in an extremely short half-life, requiring continuous infusion because clinical effects subside quickly when the infusion is stopped. Whereas fentanyl can build up over time with long infusions and potentially overwhelm metabolic pathways leading to prolonged elimination times, remifentanil displays a stable half-life no matter how long it has been infused (i.e. it displays a stable context sensitive half life). This pharmacological profile makes it appealing for use in patients with significant hepatic dysfunction and for those with neurologic disease that requires the ability to quickly decrease sedation for evaluation. Remifentanil is unfortunately very expensive.


Do you have a preferred opioid for clinical use? Are you comfortable with more than one opioid if backorders occur? How do you balance side effect profile and costs?



Recommended doses of full mu agonist opioids in dogs and cats

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