Chemicals / Complex Chemical Agents/ Chemical:

Buprenorphine (with special reference to Ruminants, Hedgehogs, Elephants, 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 which is used as an injectable analgesic agent and sedative.

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Names and Formulae
Type Opiate: synthetic partial agonist. A thebaine derivative. (B263)
Alternative Names "17-(Cyclopropylmethyl)-alpha-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-alpha-methyl-6,14 -ethenomorphinan-7-methanol; Buprenex." (W324)
Chemical Formula C29H41NO4 (W324)
Chemical Structure --
Molecular Weight 467.6472  (W324)
Related Chemicals --

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Physical Properties / Chemistry
Appearance

White crystalline powder. (B263); clear and colourless in solution. (B266)

Melting point --
Boiling point --
Density --
Water solubility 17 mg/mL. (B263)
Other solubility Alcohol: 42 mg/mL. (B263)
Acid/Base pH 3.5-5 (commercially available product for injection containing 0.324 mg/mL buprenorphine hydrochloride in 5% dextrose, equivalent to 0.3 mg/mL buprenorphine). (B263)

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Pharmacology & General Information
Pharmacology --
Storage / Stability
  • Store at room temperature 15-30C; avoid freezing, avoid temperatures above 40C. (B263); store below 25 C. (B266)
  • Protect from bright light. (B263); protect from light. (B266)
Legal Category (In UK) CD (Sch 3) 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); Becki Lawson (V.w26)

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Therapeutic Information

Uses/Indications
Activity
  • Partial agonist at the mu receptor. Considered to be 30 times as potent as morphine and exhibiting many of the same actions as full opiate agonists. (B263)
  • Produces a dose-related analgesia. (B263)
  • Relatively long duration of activity may be due to high affinity for CNS mu receptors. (B263)
  • Cardiovascular effects: decrease in blood pressure, decreased cardiac rate (in humans rarely an increase in both blood pressure and heart rate). (B263)
  • Respiratory effects: may cause respiratory depression (B263)
  • Gastrointestinal: effects appear minimal. (B263)
Appropriate Use
  • In small animals: as an analgesic agent. (B263)
  • In horses: in combination with acepromazine or xylazine as a neuroleptanalgesic. (B263)

In Erinaceus europaeus - West European Hedgehog

  • Particularly useful for severe pain associated with trauma, and for post-operative analgesia. (B284.6.w6)
Limitations --
Notes --

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Pharmacokinetics and Drug Interactions
Absorption /Bioavailability
  • Opioid analgesics are generally well absorbed from intramuscular tissue, subcutaneous tissue, the 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)
  • Following intramuscular injection, rapid absorption. (B263)
    • In horses: Onset of action about 15 minutes, peak effect 30-45 minutes, duration of action up to eight hours. (B263)
  • In humans: 
    • 40-90% systemic absorption following intramuscular injection. (B263)
    • 55% bioavailability following sublingual absorption. (B263
  • Following oral dosing, apparent high first-pass effect (metabolism in the gastro-intestinal mucosa and liver. (B263)
  • Oral availability is low, about 3 to 6%. (B322.3.w3)
  • Intranasal bioavailability is high: experimental administration of 0.9 mg in sheep of 35-40 kg, in a 30% polyethylene glycol 300 formulation gave 70% +/- 27% absorption (mean +/- SD) and in a 5% dextrose formulation gave 89% +/- 23% absorption. The maximum plasma concentration was reached at 10 minutes after administration. (J309.205.w1)
Distribution
  • Opioids rapidly localise in tissues which are highly perfused (e.g. lungs, liver, kidneys, spleen). Skeletal muscles have higher bulk and therefore serve as the main reservoir for the drug. (B135.30.w30)
  • Limited data available.
    • In rats: concentrated in the liver, also found in the brain, gastro-intestinal tract, placenta. (B263)
    • Crosses the placenta. B135.30.w30, B263)
    • In milk at concentrations equal to or greater than those in plasma. (B263)
Plasma Protein binding / Storage
  • Highly bound to plasma proteins (not albumin): 96% binding. (B263)
Elimination Route
  • Liver metabolism (N-dealkylation and glucuronidation) followed by biliary excretion (about 70%) and urinary excretion (about 27%).  (B263)
Elimination half-life / Clearance Rate
  • In horses: Duration of action up to eight hours. (B263)
  • In humans: Duration of analgesia four to eight hours. (B135.30.w30)
  • In sheep:  Short duration of action, approximately three hours, with rapid elimination. (B322.3.w3)
Drug Interactions
  • If used with other CNS depressants such as anaesthetic agents, antihistamines, phenothiazines, barbiturates, tranquillizers, alcohol etc., increased CNS depression may occur. (B263)
  • If used with pancuronium there may be increased conjunctival changes. (B263)
  • May potentiate local anaesthetics such as mepivacaine and bupivacaine. (B263)
  • Reported physically incompatible with: diazepam, lorazepam. (B263)
  • Reported physically compatible with: acepromazine, atropine, 5% dextrose, 5% dextrose saline, droperidol, glycopyrollate, hydroxyzine, lactated Ringer's solution, normal saline, scopolamine, xylazine. (B263)

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Administration
Formulations available
  • Commercially available product for injection contains 0.324 mg/mL buprenorphine hydrochloride in 5% dextrose, equivalent to 0.3 mg/mL buprenorphine). (B263)
Doses / Administration Routes / Frequencies

Sheep:

  • 0.005 mg/kg by intramuscular injection at 12 hour intervals. (J4.191.w12, P54.2.w4)
  • 0.006 mg/kg intravenously; administration may be required every four hours. (J16.28.w1)
  • 6g/kg intravenously provides analgesia after about 30 minutes and lasting for about four to eight hours. (B217.69.w69)
  • Note: no opiate is authorized for use in food-producing animals in the UK. (B217.69.w69)

Experimental data in sheep:

  • Buprenorphine at 0.005 mg/kg intramuscularly in sheep failed to provide analgesia against somatic pain as indicted by an electrical stimulation test to the leg. The drug did not have any effect on the behaviour of the sheep. (J24.73.w1)
  • Buprenorphine at 6 g/kg intravenously in sheep provided a clear antinociceptive effect against a thermal stimulus to the ear, increasing gradually from approximately 55C pre-injection to the maximum 70C by 45 minutes post injection and the threshold then fell slowly, remaining elevated for 210 minutes and returning to levels not significantly different from normal by 240 minutes. However, this dose rate did not produce a detectable antinociceptive effect against a mechanical stimulus to the leg. Pre-treatment with naloxone abolished the antinociceptive effect to the thermal stimulus, indicating that the response was due to opiate receptors. It was noted that the buprenorphine produced a marked excitement in sheep, slow in onset, with obvious alterations in behaviour by five to 15 minutes post injection, including chewing intensely on any solid item within reach, occasional bleating and rapid frequent head movements. (J299.92.w1)
  • Buprenorphine at 1.5 g/kg intravenously in sheep produced an antinociceptive effect against a thermal stimulus applied to the ear, reaching a maximum threshold temperature of 64.0 +/- 3.4C (no response to 70C (maximum used) in three sheep) at 40 minutes after injection and returning to control levels by 70 minutes post injection; this dose rate did not produce a detectable anti-nociceptive effect against a mechanical stimulus to the leg. At a dose rate of 12 g/kg intravenously, there was also no detectable anti-nociceptive effect against a mechanical stimulus to the leg. (J289.14.w1)
  • Buprenorphine provided effective analgesia in sheep undergoing tibial osteotomy. (P61.62.w1)
  • Buprenorphine has been shown to have an effective antinociceptive effect against thermal stimuli in sheep. (P61.62.w1) However it was ineffective against an electrical or mechanical stimulus. (P61.62.w1, J24.73.w1)
Erinaceus europaeus - West European Hedgehog:
  • 0.04 mL/kg Temgesic (Reckitt and Colman) mL/kg intramuscularly. For analgesia. (B156.7.w7)
  • 0.05-0.1 mg/kg intramuscularly every 8-12 hours. (D107)
  • 20-30 g/kg intramuscularly three times daily. Particularly useful for severe pain associated with trauma, and for post-operative analgesia. (B284.6.w6)

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

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

Lagomorphs - Oryctolagus cuniculus domesticus - Domestic rabbit:

  • 50 micrograms/kg subcutaneously or intravenously. (B373.Guide.w41)
  • 0.05 - 0.1 mg/kg intramuscularly or subcutaneously every 6 - 12 hours. (B546)
  • 0.01 - 0.05 mg/kg subcutaneously, intravenously or intramuscularly every 6 - 12 hours. (B601.15.w15)
  • 0.01 - 0.05 mg/kg subcutaneously, intramuscularly or intravenously every 6 - 12 hours. (B602.41.w41)
  • 0.01 - 0.05 mg/kg intravenously or subcutaneously every 6 - 12 hours. (B603.5.w5)
  • 0.01 - 0.05 mg/kg subcutaneously, intraperitoneally or intravenously every 6 - 12 hours. (B548.w8)
  • 0.02 - 1.0 mg/kg subcutaneously or intravenously. (B548.w8)
  • 0.5 mg/kg per rectum every 12 hours. (B548.w8)

Ferrets - Mustela putorius furo - Ferret:

  • 0.01 - 0.03 mg/kg subcutaneously, intramuscularly or intravenously every 8 - 12 hours. (B602.41.w41)
  • 0.01 - 0.03 mg/kg subcutaneously or intramuscularly every 8 - 12 hours. (B626.App.w22)
  • 0.01 - 0.05 mg/kg subcutaneously or intramuscularly, twice or three times daily. (J213.3.w1)

Great Apes

  • 0.01 - 0.02 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)
  • Adult Pan troglodytes - Chimpanzee: 0.3 mg intramuscularly three times daily. (W768.Jun2012.w1)
  • Primates: 0.02 - 0.05 mg/kg intramuscularly twice daily. (D425.3.15.w3o)
Monitoring parameters

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Withdrawal period / Withholding time
Notes
  • Small amounts are excreted in milk. (P61.62.w1)

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Toxic Information

Toxic effects of Pharmaceutical Products
Contraindications / Precautions
  • Contraindicated in individuals with known hypersensitivity to buprenorphine. (B263)
  • In humans: contraindicated in individuals receiving monamine oxidase (MAO) inhibitors, for at least 14 days. (B263)
  • Use with caution in individuals with hypothyroidism, severe renal insufficiency or adrenocortical insufficiency (Addison's disease).  (B263)
  • Use with caution in individuals which are geriatric or severely debilitated. (B263)
  • Use with caution in individuals with compromised cardiopulmonary function as (rarely) respiratory depression may develop. (B263)
  • Use with extreme caution in individuals with head trauma, increased CSF pressure, coma or other CNS dysfunction. (B263)
  • "Not for use in conjunction with morphine or other opioid-type analgesics e.g. etorphine, fentanyl, pethidine, methadone, papaveretum and butorphanol." (B266)
Adverse Effects / Side Effects / Warnings
  • The elimination rate may be decreased in individuals with severe hepatic dysfunction, therefore the effect may be prolonged. (B263, B266)
  • Caution is required in individuals with biliary tract disease as this drug may increase bile duct pressure. (B263)
  • Respiratory depression is the major adverse effect. It occurs only rarely but monitoring is recommended. (B263)
    • Respiratory depression is not a major risk with this drug. Doxapram should be used as a reversal agent if respiratory depression does occur, since naloxone is relatively ineffective at reversing buprenorphine's depressive effects. (P54.2.w4)
    • Buprenorphine at 6 g/kg intravenously in sheep did not produce any respiratory depression as measured by arterial blood gas concentrations, pH and bicarbonate. (J289.14.w1)
  • In humans, sedation is noted in about two thirds of patients. (B263)
  • Milk production may be depressed. (P61.62.w1)
  • Use with caution in pregnant bitches; if used in such individuals prior to parturition, and still producing analgesia in the bitch at the time of parturition, there may be some effect on the neonates. (B266)
  • Rarely, vomiting occurs following administration. (B266)
Operator Warnings
  • "Buprenorphine has opioid-like activity. Care should be taken to avoid accidental self-administration with this potent drug." (B266)
Overdose / Acute Toxicity
  • In rodents: Lethal dose to effective dose ratio at least 1000:1. (B263)
  • Acute overdose is expected to occur rarely. If respiratory or cardiac effects of overdose are seen, naloxone and doxapram are suggested. (B263)
  • Respiratory depression, if apparent, may be treated with high doses of naloxone. (B263)

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Detailed Toxicological Information
Classification  
Acute Toxicity
Chronic Toxicity --
Reproductive effects
  • No evidence of impaired fertility in laboratory animals. (B263)
Teratogenic effects
  • No evidence of teratogenic effects in laboratory animals. (B263)
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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