Chapter 77 The Use of Butorphanol in Anesthesia Protocols for Zoo and Wild Mammals

Mitchell Bush, Scott B. Citino, William R. Lance

Butorphanol tartrate is a synthetically derived opioid agonist-antagonist analgesic of the phenanthrene series, with a potency of about four to seven times that of morphine. In the United States, it is a U.S. Drug Enforcement Administration (DEA) class IV controlled substance. Butorphanol is a mixed agonist-antagonist with low intrinsic antagonist activity at receptors of the mu₁ (µ₁) and mu₂ (µ₂) opioid type (morphine-like), which are responsible for the significant opioid side effects and also an agonist with a high affinity for kappa (κ) opioid receptors. Butorphanol is also a sigma (σ) receptor agonist, which stimulates respiratory drive. Its interactions with these receptors in the central nervous system apparently mediate most of its pharmacologic effects, including analgesia. Generally, there is minimal cardiopulmonary depression with its use compared with other opioids and, at lower doses, there is a dose-dependent effect on respiratory depression but then a ceiling is reached and no further respiratory depression occurs. However, there is species variability, such as a fairly marked respiratory depression when used in primates.

In veterinary medicine, butorphanol tartrate is widely used as a sedative and analgesic in dogs, cats, and horses. It is administered either IM or IV, with its analgesic properties beginning to take effect about 15 minutes after IM injection and lasting about 4 hours. The elimination half-life is about 18 hours. For increased sedation or light anesthesia, it may be combined with sedatives such as α-adrenergic agonists (e.g., medetomidine, xylazine) or tranquilizers such as benzodiazepines (e.g., midazolam, diazepam) or phenothiazines (e.g., acepromazine) in dogs and cats. In horses, butorphanol is frequently combined with sedatives (e.g., xylazine, detomidine, romifidine) to make the horse easier to handle during veterinary procedures.

Butorphanol is relatively safe, with a high therapeutic index, and may be completely reversed rapidly with naloxone, nalmefene, or naltrexone, or partially reversed by diprenorphine, which antagonizes only the µ opioid receptors but not the κ opioid receptors. This partial reversal of the undesirable µ opioid receptor effects (muscle tremors, tachycardia-bradycardia, gastrointestinal stasis, euphoria-dysphoria, respiratory depression) while maintaining the sedative κ effect produces some useful and safer anesthetic protocols in nondomestic species.

As with other opioid analgesics, central nervous system effects (e.g., sedation, excitement) are considerations with the use of butorphanol. Nausea and vomiting are common. Less common are the gastrointestinal effects of other opioids, mostly constipation. Butorphanol is transported across the blood-brain and placental barriers and into milk. It is extensively metabolized in the liver with urinary excretion.

In zoo and wildlife species (mainly mammal), it is being used for one or more of the following: (1) pain control; (2) combined with sedatives to assist in minor manipulative procedures; (3) combined with α₂-adrenergic agonists and/or more potent opioids for anesthesia or neuroleptanalgesia. Butorphanol, when used alone, causes apathetic sedation that may allow arousal when the animal is stimulated, a potential danger when working with dangerous species.

Butorphanol combined with α₂-adrenergic agonists, potent opioids, dissociative anesthetics and/or tranquilizers may produce safer anesthesia procedures by minimizing many adverse effects. These combinations use lower doses of each agent and use the synergistic effects of the various drugs in the combination.

Butorphanol appears to be the opioid analgesic of choice for birds because analgesia is primarily regulated thorough κ receptors in birds; however, its analgesic efficacy is limited because of its short half-life in birds.²⁵ The development of a liposome-encapsulated formulation of butorphanol tartrate has extended its analgesic efficacy in birds to 3 to 5 days. Butorphanol has shown promise as a premedication for some avian species undergoing isoflurane inhalation anesthesia (see Chapter 41).

Butorphanol use in reptiles has shown limited analgesic effect and minor effects have also been seen when it is incorporated into various anesthetic protocols.^24,²⁶ Because analgesia, in most reptiles studied to date, is µ opioid receptor–dependent, drugs such as morphine work best for analgesia.

The initial low commercial concentrations of butorphanol (10 mg/mL) made larger dart volumes necessary, which in turn adversely affected the performance and range of the dart. The various anesthetic protocols that use butorphanol are becoming more popular with the development of more concentrated formulations (30 and 50 mg/mL) that allow its use in remote delivery systems. One such formulation, containing butorphanol, azaperone, and medetomidine (BAM), has proved successful in a wide range of species.

Butorphanol combinations with tranquilizers and/or an α₂ agonist at low dosages are used together with restraint devices for standing restraint procedures in captive elephants, rhinoceros, giraffes, and tapirs.

Use in Various Species

Captive Elephant

As with other species, drug dosages for the sedation and anesthesia of elephants often vary among species and among individuals, so extrapolations should be used with caution. Butorphanol has been used mainly in combination with azaperone or α₂-adrenergic agonists (e.g., detomidine, xylazine) to manage excitable animals and/or for minor manipulative procedures.

In one report involving 14 standing clinical procedures in African elephants (Loxodonta africana), a recommended starting dosage range of 14.7 to 16.2 µg/kg of both detomidine and butorphanol in a ratio of 1 : 1, on a microgram to microgram basis, were administered simultaneously IM. The initial effect was noted within 3.0 to 25 minutes (mean, 11.6 minutes; standard deviation [SD], ±5.9 minutes), with maximal effect occurring at 25 to 30 minutes for those procedures not requiring supplementation. This could subsequently be supplemented as needed using 4.0 to 7.3 µg/kg of each drug. Recovery after administration of reversal agents was rapid and complete, ranging from 2 to 20 minutes (mean, 9.0 minutes; SD, ±7.0 minutes).¹⁸

In Asian elephants (Elephas maximus), a dose of 0.01 to 0.03 mg/kg administered IV, IM, or SC is suggested for minor manipulative procedures.¹⁰ For aggressive adult African elephants, xylazine, 700 to 1000 mg/adult elephant (≈0.2 to 0. 3 mg/kg), followed by IV butorphanol, 50 to 180 mg/adult elephant (≈0.01 to 0.03 mg/kg), has proven effective.²²

A xylazine-butorphanol combination was successfully used for standing restraint of Asian elephants at average doses of xylazine (70 µg/kg) and butorphanol (25 µg/kg) IV and reversal with naltrexone at approximately 50 µg/kg and yohimbine at 0.1 mg/kg. Atipamezole administered at 4 µg/kg IV provided better xylazine reversal than yohimbine.

Captive Rhinoceros

Butorphanol alone and in combinations with other tranquilizers and/or α₂-adrenergic agonists may facilitate many management and medical procedures, with or without restraint devices.

The use of a medetomidine-butorphanol combination for standing and recumbent chemical restraint of the white rhinoceros (Ceratotherium simum) has produced good results.²¹ A mean dose of 63 ± 1.2 µg/kg butorphanol plus 2.64 ± 0.17 µg/kg medetomidine is given IM. Average doses for adult white rhinos are medetomidine, 5 to 7 mg, and butorphanol, 80 to 150 mg. Midazolam may be added to this cocktail at a total dose of 20 to 40 mg to improve relaxation. Animals become safe to work on in a standing position in about 8 to 20 minutes and then may be pulled down into recumbency, or supplemented with ketamine, 200 to 400 mg IV, to induce recumbency. Supplemental drugs used to maintain chemical restraint for long procedures include a constant rate IV infusion using guaifenesin 5% in dextrose, ketamine, butorphanol, medetomidine, propofol, or a combination of these. A wide range of procedures has been accomplished using these combinations, including electroejaculation, fiberoptic endoscopy, ophthalmic surgery, dental procedures, and daily repeated IV therapy. Reversal is accomplished with naltrexone, 233 ± 29 µg/kg (one to two times the butorphanol dose) and atipamezole, 14.7 ± 3.8 µg/kg (five times the medetomidine dose).⁶

Butorphanol is useful for modulating opioid receptor effects when etorphine is used in rhinoceroses. If etorphine combinations are used, partial reversal with butorphanol (titrate with 10 mg IV boluses) will reduce respiratory depression without getting arousal in the white rhinoceros.

For crate loading white rhinoceroses, a combination of etorphine-butorphanol-midazolam is useful. Doses are etorphine, 0.5 to 0.7 µg/kg, butorphanol, 15 to 25 µg/kg, and midazolam 15 to 25 µg/kg (average total doses for adults—etorphine 1.0 mg, butorphanol, 30 mg, midazolam, 30 mg). Etorphine causes the animal to continue to walk forward for loading. Once in the crate and loaded on the truck, the etorphine is reversed with diprenorphine at twice the etorphine dose; this only reverses the etorphine and leaves the butorphanol and midazolam on board for travel. Animals should be observed during travel for excessive pressing or getting into dangerous positions. If animals need to be fully reversed, they may be given naltrexone at one to two times the butorphanol dose. If various butorphanol combinations without etorphine are used for loading white rhinoceroses, the animals will tend to just stand and not move forward, so they may be difficult to load.

Two butorphanol combinations have been used in the captive black rhinoceros (Diceros bicornis)—butorphanol-azaperone and butorphanol-detomidine—but they are not recommend because restraint is not as good as with the white rhinoceros, which could be very dangerous for less experienced people. The black rhinoceros does not experience as much respiratory depression and other physiologic disturbances with etorphine as the white rhinoceros, so butorphanol combinations are generally not necessary.

Standing procedures on the Asian greater one-horned rhinoceros (Rhinoceros unicornis) using medetomidine-butorphanol-midazolam has been used successfully; average doses are medetomidine, 3 to 4 µg/kg, butorphanol, 50 to 60 µg/kg, and midazolam, 12 to 15 µg/kg. Most of these procedures have been for reproductive examinations on females (rectal ultrasound) and for IV therapy in sick rhinoceroses. Supplemental ketamine (200 to 400 mg IV) will produce recumbency. Reversal is with naltrexone at twice the butorphanol dose and atipamezole at five times the medetomidine dose. Standing sedation has also been produced in the Indian rhinoceros (R. unicornis) using a butorphanol-azaperone combination (adult, 100 mg of each).²⁰

As with white rhinoceroses, butorphanol combinations are preferred in Sumatran rhinoceroses (Dicerorhinus sumatrensis) because better muscle relaxation and improved cardiopulmonary function are obtained when compared with the more potent opioids. A butorphanol (30 to 50 mg) and azaperone (50 to 60 mg) combination in adults may be used for standing sedation at the lower end of the dosage range or recumbency at the higher dosages.²⁰ A second combination using medetomidine (2.0 to 2.5 µg/kg) and butorphanol (70 to 72 µg/kg) produces a good standing chemical restraint in Sumatran rhinoceroses, after which they may be pulled into sternal recumbency. This combination also maintains acceptable physiology. Reversal is with naltrexone at twice the butorphanol dose and atipamezole at five times the medetomidine dose.