BUTORPHANOL TARTRATE
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.
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.
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 opiateagonists, not depress respiratory center sensitivity. Butorphanol, unlike morphine, apparently doesnot cause histamine release in dogs. CNS depression may occur in dogs, while CNS excitation hasbeen noted (usually at high doses) in horses and dogs.
Although possessing less cardiovascular effects than the classical opiate agonists, butorphanol cancause a decrease in cardiac rate secondary to increased parasympathetic tone and mild decreases inarterial blood pressures.
The risk of causing physical dependence seems to be minimal when butorphanol is used in veterinary patients.
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 andneonatal plasma levels have been roughly equivalent to maternal levels. The drug is also distributedinto maternal milk.
Butorphanol is metabolized in the liver, primarily by hydroxylation. Other methods of metabolisminclude N-dealkylation and conjugation. The metabolites of butorphanol do not exhibit anyanalgesic 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 withthe feces.
Following IV doses in horses, the onset of action is approximately 3 minutes with a peak analgesiceffect at 15-30 minutes. The duration of action in horses may be up to 4 hours after a single dose.
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 horsesand yearlings" (Package Insert; Torbugesic® ¯ Fort Dodge). It has also been used clinically as ananalgesic 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 geriatricor 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 liverdisease", and because of its effects on suppressing cough, "it should not be used in conditions ofthe lower respiratory tract associated with copious mucous production." The drug should be usedcautiously in dogs with heartworm disease as safety for butorphanol has not been established inthese cases.
Although no controlled studies have been performed in domestic animals or humans, the drug hasexhibited no evidence of teratogenicity or of causing impaired fertility in laboratory animals. Themanufacturer, 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 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 intestinalmotility. 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 indogs is reportedly 50 mg/kg. However, because butorphanol injection is available in two dosagestrengths (0.5 mg/ml and 10 mg/ml) for veterinary use, the possibility exists that inadvertentoverdoses may occur in small animals. It has been suggested that animals exhibiting symptoms ofoverdose (CNS effects, cardiovascular changes, and respiratory depression) be treated immediatelywith intravenous naloxone. Additional supportive measures (e.g., fluids, O2, vasopressor agents, &mechanical ventilation) may be required. Should seizures occur and persist, diazepam may used forcontrol.
Pancuronium if used with butorphanol may cause increased conjunctival changes.
Storage, Stability, Compatibility
The injectable product should be stored out of bright light andat 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 TARTRATE
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 opiateagonists, not depress respiratory center sensitivity. Butorphanol, unlike morphine, apparently doesnot cause histamine release in dogs. CNS depression may occur in dogs, while CNS excitation hasbeen noted (usually at high doses) in horses and dogs.
Although possessing less cardiovascular effects than the classical opiate agonists, butorphanol cancause a decrease in cardiac rate secondary to increased parasympathetic tone and mild decreases inarterial blood pressures.
The risk of causing physical dependence seems to be minimal when butorphanol is used in veterinary patients.
Pharmacokinetics - BUTORPHANOL TARTRATE
Butorphanol is absorbed completely in the gut when administered orally, butbecause of a high first-pass effect only about 1/6th of the administered dose reaches the systemiccirculation. 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 andneonatal plasma levels have been roughly equivalent to maternal levels. The drug is also distributedinto maternal milk.
Butorphanol is metabolized in the liver, primarily by hydroxylation. Other methods of metabolisminclude N-dealkylation and conjugation. The metabolites of butorphanol do not exhibit anyanalgesic 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 withthe feces.
Following IV doses in horses, the onset of action is approximately 3 minutes with a peak analgesiceffect 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-productivecough associated with tracheobronchitis, tracheitis, tonsillitis, laryngitis and pharyngitis originatingfrom inflammatory conditions of the upper respiratory tract" (Package Insert; Torbutrol® ¯ FortDodge). 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 horsesand yearlings" (Package Insert; Torbugesic® ¯ Fort Dodge). It has also been used clinically as ananalgesic 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 geriatricor 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 liverdisease", and because of its effects on suppressing cough, "it should not be used in conditions ofthe lower respiratory tract associated with copious mucous production." The drug should be usedcautiously in dogs with heartworm disease as safety for butorphanol has not been established inthese cases.
Although no controlled studies have been performed in domestic animals or humans, the drug hasexhibited no evidence of teratogenicity or of causing impaired fertility in laboratory animals. Themanufacturer, 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 intestinalmotility. 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 indogs is reportedly 50 mg/kg. However, because butorphanol injection is available in two dosagestrengths (0.5 mg/ml and 10 mg/ml) for veterinary use, the possibility exists that inadvertentoverdoses may occur in small animals. It has been suggested that animals exhibiting symptoms ofoverdose (CNS effects, cardiovascular changes, and respiratory depression) be treated immediatelywith intravenous naloxone. Additional supportive measures (e.g., fluids, O2, vasopressor agents, &mechanical ventilation) may be required. Should seizures occur and persist, diazepam may used forcontrol.
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.