The Use of Ultrapotent Opioids in Veterinary Medicine
Feb 1, 2021
Imagine you are called in to provide anesthetic care for a combative patient. This patient is 70 inches (180 cm) tall and has an estimated weight of 650 kg. Venous access sites are good although the patient’s temperament does not allow for awake intravenous catheterization. While this scenario may seem far-fetched, it is not beyond the scope of a normal day when providing anesthetic care for veterinary species. Sedation and/or anesthesia of exotic animal patients, such as the giant eland described in this scenario, is a major undertaking that requires careful planning and knowledge of the behavior, anatomy, and physiology of the species. Choice of anesthetic agents and anesthetic techniques must be made by carefully considering animal factors such as size, temperament, species, comorbidities, and available routes of injection. It is vital that veterinarians providing anesthetic care to multiple and diverse species possess an in-depth knowledge of the pharmacology and clinical effects of anesthetic agents available for use.
Veterinarians working with ultrapotent agents must be aware of the dangers of exposure.
One of the tenets of providing safe anesthetic care to free-ranging and captive non-domestic species is the avoidance of myopathy and orthopedic injury. This requires the avoidance of excitation and exertion prior to recumbency, careful positioning, minimizing anesthetic time, and providing a rapid, smooth recovery. Furthermore, these are often sensitive species that do not tolerate excessive postanesthetic sedation; free-ranging patients need to be alert in order to return to defensive or predatory behavior, rejoin social groups, and/or avoid environmental hazards. Captive non-domestic species may be more tolerant of postanesthetic sedation, but many large species are not adapted to recumbency and may develop neuropathy or myopathy if they are unable to return to normal ambulation soon after an anesthetic event.
Hands-on examination and procedures of non-domestic species, ranging from antelope to zebra, often require intramuscular injection of anesthetic agents that provide either heavy sedation or complete immobilization. Hand (in animals trained for intramuscular injections or squeeze-style restraint devices) or remote (via dart or pole syringe) injection of agents requires small volumes in order to facilitate proper dart ballistics, rapid administration, and complete delivery. While a 500 kg domestic horse could be anesthetized with an intravenous combination of ketamine and midazolam, the volume of this combination would exceed 20 mL. Not only is intravenous access often not a luxury in the awake non-domestic animal, these species are often excitable and require higher drug dosages with intramuscular administration. Telazol® (Zoetis Inc, Kalamazoo, MI) is a product available to veterinarians that is a combination of tiletamine, a dissociative agent, and zolazepam, a benzodiazepine. This agent is available as a sterile powder that can be reconstituted with either sterile water or sedative agents such as alpha-2 adrenergic receptor agonists (e.g. dexmedetomidine). It offers the advantage of a much more concentrated immobilizing agent that can be easily administered intramuscularly via remote delivery system or hand injection. However, tiletamine does not have an antagonist agent available and animals immobilized with Telazol® often have slow recoveries, potentially leading to hypothermia, myopathy, and/or an inability to return to social interaction with cohorts. Medetomidine, the racemic mixture of levo- and dexmedetomidine, is available as a highly concentrated solution (20 ml mL-1) to facilitate adequate doses in smaller volumes via hand or remote delivery system. Combinations of high dosages of this alpha-2 adrenergic receptor agonist with ketamine offers relatively predictable and reversible immobilization and is commonly utilized in non-domestic species such as large cats and primates. However, megafauna such as elephant, rhinoceros, and large hoofstock may require an even more concentrated agent that can be easily administered in small volumes via a remote delivery system, such as a dart.
Ultrapotent opioids are a subclass of opioids that offer a number of substantial advantages to the veterinary anesthesia provider. These include rapid immobilization following intramuscular administration of a relatively small volume, muscle relaxation when combined with sedatives, analgesia, and a smooth and rapid recovery following the administration of antagonist agents. Reversal of anesthesia is readily performed via intravenous or intramuscular administration of opioid receptor antagonists, most commonly naltrexone. Renarcotization is a relatively rare phenomenon which may occur up to 24 hours following reversal.1 Affected animals may present with lethargy, recumbency, or a paradoxical increase in motor activity. The most commonly utilized agents are etorphine, thiafentanil and, historically, carfentanil. These agents have historically been used exclusively for veterinary species but have recently gained in notoriety due to concerns with public safety. At this time, ultrapotent opioids are listed as schedule II by the Drug Enforcement Administration (DEA).
First synthesized in 1974, the first uses of carfentanil in free-ranging wild animals was described in 1978.2 Following that report, this agent became the mainstay for use in captive and free-ranging large species due to its high potency (approximately 10,000 times that of morphine3) and concentration, rapid onset, and reversibility. Carfentanil was available commercially under the trade name Wildnil® and later became available via compounding pharmacies as a 3 mg mL -1 solution. Dosages vary greatly among species and individuals and may range from 7-40 µg kg-1 either as a sole agent or combined with a sedative such as an alpha-2 adrenergic receptor agonist (e.g. xylazine, detomidine, or medetomidine). Intramuscular injection is the most commonly utilized route of administration, but other routes of administration have been reported. Wild and captive bears, for instance, have been safely immobilized using carfentanil mixed with honey and transmucosal administration for preanesthetic sedation has been reported in chimpanzee.4-7 Time to recumbency following intramuscular injection may be variable and impacted by variation in environmental stimuli, animal temperament, drug dosage, concurrent administration of sedatives and location of injection but is generally rapid, often within five minutes. Antagonism is often even more rapid with a nearly complete recovery in approximately two minutes following intramuscular administration of naltrexone. In general, carfentanil was the preferred agent for use in hoofstock such as cervids (deer, moose elk) and antelope. However, in 2016, reports of human deaths due to carfentanil intoxication began to emerge and the DEA issued warnings to the public and law enforcement officers detailing the dangers of this agent. Carfentanil was pulled from the veterinary market at that time.
Thiafentanil, or A3080, is a relatively new ultrapotent opioid that is structurally similar to carfentanil and sufentanil and has a potency approximately 6,000 times that of morphine.8 This agent provides a similar quality of immobilization with a higher therapeutic index, more rapid induction time, and shorter half-life when compared to other agents of this drug class.9 Its use has been described in a number of species and has largely filled the void left by the loss of carfentanil for the immobilization of large nondomestic species. It is supplied as a 10 mg mL-1 solution. Dosages vary widely and are impacted by species and concurrent administration of sedatives (15-100 µg kg-1).9 Like carfentanil, thiafentanil is useful for the immobilization of exotic hoofstock such as impala and caribou. Practitioners experienced with the use of ultrapotent opioids report a considerably lower incidence of renarcotization with thiafentanil due to its shorter half-life as compared to other narcotics.
The use of etorphine, or M99, was first reported in the 1960’s and the actions of this ‘potent morphine-like agent’ were described in detail in rodents.10 At that time, it was reported to have a potency roughly 1,000-80,000 times that of morphine, but it is currently accepted to possess a potency 6,000 times that of morphine.11 Clinically, the characteristics of an etorphine-based immobilization protocol are similar to that of carfentanil with time to recumbency being slightly longer in comparison to the other ultrapotent opioids. It is supplied as a 10 mg mL-1 solution and dosages vary with species, ranging from 8-20 µg kg-1, although it is common to dose on a ‘per-animal’ basis, depending on the species, size and age group (e.g. 4.5 mg etorphine per adult white rhinoceros or 10 mg per African elephant).12,13 While etorphine has been used and evaluated in many species, it is used more commonly in species that have a more equine-like physiology. This would include species such as zebra, rhinoceros, and elephants. It is often combined with other sedative agents, such as alpha-2 adrenergic receptor agonists in order to improve muscle relaxation and may be combined with butorphanol, a kappa-opioid receptor agonist/mu-opioid receptor antagonist, in an attempt to decrease respiratory depression.14,15 Antagonism of etorphine via administration of diprenorphine, or M50/50, a lipophilic opioid receptor antagonist used specifically for etorphine, is generally smooth and rapid. It is important to note that inadvertent human exposure to diprenorphine has been described and has resulted in cyanosis, lethargy, and dizziness.16 In the event of human ultrapotent opioid exposure, described elsewhere, naloxone or naltrexone are the preferable antagonists.
While there are marked differences among species in the response to anesthetic agents, the overall characteristics of immobilization with ultrapotent opioids is relatively consistent. Prior to recumbency, animals often display an excitatory phase which may result in hypermetria, hyperthermia, hypertension, tachycardia, rhabdomyolysis, and/or injury. When choosing a dosage of anesthetic agent, it is often prudent in these species to err on the higher side of the dosing range in order to avoid prolonged induction times and excitation or the need for repeat administration of immobilizing or sedative agents. Recumbency is often achieved within ten minutes or less. However, with initial anesthetic effect, animals may be safe to approach even if they have not yet achieved recumbency. If an experienced veterinarian feels it is safe and necessary, the animal may be approached before it is completely anesthetized to allow intravenous catheterization for the administration of additional anesthetics such as propofol or to be repositioned if the animal has been caught in a corner or against a wall. Like humans, regurgitation, passive reflux, and gastrointestinal bloating are common effects of opioids and may lead to aspiration and/or, in the case of ruminants with stomach compartments that do not empty completely and can comprise roughly half of the abdomen, decreased venous return and direct compression of the diaphragm. Anesthetized animals must be carefully positioned and intubated to encourage gastric drainage and avoid aspiration of gastrointestinal contents and should be closely monitored for signs of gastrointestinal bloating (a condition known as ruminal tympany). Muscle tremors and rigidity are common during immobilization, necessitating the need for coadministration of sedatives and/or muscle relaxants. The most common and life-threatening effect of these opioid agents, similar to what is seen in humans, is respiratory depression. For instance, white rhinoceros receiving an age-based intramuscular dose of etorphine combined with azaperone, a tranquilizer, and hyaluronidase, an additive to facilitate drug uptake, had initial mean PaO2 values of 27 mmHg and mean PaCO2 values of 82 mmHg.15 This highlights the importance of high-flow oxygen supplementation via nasal cannula or endotracheal tube.
Veterinarians working with ultrapotent agents must be aware of the dangers of exposure. Most institutions and field researchers have protocols for prevention of exposure as well as emergency treatment of personnel should an exposure occur. Careful handling of agents, darts, needles and syringes, as well as drug injection sites on the animal are critical to avoid potentially fatal errors.
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Carrie Schroeder, DVM, DACVAA, is a clinical assistant professor of anesthesia and pain management in the Department of Surgical Sciences and the University of Wisconsin School of Veterinary Medicine in Madison.
Dominique Keller, DVM, PhD, DACZM, is the chief veterinarian and director of Animal Wellness Programs at the Los Angeles Zoo.