Elephant specific information, if available, is in blue.

Chemistry – A synthetic opiate partial agonist, butorphanol tartrate is related structurally to morphine but exhibits pharmacologic actions similar to other partial agonists such as pentazocine or nalbuphine. The compound occurs as a white, crystalline powder that is sparingly soluble in water and insoluble in alcohol. It has a bitter taste and a pKa of 8.6. The commercial injection has a pH of 3-5.5. One mg of the tartrate is equivalent to 0.68 mg of butorphanol base.

 

Storage/Stability/Compatibility – The injectable product should be stored out of bright light and at room temperature; avoid freezing.

 

The injectable product is reported to be compatible with the following IV fluids and drugs: acepromazine, atropine sulfate, chlorpromazine, diphenhydramine HCl, droperidol, fentanyl citrate, hydroxyzine HCl, meperidine, morphine sulfate, pentazocine lactate, perphenazine, prochlorperazine, promethazine HCl, scopolamine HBr, and xylazine.

 

The drug is reportedly incompatible with the following agents: dimenhydrinate, and pentobarbital sodium.

 

Pharmacology – Butorphanol is considered to be, on a weight basis, 4-7 times as potent an analgesic as morphine, 15-30 times as pentazocine, and 30-50 times as meperidine. Its agonist activity is thought to be exerted primarily at the kappa and sigma receptors and the analgesic actions at sites in the limbic system (sub-cortical level and spinal levels).

 

The antagonist potency of butorphanol is considered to be approximately 30 times that of pentazocine and 1/40th that of naloxone and will antagonize the effect of true agonists (e.g., morphine, meperidine, oxymorphone).

 

Besides the analgesic qualities of butorphanol, it possesses significant antitussive activity. In dogs, butorphanol has been shown to elevate CNS respiratory center threshold to CO2, but unlike opiate agonists, not depress respiratory center sensitivity. Butorphanol, unlike morphine, apparently does not cause histamine release in dogs. CNS depression may occur in dogs, while CNS excitation has been noted (usually at high doses) in horses and dogs.

 

Although possessing less cardiovascular effects than the classical opiate agonists, butorphanol can cause a decrease in cardiac rate secondary to increased parasympathetic tone and mild decreases in arterial blood pressures.

 

The risk of causing physical dependence seems to be minimal when butorphanol is used in veterinary patients.

 

Pharmacokinetics – Butorphanol is absorbed completely in the gut when administered orally, but because of a high first-pass effect only about 1/6th of the administered dose reaches the systemic circulation. The drug has also been shown to be completely absorbed following IM administration.

 

Butorphanol is well distributed, with highest levels (of the parent compound and metabolites) found in the liver, kidneys, and intestine. Concentrations in the lungs, endocrine tissues, spleen, heart, fat tissue and blood cells are also higher than those found in the plasma. Approximately 80% of the drug is bound to plasma proteins (human data). Butorphanol will cross the placenta and neonatal plasma levels have been roughly equivalent to maternal levels. The drug is also distributed into maternal milk.

 

Butorphanol is metabolized in the liver, primarily by hydroxylation. Other methods of metabolism include N-dealkylation and conjugation. The metabolites of butorphanol do not exhibit any analgesic activity. These metabolites and the parent compound are mainly excreted into the urine (only 5% is excreted unchanged), but 11-14% of a dose is excreted into the bile and eliminated with the feces.

 

Following IV doses in horses, the onset of action is approximately 3 minutes with a peak analgesic effect at 15-30 minutes. The duration of action in horses may be up to 4 hours after a single dose.

 

Uses/Indications – Approved indication for dogs is “for the relief of chronic non-productive cough associated with tracheobronchitis, tracheitis, tonsillitis, laryngitis and pharyngitis originating from inflammatory conditions of the upper respiratory tract” (Package Insert; Torbutrol® — Fort Dodge). It is also used in practice in both dogs and cats as a preanesthetic medication, analgesic, and as an antiemetic prior to cisplatin treatment.

 

The approved indication for horses is “for the relief of pain associated with colic in adult horses and yearlings” (Package Insert; Torbugesic® — Fort Dodge). It has also been used clinically as an analgesic in cattle, although published data is apparently lacking.

 

Contraindications/Precautions – All opiates should be used with caution in patients with hypothyroidism, severe renal insufficiency, adrenocortical insufficiency (Addison’s), and in geriatric or severely debilitated patients.

 

Like other opiates, butorphanol must be used with extreme caution in patients with head trauma, increased CSF pressure or other CNS dysfunction (e.g., coma).

 

The manufacturer states that butorphanol “should not be used in dogs with a history of liver disease”, and because of its effects on suppressing cough, “it should not be used in conditions of the lower respiratory tract associated with copious mucous production.” The drug should be used cautiously in dogs with heartworm disease as safety for butorphanol has not been established in these cases.

 

Although no controlled studies have been performed in domestic animals or humans, the drug has exhibited no evidence of teratogenicity or of causing impaired fertility in laboratory animals. The manufacturer, however, does not recommend its use in pregnant bitches, foals, weanlings (equine), and breeding horses.

 

The drug is contraindicated in patients having known hypersensitivity to it.

 

Adverse Effects/Warnings – Adverse effects reported in dogs include, sedation (occasionally), anorexia or diarrhea (rarely).

 

Adverse effects seen in horses (at usual doses) may include a transient ataxia and sedation. Although reported to have minimal effects, butorphanol has the potential to decrease intestinal motility. Horses may exhibit CNS excitement (tossing and jerking of head, increased ambulation, augmented avoidance response to auditory stimuli) if given high doses (0.2 mg/kg) IV rapidly. Very high doses IV (1 – 2 mg/kg) may lead to the development of nystagmus, salivation, seizures, hyperthermia and decreased GI motility. These effects are considered to be transitory in nature.

 

Overdosage – Acute life-threatening overdoses with butorphanol should be unlikely. The LD50 in dogs is reportedly 50 mg/kg. However, because butorphanol injection is available in two dosage strengths (0.5 mg/ml and 10 mg/ml) for veterinary use, the possibility exists that inadvertent overdoses may occur in small animals. It has been suggested that animals exhibiting symptoms of overdose (CNS effects, cardiovascular changes, and respiratory depression) be treated immediately with intravenous naloxone. Additional supportive measures (e.g., fluids, O2, vasopressor agents, & mechanical ventilation) may be required. Should seizures occur and persist, diazepam may used for control.

 

Drug Interactions – Other CNS depressants (e.g., anesthetic agents, antihistamines, phenothiazines, barbiturates, tranquilizers, alcohol, etc.) may cause increased CNS or respiratory depression when used with butorphanol, dosage may need to be decreased.  Pancuronium if used with butorphanol may cause increased conjunctival changes.

 

 

 

Doses – Note: All doses are expressed in mg/kg of the base activity. If using the human product (Stadol®), 1 mg of tartrate salt = 0.68 mg base.

Horses:

As an analgesic:

a)   0.1 mg/kg IV q3-4h; not to exceed 48 hours (Package Insert; Torbugesic®; – Fort Dodge)

b)   0.02 – 0.05 mg/kg IV (Muir 1987)

c)   0.01 – 0.1 mg/kg IV (Thurmon and Benson 1987)

d)   0.02 – 0.1 mg/kg IV; or 0.04 – 0.2 mg/kg IM q3-4h (combined with acepromazine or xylazine) (Orsini 1988)

 

As a preanesthetic, outpatient surgery, or chemical restraint:

a)   0.01 – 0.04 mg/kg IV (with xylazine 0.1 – 0.5 mg/kg IV) (Orsini 1988)

 

As an antitussive:

a)   0.02 mg/kg IM bid-tid (Orsini 1988)

 

 

Elephants:

 

CAUTION!  Sedative and anesthetic drug dosages for African elephants often vary from those for Asian elephants.  Do not assume that the recommendations for one species can be applied to the other.  Significant variation may also occur between individual elephants.  The information provided here should be used as a guideline only.  Consultation with experienced colleagues is advised. 

 

a) Butorphanol combined with azaperone was used in two captive female African elephants for standing sedation.  See details below (Ramsey, 2000).

 

b) For aggressive adult African elephants, give IM xylazine at total doses of 700 – 1000 mg/ adult elephant (approximate dosages of 0.2 – 0. 3 mg/kg) followed by intravenous butorphanol at doses of 50 – 180 mg/adult elephant (approximate dosages of 0.01 – 0.03 mg/kg), depending on size and temperament.  See details below (Ramsey, 2000)

 

c) For sedation of adult captive African elephants: 0.01 ± 0.003 mg/kg (Fowler, 1995).

 

d) 8-10 mg total dose was given IV to 1500 kg African elephants following administration of a xylazine-ketamine combination to improve upon the sedative response to this drug combination (Jacobsen, 1988).

 

e) Xylazine (150 mg IM) combined with butorphanol (6 mg IV) was given to an 8 yr old African elephant weighing 1500 kg for radiography of a broken tusk (Heard et.al. 1986).

 

f) Butorphanol 0.015 mg/kg IV or IM for analgesia without sedation in Asian elephants (Ingram, 2005)

 

Elephant References:

a) Ramsay,E.  2000. Standing sedation and tranquilization in captive African elephants (Loxodonta africana). Proc. Am. Assoc. Zoo Vet. Pages: 111-114

Excerpt from abstract: Intramuscular azaperone in combination with butorphanol was used on one female elephant for aggressive debridement of a facial abscess and on another aggressive cow.  The azaperone doses ranged from 0.068 – 0.12 mg/kg.  In one immobilization, 10 mg butorphanol was mixed with azaperone (0.12 mg/kg) in the initial dart (tranquilization was rated good). In the other procedures, butorphanol, 0.006 – 0.014 mg/kg (total doses = 20 – 50 mg), was given IV 24 – 73 minutes post-azaperone administration, to attain (0.006 mg/kg given at 24 and 25 minutes) or maintain (0.013 and 0.014 mg/kg given at 40 and 73 min, respectively) control.  The azaperone and butorphanol combination sedation events were ranked as good (n=3) or excellent (n=2). Naloxone (0.004 mg/kg IV; total dose =12.8 mg) was used to reverse the effects of butorphanol in the animal receiving the highest butorphanol dosage.

 

b) Ramsay,E.  2000. Standing sedation and tranquilization in captive African

elephants (Loxodonta africana). Proc. Am. Assoc. Zoo Vet. Pages: 111-114

Excerpt from abstract: Xylazine in combination with butorphanol was used to sedate 2 African elephants, twice each.  The adult male elephant (estimated weight = 5000 kg) received a total dose of 800 mg (0.16 mg/kg) xylazine IM, and 26 minutes later received 180 mg (0.036 mg/kg) butorphanol IV for radiology, performed outside of the elephant restraint device.  This immobilization was rated excellent but when the same dosages were used 2 years later, the immobilization was initially rated only as good.  Supplemental butorphanol (20 mg) was given during the second immobilization 77 min after xylazine injection and the subsequent phase of the immobilization was rated as fair.  One female elephant (estimated weight = 3500 kg)  received 100 mg (0.035 mg/kg) xylazine IV mixed with 15 mg (0.005 mg/kg) butorphanol IV.  Fourteen minutes later an additional 50 mg xylazine and 10 mg butorphanol were given IV.  A local block was subsequently used to lance a subcutaneous abscess on the abdomen and this immobilization was rated as good.  On a subsequent immobilization for physical examination and blood collection, this animal received 500 mg (0.14 mg/kg) xylazine IM, followed 44 min later by 50 mg (0.014 mg/kg) butorphanol IV.  This immobilization was rated only as fair.

 

c) Fowler,M.E., 1995. Elephants. In: Restraint and handling of wild and domestic animals. Iowa State University Press, Ames, Iowa, USA p. 265.

 

d) Jacobson,E.R.  1988. Chemical restraint and anesthesia of elephants. Proc.Ann.Elephant Workshop 9. pp. 112-119.

 

e) Heard,D.J., Jacobson,E.R., and Brock,K.A. 1986. Effects of oxygen supplementation on blood gas values in chemically restrained juvenile African elephants. Journal of the American Veterinary Medical Association 189:(9):1071-1074  Abstract: Arterial oxygen and carbon dioxide tensions were determined in sedated immature African elephants and in elephants immobilized with etorphine hydrochloride or with an etorphine-ketamine combination.  For manipulative and surgical procedures, the Hudson demand value was used for oxygen supplementation during 6 procedures, and insufflation was used during 2 procedures.  The Hudson demand value was more effective than insufflation in sustaining adequate arterial oxygenation.

f) Ingram, L.M., Isaza, R., Koch, D.E., and Hunter, R.P. 2005. Pharmacokinetics of intravenous and intramuscular butorphanol in Asian elephants (Elephas maximus). 2005 Proceedings AAZV, AAWV, AZA Nutrition Advisory Group, pp. 70-71.

Captive Asian elephants (Elephas maximus) are susceptible to lameness resulting from foot and
joint pain.1 In the past, opioid analgesics, such as the agonist-antagonist butorphanol, have been used clinically for pain management. However, dosages used in treating elephants were often extrapolated from data in horses, with the risk of administering either a sub-efficacious dose or an overdose, both of which are undesirable. In this study, six adult captive Asian elephants (five female, one male) were administered butorphanol intravenously (i.v.) and intramuscularly (i.m.) in a cross over design. The dose was 0.015 mg/kg for both routes with at least 21 days between administrations. Serial blood samples were collected immediately prior to butorphanol administration and at 5, 10, 20, 40 min, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 24 hr after injection. The samples were collected into Li heparin vacutainer tubes and centrifuged to obtain plasma. The plasma was separated into cryovials and frozen at -70°C until analyzed using a validated LC/MS assay with a LOQ of 0.025 ng/ml. The dosage selected for this pharmacologic study in elephants is within the recommended analgesic butorphanol dose range for horses.2 Following i.v. administration the median pharmacokinetic values that were calculated include: Vdarea, Vdss, Clp, MRT, and half life (t½). After i.m. injection the median Cmax, Tmax, and bioavailability (F) were calculated. The Vd data used for extrapolation from published literature on five domestic mammalian species correlated with the values found for elephants. Thus, Vd may be useful to extrapolate an efficacious dose in Asian elephants. Our preliminary results suggest a dosage of 0.015 mg/kg may provide analgesia without evidence of severe sedation. Further studies are necessary to determine the quality and duration of analgesia from the administration of butorphanol in elephants at this recommended dose.

1. Mikota, S.K., E. Sargent, and G. Ranglack. 1994. Medical Management of the Elephant. Indira Publishing House
2. Plumb, D.C. 2005. Plumb’s Veterinary Drug Handbook. Blackwell Publishing, Ames, Iowa. Pp. 102-105.
 

Monitoring Parameters –

1)   Analgesic &/or antitussive efficacy

2)   Respiratory rate/depth

3)   Appetite/bowel function

4)   CNS effects

 

Client Information – Clients should report any significant changes in behavior, appetite, bowel or urinary function in their animals.

 

Dosage Forms/Preparations/FDA Approval Status/Withholding Times – Note: Butorphanol is a class IV controlled substance. The veterinary products (Torbutrol®, Torbugesic®) strengths are listed as base activity. The human product (Stadol®) strength is labeled as the tartrate salt.

 

Veterinary-Approved Products:

Butorphanol Tartrate Injection; 0.5 mg/ml (activity as base) 10 ml vials; Torbutrol®   (Fort-Dodge); (Rx)  Approved for use in dogs.

 

Butorphanol Tartrate Injection; 10 mg/ml (activity as base) 50 ml vials; Torbugesic®   (Fort-Dodge); (Rx)  Approved for use in horses not intended for food.

 

Butorphanol Tartrate Tablets (Veterinary); 1 mg, 5 mg, & 10 mg (activity as base) tablets; bottles of 100; Torbutrol® (Fort-Dodge); (Rx)  Approved for use in dogs.

 

Human-Approved Products:

Butorphanol Tartrate Injection; 1 mg/ml (as tartrate salt; equivalent to 0.68 mg base) in 1 ml vials and 2 mg/ml (as tartrate salt) in 1, 2, & 10 ml vials;  Stadol®  (Mead Johnson); (Rx)

Butorphanol Nasal Spray: 10 mg/ml (2.5 ml metered dose) Stadol NS® (Mead Johnson) (Rx)

 

Dosage Forms/Preparations/FDA Approval Status/Withholding Times –

 

Veterinary-Approved Products:  None

 

Buprenorphine HCl for Injection: 0.324 mg/ml (equivalent to 0.3 mg/ml buprenorphine); 1 ml ampules; Buprenex®   (Reckitt & Colman); (Rx)