Chemicals / Complex Chemical Agents/ Chemical:

Butorphanol (with special reference to Ruminants, Hedgehogs, Elephants, Bears, Lagomorphs, Ferrets and Great Apes)

INFORMATION AVAILABLE

GENERAL CHEMICAL INFORMATION THERAPEUTIC INFORMATION [DOSE, FREQUENCY & ROUTE]

NUTRITIONAL INFORMATION

TOXICITY INFORMATION ENVIRONMENTAL INFORMATION
Information in this page has been entered to support the current volumes of Wildpro and further information will be added as new volumes are completed. This page is not intended to substitute for the manufacturer's data sheet and the information is not yet complete for all species, or for all contra-indications etc.

CAUTION: Before any pharmaceutical product is used, the manufacturer's data sheet, containing information on uses, dosage and administration, contra-indications, warnings etc., should always be consulted. It is important to remember that licensing of pharmaceutical products for use in a particular species/condition, as well as mandatory meat and milk withdrawal times for food-producing animals, varies between countries and changes with time. Withdrawal times also may vary between different pharmaceutical formulations and depending on route of administration. In the EU, the prescription cascade must be followed (see LCofC1.2H and W564.Apr05.w1); note that specific restrictions apply for food-producing animals. In the USA, FARAD may be consulted regarding residues and meat and milk withdrawal times.

General Chemical Information

Summary 
Opiate partial agonist/antagonist used for analgesia, anaesthetic premedication, as an antitussive and an antiemetic. 

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Names and Formulae
Type Opioid analgesic. (W324)
Alternative Names
  • Butorphanol tartrate. (B263)
  • "Stadol; 17-(Cyclobutylmethyl)morphinan-3,14-diol; L-N-Cyclobutylmethyl-3,14-dihydroxymorphinan." (W324)
  • levo-N-cyclobutyl-methyl-3,14-dihydroxymorphinan tartrate. (J289.15.w1)
Chemical Formula C21H29NO2 (W324)
Chemical Structure --
Molecular Weight 327.4656 (W324)
Related Chemicals --

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Physical Properties / Chemistry
Appearance

White crystalline powder, bitter tasting. (B263)

Melting point --
Boiling point --
Density --
Water solubility
  • Sparingly soluble. (B263)
Other solubility
  • Alcohol: insoluble. (B263)
Acid/Base
  • pKa of the powder 8.6. (B263)
  • Commercially available injection pH 3-5.5. (B263)

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Pharmacology & General Information
Pharmacology
  • Weight for weight, butorphanol is four to seven times as potent as morphine as an analgesic agent. (B263)
  • The agonistic activity of this drug "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". (B263)
  • As an antagonist, butorphanol has about one fortieth (1/40) the effect of naloxone. It will antagonise the effects of agonists such as morphine. (B263)
Storage / Stability
  • Store at room temperature, protect from freezing. (B263)
  • Avoid bright light. (B263)
Legal Category (In UK) POM (B266)

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References

Associated Techniques

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ORGANISATIONS

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ELECTRONIC LIBRARY
(Further Reading)
Click image for full contents list of ELECTRONIC LIBRARY

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Authors Debra Bourne (V.w5)
Referees Suzanne I. Boardman (V.w6)

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Therapeutic Information

Uses/Indications
Activity
  • Analgesia, antitussive activity. (B263)
  • CNS: In dogs: may act as a depressant. In horses and dogs: excitation may occur, usually with high dose rates. (B263)
  • Respiratory: No depression of respiratory centre sensitivity. However in dogs it has been shown to elevate the threshold of the CNS respiratory centre to CO2. (B263)
  • Cardiac: May decrease cardiac rate as a secondary effect of increased parasympathetic tone and mild decrease in arterial blood pressure. (B263)
  • Analgesic. in cats and dogs analgesia of about 1.5 to 2 hours duration for control of postoperative pain. (B322.3.w3)
Appropriate Use --
Limitations
  • In horses, if used alone this drug induces increased locomotor activity. (B322.3.w3)
Notes --

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Pharmacokinetics and Drug Interactions
Absorption /Bioavailability
  • Opioid analgesics are generally well absorbed from muscular tissue, subcutaneous tissue, mucosal surfaces of the nose or mouth and the gastro-intestinal tract. (B135.30.w30)
    • There may be significant first-pass metabolism of opioid analgesics following gastro-intestinal dosing. (B135.30.w30)
  • Intramuscular: complete absorption. (B263)
  • Oral: Complete absorption from the gut but a high first-pass effect, therefore only about 16.7% of the dose reaches the systemic circulation. (B263)
  • In horses: Following intravenous injection, onset of activity about three minutes, peak analgesic effect 15-30 minutes and duration of analgesia up to four hours.
  • Goats: Following intramuscular injection of 0.1 mg/kg body weight butorphanol, bioavailability was 82 +/- 41% (mean +/-SD). (J290.28.w1)
Distribution Good distribution. (B263)
  • High levels of parent drug and metabolites in the liver, kidneys and intestines particularly, also the lungs, endocrine tissues, spleen, heart, fat and blood cells (all higher concentrations than in plasma). (B263)
  • Distributed into milk. (B263)
  • Crosses the placenta. (B135.30.w30, B263)
  • Greater volume of distribution in cattle than in horses, therefore a higher dose may be required to achieve the same level of analgesia if the therapeutic plasma concentration is similar. (B322.3.w3)
  • Cattle:
    • Following administration of butorphanol tartrate to three dairy cows at 0.045 mg/kg body weight, distribution half-life t1/2α 6.4 min (geometric mean) and apparent volume of distribution 4.178 +/- 1.145 L/kg (mean +/- SD). (J289.15.w1)
  • Goats: Following intravenous injection of 0.1 mg/kg body weight butorphanol, (mean +/-SD) volume of distribution at steady state was 1.27 +/- 0.73 L/kg. (J290.28.w1)
Plasma Protein binding / Storage
  • In humans: Approximately 80% plasma protein bound. (B263)
Elimination Route
  • Metabolised in the liver mainly by hydroxylation, also by N-dealkylation and by conjugation. (B263)
  • Excretion in urine (parent compound as well as metabolites); about 5% is excreted unchanged. (B263)
  • Excretion in bile and eliminated in faeces (about 11 - 14%). (B263)
Elimination half-life / Clearance Rate
  • In humans: Duration of analgesia 3 to 4 hours. (B135.30.w30)
  • In horses: Duration of analgesia up to four hours. (B263)
  • High clearance in cattle, dogs and humans. (B322.3.w3)
  • Slower body clearance in horses. (B322.3.w3)
  • Short elimination half-life in dogs, cattle and horses, of one to two hours. (B322.3.w3)
  • Cattle:
    • Following administration of butorphanol tartrate to three dairy cows at 0.045 mg/kg body weight, elimination half-life t1/2 β  82 minutes (geometric mean) and clearance Cl 34.6 +/- 7.7 (mean +/- SD) mL/min/kg. (J289.15.w1)
  • Goats: 
    • Following intravenous injection of 0.1 mg/kg body weight butorphanol, elimination half-life was 1.87 +/- 1.49 hours; (mean +/-SD); following intramuscular injection of 0.1 mg/kg body weight butorphanol, elimination half-life was 2.75 +/- 1.93 hours (mean +/-SD). (J290.28.w1)
  • Rabbits:
    • Following intravenous administration, elimination half-life 1.64 hours; following subcutaneous administration, elimination half-life 3.16 hours. (J13.53.w1)
Drug Interactions
  • Increased CNS or respiratory depression may occur if butorphanol is used with other CNS depressants such as anaesthetic agents, antihistamines, phenothiazines, barbiturates, tranquillizers, alcohol etc.; it may be necessary to reduce the dose. (B263)
  • If used with pancuronium there may be increased conjunctival changes. (B263)
  • Reported physically incompatible with: dimenhydrinate, pentobarbital sodium. (B263)
  • Reported physically compatible with: acepromazine, atropine sulphate, chlorpromazine, diphenhydramine hydrochloride, droperidol, fentanyl citrate, hydroxyzine hydrochloride, meperidine, morphine sulphate, pentazocine lactate, perphenazine, prochlorperazine, promethiazine hydrochloride, scopolamine hydrobromide, zylazine. (B263)

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Administration
Formulations available
  • Torbugesic Injection (Fort Dodge Animal Health): "clear colourless solution containing as active ingredient butorphanol as tartrate (USP) 10 mg/ml. The product also contains 0.1 mg/ml benxethonium chloride (PhEur) as an antimicrobial preservative." (B266)
  • Torbutrol Tablets (Fort Dodge Animal Health): "white tablets containing 5 mg or 10 mg butorphanol as tartrate." (B266)
    • For use as a cough suppressant in relief of acute or chronic non-productive cough due to upper respiratory tract inflammatory conditions in dogs. (B266)
  • 1 mg of butorphanol tartrate is equivalent to 0.68 mg of butorphanol base. (B263)
Doses / Administration Routes / Frequencies Cattle

Experimental data in sheep:

  • Butorphanol was effective in sheep when tested against a thermal stimulus, but not when tested against a mechanical stimulus. (P61.62.w1) 
    • Butorphanol at dose rates of 0.05, 0.1 and 0.2 mg/kg intravenously in sheep produced a clear antinociceptive effect against a thermal stimulus to the ear with statistically significant increases in threshold at 5 to 60, 15 to 80 and 15 to 130 minutes after drug injection respectively. However, doses of 0.05, 0.1, 0.2 and 0.4 mg/kg all failed to increase the mechanical nociceptive threshold. (J21.51.w2)

Erinaceus europaeus - West European Hedgehog:

Atelerix albiventris - Four-toed hedgehog:

"Hedgehog" (species not distinguished between Atelerix albiventris - Four-toed hedgehog or Erinaceus europaeus - West European Hedgehog):

  • 0.2-0.4 mg/kg subcutaneously or intramuscularly, every six to eight hours as required. For analgesia. (B150.w1)

Elephants:

The following information is taken with permission directly from the Elephant Care International website (W580.Aug2005.w7):

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).

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.

Bears (Ursidae - Bears (Family)):

  • 0.075 mg/kg intramuscularly into the pectoral muscles 20 minutes before the onset of surgery then hourly during surgery. (during Cholecystectomy in Bears). (V.w89, V.w90)

Lagomorphs - Oryctolagus cuniculus domesticus - Domestic rabbit:

  • 100 - 500 micrograms/kg subcutaneously or intravenously. (B373.Guide.w41)
  • 0.5 mg/kg plus acepromazine 0.5 mg/kg, subcutaneously or intramuscularly, for sedation. (B600.4.w4) Note: 
    • Can be given mixed in the same syringe. (B600.4.w4)
    • The combination causes vasodilatation. (B600.4.w4)
  • 0.1 - 0.4 mg/kg subcutaneously, intramuscularly or intravenously every 2 - 4 hours. Analgesia lasts for 2 - 4 hours. (B601.15.w15, B603.5.w5)
  • 0.1 - 1.0 mg/kg subcutaneously, intramuscularly or intravenously every four to six hours. (B602.41.w41, B548.w8)
  • 0.1 - 1.0 mg/kg subcutaneously, intramuscularly or intravenously every four hours. (B548.w8)
  • 0.1 - 0.5 mg/kg subcutaneously every four hours. (B546)
  • Note: use of higher doses has also been suggested: 1.0 - 5.0 mg/kg subcutaneously every 4 - 6 hours. (B548.w8)
    • However, "Lower dose preferred." (B548.w8)
  • Used in combination with Medetomidine and Ketamine for sedation/anaesthesia. See: Medetomidine-Ketamine-Butorphanol Anaesthesia in Rabbits

Ferrets - Mustela putorius furo - Ferret:

  • 0.05 - 0.5 mg/kg subcutaneously or intramuscularly every 8 - 12 hours. (B602.41.w41)
  • 0.05 - 0.5 mg/kg subcutaneously or intramuscularly every four hours. (B626.App.w22)
  • 0.05 - 2.0 m/kg intramuscularly or subcutanoeuly, every four hours. (J213.3.w1)
  • Anaesthesia:
    • Ketamine 5 mg/kg plus Medetomidine 80 g plus Butorphanol 100 g intramuscularly or subcutaneously. Note: if the 100 g dose of butorphanol is exceeded, hypoxia may occur. (B626.App.w22)
    • Tiletamine-Zolazepam 1.5 mg plus Xylazine 1.5 mg/kg plus Butorphanol 0.2 mg/kg intramuscularly. Can be combined in one syringe. Xylazine can be reversed using yohimbine 0.5 mg/kg intramuscularly. (J213.3.w1)

Great Apes

  • 0.1 - 0.2 mg/kg intramuscularly or intravenously. (B336.39.w39)
    • This is used in combination with other agents, in chemical restraint. (B336.39.w39)
    • Can be reversed with Naloxone, 0.02 mg/kg intramuscularly or intravenously. (B336.39.w39)
  • Induction of anaesthesia:
    • Ketamine 2.0 - 3.0 mg/kg plus Medetomidine 0.02 - 0.04 mg/kg plus butorphanol 0.2 - 0.4 mg/kg can be used for induction of anaesthesia in great apes. Oxygen should be supplied, plus additional inhalant anaesthetic agent as required. The anaesthetised individual should be monitored closely. (B336.39.w39)
  • Primates: 0.05 - 0.1 mg/kg intramuscularly twice daily. (D425.3.15.w3o)
Monitoring parameters --

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Withdrawal period / Withholding time
Notes
  • Cattle:
    • Following administration of butorphanol tartrate to three dairy cows at 0.045 mg/kg body weight, trace quantities of the drug were detectable in milk for up to 36 hours. (J289.15.w1)

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Toxic Information

Toxic effects of Pharmaceutical Products
Contraindications / Precautions
  • Contraindicated in individuals with known hypersensitivity to butorphanol. (B263)
  • Use opiates with caution in individuals with hypothyroidism, severe renal insufficiency, adrenocortical insufficiency (Addison's disease). (B263)
  • Do not use in individuals with a history of liver disease. (B266)
  • Use with caution in individuals which are geriatric or severely debilitated. (B263)
  • Use with extreme caution in individuals with head trauma, increased CSF pressure, coma or other CNS dysfunction. (B263)
  • In dogs: 
    • If given intravenously do not administer as a bolus. (B266)
    • Not for use in individuals with lower respiratory tract conditions resulting in copious production of mucus, due to the cough-suppressant effects. (B263, B266)
Adverse Effects / Side Effects / Warnings
  • In dogs: Rarely transient ataxia, anorexia and diarrhoea. (B266); occasional sedation, rarely ataxia anorexia or diarrhoea. (B263)
  • In cats: Mydriasis is likely. (B266); occasional sedation, rarely ataxia, anorexia or diarrhoea. (B263)
  • In horses: 
    • Slight ataxia for 3 to 15 minutes. (B266)
    • Mild sedation (in about 15%). (B266)
    • Sometimes excitation. B263)
  • In sheep - experimental data: 
    • A dose rate of 0.2 mg/kg did not produce significant changes in arterial blood gases, pH or bicarbonate although in one of five individuals there was a brief period of respiratory depression indicated by a decrease in the partial pressure of oxygen at five and 15 minutes and an elevation in PaCO2 at five minutes. (J21.51.w2)
    • Severe behavioural changes occurred with doses over 0.2 mg/kg; this dose is suggested as the highest dose rate for safe use in sheep. (J21.51.w2)
  • In goats - experimental data:
    • Following intravenous or intramuscular administration of 0.1 mg/kg bodyweight, hyperactivity was noted within five minutes of administration of the drug. Behaviours were significantly different from baseline from 15 minutes after intravenous and 15 to 30 minutes after intramuscular injection, and returned to baseline by 120 minutes or 240 minutes respectively. (J290.28.w1)
  • In bears (Ursidae - Bears (Family)): no problems reported with use in more than 150 bears (mainly Ursus thibetanus - Asiatic black bear). (V.w90)
Operator Warnings
  • "Butorphanol has opioid-like activity. Precautions should be taken to avoid accidental injection/self-injection with this potent drug. If accidental self-injection occurs, seek immediate medical attention showing a copy of product literature." (B266)
  • "Wash splashes from skin and eyes immediately." (B266)
Overdose / Acute Toxicity
  • Possibility of inadvertent overdose in small animals due to confusion between formulations at different strengths. (B263)
  • Naloxone may be used in individuals showing signs of overdose (CNS effects, cardiovascular changes, respiratory depression). (B263)
  • In cats: If respiratory depression occurs naloxone may be used as an antidote. (B266)
  • Additional supportive treatment as required: fluids, oxygen, vasopressor agents, mechanical ventilation. (B263)

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Detailed Toxicological Information
Classification --
Acute Toxicity
  • In dogs: LD50 reported as 50 mg/kg. (B263)
Chronic Toxicity --
Reproductive effects --
Teratogenic effects --
Mutagenic effects --
Carcinogenic effects

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Organ toxicity --
Bird Toxicity --
Aquatic organism activity --
Other organism toxicity --

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Nutrient Information

Nutritional Data
Sources --
Biological Use --
Recommended Daily Allowance / Recommended level in food --
Stability in food (Storage time) --
Interactions --

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External / Environmental Information

External / Environmental Uses
Use --
Formulation --
Application method --
Application Concentration --
Persistence of Effect / Frequency of Application --

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Sources in the Environment
Natural sources --
Human-associated sources --

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Effects on the Environment
Effects in the aquatic environment

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Effects on land --

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Persistence in the Environment
Breakdown in soil and groundwater

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Breakdown in water --
Breakdown in vegetation --

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