VA Class:CN101

AHFS Class:

• Opioid Partial Agonists 28:08.12

Generic Name(s):

• Butorphanol Tartrate

Butorphanol tartrate is a synthetic opiate partial agonist analgesic.

Butorphanol tartrate injection is used for the relief of pain that is severe enough to require an opiate analgesic; because of the risks of addiction, abuse, and misuse associated with opiates even at recommended dosages, butorphanol should be reserved for use in patients for whom alternative treatment options (e.g., nonopiate analgesics) have not been, or are not expected to be, adequate or tolerated.704 Butorphanol tartrate injection also is used to provide preoperative sedation and analgesia and as a supplement to surgical anesthesia. However, butorphanol should be used with caution in patients undergoing surgery of the biliary tract. Butorphanol tartrate injection also is used for obstetric analgesia during labor.

In equianalgesic doses, parenteral butorphanol is as effective as morphine, meperidine, and pentazocine, but determination of the relative potential for abuse of butorphanol reportedly is less than that of codeine or propoxyphene.

Butorphanol tartrate nasal solution is used as an analgesic for the relief of moderate to severe postoperative (including that associated with orthopedic surgery), postpartum, and orthopedic (including musculoskeletal) pain.113,114,117 Butorphanol tartrate nasal solution also is used for the management of migraine headache.113,114,116,122 Some experts state that butorphanol tartrate nasal spray may be considered when other antimigraine drugs cannot be used or as rescue therapy when sedative effects will not place the patient at risk.130 In patients in whom butorphanol tartrate might be indicated for management of migraine headache, special attention should be given to the potential for overuse and dependence.130 When used to relieve postoperative pain, single intranasal butorphanol tartrate doses of 1 or 2 mg have been as effective as IM meperidine hydrochloride doses of 37.5 or 75 mg, respectively.113,114,125 When used to relieve migraine headache, butorphanol tartrate nasal solution administered as two 1-mg doses (given 1 hour apart) was as effective as a single 10-mg dose of IM methadone hydrochloride.113,114 (For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.)

Because it does not suppress the abstinence syndrome and may induce withdrawal in opiate-dependent patients, butorphanol cannot be substituted for opiate agonists after physical dependence has been established without prior detoxification. (See Cautions: Precautions and Contraindications.) Butorphanol probably is not an effective antidote in the treatment of cardiovascular, respiratory, or behavioral depression induced by opiate agonists because of its relatively weak antagonistic effects.

For further information on the role of opiate analgesics in pain management, see Uses: Pain, in the Opiate Agonists General Statement 28:08.08.

Administration

Butorphanol tartrate is administered by IM or IV injection or by nasal inhalation using a spray pump.113 The nasal solution spray pump containing butorphanol tartrate should be assembled according to the manufacturer's instructions.113 Prior to initial use, the spray pump should be fully primed; priming of the pump should be repeated whenever the pump has not been used for 48 hours or longer.113 The patient instructions provided by the manufacturer should be consulted for use of the nasal solution spray pump.113,124 Since butorphanol nasal solution spray pump is an open delivery system that may increase environmental exposure of health-care personnel and visitors, the pump spray should be aimed away from such individuals.113

Dosage

Opiate analgesics should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient.411,413,431,432,435 Dosage of butorphanol tartrate should be adjusted according to the severity of pain, physical status of the patient, and other drugs that the patient is receiving. If concomitant therapy with other CNS depressants is required, the lowest effective dosages and shortest possible duration of concomitant therapy should be used.700,703 (See Cautions: Precautions and Contraindications, Chronic Toxicity, and Drug Interactions.)

The usual adult dose of butorphanol tartrate is 2 mg IM or 1 mg IV. These doses may be repeated every 3-4 hours as necessary. The usual effective dosage, depending on the severity of the pain, ranges from 1-4 mg IM or 0.5-2 mg IV, repeated every 3-4 hours. There are insufficient clinical data to recommend IM doses greater than 4 mg.

After initial priming, the nasal solution spray pump delivers about 14-15 metered doses containing 1 mg of butorphanol tartrate per spray. If repriming of the pump is necessary because of intermittent use, the spray pump will deliver about 8-10 metered doses, depending on the extent of repriming.113 The usual initial intranasal butorphanol tartrate dose is 1 mg (1 spray in one nostril); if adequate analgesia is not achieved, an additional 1-mg dose may be given within 60-90 minutes.113 This initial dose sequence may be repeated in 3-4 hours if needed.113 For the management of severe pain, an initial dose of 2 mg (1 spray in each nostril) may be given to patients who can remain recumbent if drowsiness or dizziness occurs; however, these patients should not receive additional 2-mg doses at intervals shorter than 3-4 hours, since the incidence of adverse effects may be increased.113

In the treatment of postepisiotomy and musculoskeletal pain, 4-16 mg of butorphanol tartrate has been given orally† every 4-6 hours.

For acute pain not related to trauma or surgery, the prescribed quantity should be limited to the amount needed for the expected duration of pain severe enough to require opiate analgesia (generally 3 days or less and rarely more than 7 days).411,433,434,435

For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.

Dosage in Hepatic or Renal Impairment and in Geriatric Patients

Patients with hepatic or renal impairment and geriatric patients should receive half of the recommended parenteral adult dose (i.e., 1 mg IM or 0.5 mg IV).113 If needed these doses may be repeated within usually not less than 6 hours.113 The usual initial dose of butorphanol tartrate nasal solution is 1 mg (1 spray in one nostril) in these patients; an additional 1-mg dose may be given within 90-120 minutes.113 This initial dose sequence may be repeated within usually not less than 6 hours.113

Adverse Effects

Incidence and type of adverse effects of butorphanol tartrate (administered parenterally or intranasally) are similar to those of opiate analgesics. Sedation is the most frequent adverse reaction and occurs in about 43% of patients receiving butorphanol; sedation occurs more frequently with butorphanol than with morphine, meperidine, or pentazocine. Dizziness occurs in about 19% and nausea and/or vomiting has been reported in 13% of patients receiving butorphanol tartrate.113 Clamminess, sweatiness, headache, vertigo, floating feeling, asthenia, anxiety, euphoria, nervousness, paresthesia, lethargy, confusion, and lightheadedness occur in 1-10% of patients. Other adverse CNS effects, such as unusual dreams, agitation, hallucinations, seizures, hostility, transient difficulty in speaking and/or executing purposeful movements, and delusion, occur in less than 1% of patients receiving butorphanol. In equianalgesic dosage, adverse psychotomimetic effects such as hallucinations, dysphoria, unreality, depersonalization, and nervousness may occur more frequently with butorphanol than with morphine or nalbuphine. Insomnia has been reported in 11% of patients receiving butorphanol tartrate nasal solution.113 In addition, taste perversion, anorexia, constipation, and tinnitus occurred in 3-9% and otic pain and tremor were reported in 1% or more of patients receiving butorphanol tartrate nasal solution.113

Other adverse GI effects, including vomiting, abdominal cramps, and constipation, occur in less than 1% of patients receiving butorphanol. Adverse cardiovascular effects include vasodilation and palpitation which occur in 1-9% of patients receiving the drug and chest pain, tachycardia, bradycardia and increased or decreased blood pressure which occur in less than 1% of patients. Hypotension associated with syncope (usually occurring within the first hour of administration) has been reported rarely in patients receiving butorphanol tartrate nasal solution, particularly in those who experienced similar adverse effects when receiving an opiate analgesic.113 Adverse dermatologic effects, such as rash or urticaria and itching, and other adverse effects, such as flushing and warmth, miosis, dry mouth, acrocyanosis, impaired urination, sensitivity to cold, tingling, diplopia, and blurred vision, also occur in less than 1% of patients receiving the drug. In addition, burning at the site of IV injection has been reported in patients receiving butorphanol tartrate injection.

Respiratory depression (decreased rate and depth of respiration) and apnea have occurred in less than 1% of patients receiving butorphanol; respiratory depression occurs mainly in patients receiving other drugs with CNS effects and in those with a history of CNS disease or respiratory impairment.113 In doses above the usual therapeutic range, butorphanol causes less respiratory depression than does morphine. Butorphanol-induced respiratory depression can be reversed by naloxone. The most common respiratory effects associated with the administration of butorphanol tartrate nasal solution are nasal congestion, which has been reported in 13% of patients, and dyspnea, epistaxis, nasal irritation, pharyngitis, rhinitis, sinus congestion, or upper respiratory infection, occurring in 3-9% of patients.113 Bronchitis, cough, and sinusitis have been reported in 1% or more of patients receiving butorphanol tartrate nasal solution.113

Adrenal insufficiency has been reported in patients receiving opiate agonists or opiate partial agonists.400 Manifestations of adrenal insufficiency are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.400 The onset generally has occurred after at least 1 month of opiate agonist or partial agonist use, although the time to onset has ranged from within 1 day to more than 1 year.400 In many of the reported cases, patients required hospitalization.400 If adrenal insufficiency is suspected, appropriate laboratory testing should be performed promptly and physiologic (replacement) dosages of corticosteroids provided; therapy with the opiate agonist or partial agonist should be tapered and discontinued to allow recovery of adrenal function.400 If the opiate agonist or partial agonist can be discontinued, follow-up assessment of adrenal function should be performed to determine if corticosteroid replacement therapy can be discontinued.400 In some patients, switching to a different opiate improved symptoms.400

Hypogonadism and androgen deficiency have been reported in patients receiving long-term opiate agonist or opiate partial agonist therapy,400,401,402,403,404 although a causal relationship has not been established.400 Patients receiving long-term opiate agonist or partial agonist therapy who present with manifestations of hypogonadism (e.g., decreased libido, impotence, erectile dysfunction, amenorrhea, infertility) should undergo laboratory evaluation.400

Precautions and Contraindications

Concomitant use of opiate agonists or opiate partial agonists and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiates, alcohol) may result in profound sedation, respiratory depression, coma, and death.416,417,418,700,701,702,703 Concomitant use of such drugs should be reserved for patients in whom alternative treatment options are inadequate; the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.700,703 Patients receiving butorphanol and/or their caregivers should be apprised of the risks associated with concomitant therapeutic or illicit use of benzodiazepines, alcohol, or other CNS depressants.700,703 Concomitant use with alcohol should be avoided.700 (See Drug Interactions: Benzodiazepines and Other CNS Depressants.)

Because of possible adverse CNS effects such as drowsiness and dizziness, ambulatory patients receiving butorphanol should be cautioned against performing hazardous tasks requiring mental alertness or physical coordination such as driving a motor vehicle or operating machinery and warned about possible additive effects with other drugs that cause CNS depression. (See Drug Interactions: Benzodiazepines and Other CNS Depressants.) Although butorphanol appears to have a low physical dependence liability compared with codeine or propoxyphene (see Chronic Toxicity), the drug should be used cautiously in patients who are emotionally unstable or have a history of opiate abuse, and these patients should be closely supervised during long-term butorphanol therapy.

Butorphanol should be administered with caution and in low doses in patients with impaired respiration caused by other drugs, uremia, severe infection, severely limited respiratory reserve, bronchial asthma, respiratory obstruction, or cyanosis. In patients with acute myocardial infarction, ventricular dysfunction, or coronary insufficiency, butorphanol should be used only if the potential benefits justify the possible risks. Since butorphanol may slightly increase blood pressure, the drug should be used cautiously before surgery or anesthesia in hypertensive patients. If hypertension occurs, butorphanol should be discontinued and a hypotensive agent administered as necessary; butorphanol-induced hypertension reportedly has been managed with naloxone in patients who were not opiate dependent.113 In addition, since hypotension associated with syncope has been reported rarely in patients receiving butorphanol tartrate nasal solution, the manufacturer states that patients should be cautioned against performing activities that may pose risks if hypotension were to occur.113 Safe use of butorphanol in patients about to undergo biliary tract surgery has not been established, and the drug should be used with caution in these patients. Because butorphanol potentially may be associated with carbon dioxide retention and secondary elevation of CSF pressure, drug-induced miosis, and alterations in mental state (that may interfere with evaluation of CNS function), the drug should be used in patients with head injury only if the potential benefits justify the possible risks.113 In patients with head injury, the drug also may interfere with evaluation of CNS function.

Because of the potential for fatal respiratory depression following overdosage, clinicians should routinely discuss the availability of the opiate antagonist naloxone with all patients receiving new or reauthorized prescriptions for opiate analgesics, including butorphanol.750 Patients should be advised of the benefits of naloxone administration following an overdose and of their options for obtaining the drug.750 Clinicians should consider prescribing naloxone for patients receiving opiate analgesics who are at increased risk of opiate overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with a history of opiate or substance use disorder, those with medical conditions that could increase sensitivity to opiate effects, those who have experienced a prior opiate overdose)411,431,750 or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.750 Even if patients are not receiving an opiate analgesic, a naloxone prescription should be considered if the patient is at increased risk of opiate overdosage (e.g., those with a current or past diagnosis of opiate use disorder [OUD], those who have experienced a prior opiate overdose).750 (See Naloxone Hydrochloride 28:10.)

Because of the drug's partial opiate antagonistic effects, butorphanol is not recommended for use in opiate-dependent patients, and such patients should have an adequate period of withdrawal from opiates before initiating butorphanol therapy.128,129 In patients who have been taking opiate analgesics chronically, administration of butorphanol tartrate has been associated with withdrawal symptoms (e.g., anxiety, agitation, mood changes, hallucinations, dysphoria, weakness, diarrhea).128,129 In addition, because it may be difficult to assess tolerance in patients who have recently received substantial amounts of opiate agonists, butorphanol should be used with caution in these patients. The drug should be used in opiate-dependent patients only after they have been detoxified since butorphanol does not suppress the abstinence syndrome in these patients, and high doses may precipitate withdrawal symptoms as a result of opiate antagonist effect.

Butorphanol should be used with caution in patients with renal or hepatic dysfunction. The drug is contraindicated in patients with known hypersensitivity to butorphanol or to benzethonium chloride contained in the multiple-dose vials of the injection or in the nasal solution of the drug.

Pediatric Precautions

Safety and efficacy of butorphanol in children younger than 18 years of age have not been established.

Geriatric Precautions

Since clearance is decreased and elimination half-life of butorphanol may be increased in patients older than 65 years of age, dosage and dosage interval of butorphanol tartrate should be modified in such patients.113 (See Dosage in Renal or Hepatic Impairment and in Geriatric Patients, in Dosage.) In addition, geriatric patients may be more sensitive to drug-induced adverse effects than younger individuals.113 Results of a long-term clinical study indicate that geriatric patients may tolerate dizziness associated with intranasal butorphanol tartrate less well than younger patients.113

Pregnancy, Fertility, and Lactation

Pregnancy

Safe use of butorphanol during pregnancy (except during labor) has not been established. Reproduction studies in rats, mice, and rabbits using butorphanol dosages of approximately 2.5-5 times the usual human dosage, during organogenesis, have not revealed evidence of harm to the fetus. However, subcutaneous butorphanol doses of 1 mg/kg were associated with higher incidences of stillbirths in rats. In addition, increased postimplantation losses occurred in rabbits receiving oral butorphanol doses of 30 and 60 mg/kg. There are no adequate and controlled studies to date using butorphanol tartrate in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risk to the fetus. When butorphanol is administered during labor and delivery, respiratory depression may occur in the neonate; the drug should be used with caution in women delivering premature infants. In one clinical study using 1-mg IV doses of butorphanol tartrate during labor, transient (10-90 minutes) sinusoidal fetal heart rate patterns were reported; however, no adverse neonatal outcomes occurred.113 Butorphanol should be used with caution in the presence of abnormal fetal heart rate pattern.113 Because of the absence of clinical experience with butorphanol nasal solution during labor and delivery, use of the nasal preparation is not recommended in such circumstances.113

Fertility

Reproduction studies in rats using oral butorphanol dosages of 160 mg/kg daily revealed a decreased pregnancy rate; however, this effect was not observed in rats using subcutaneous butorphanol dosages of 2.5 mg/kg daily.

Lactation

Butorphanol is distributed into human milk following parenteral administration of the drug in nursing women.113 The manufacturer states that the amount of the drug distributed into milk probably is clinically insignificant, estimated at 4 mcg/L of milk in a woman receiving 2 mg of butorphanol IM 4 times daily.113 Although there is no clinical experience with the use of butorphanol tartrate nasal solution in nursing women, it is assumed that the amount of the drug distributed into milk will be similar to that when administered parenterally.113

Benzodiazepines and Other CNS Depressants

Concomitant use of opiate agonists or opiate partial agonists, including butorphanol, and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiates, alcohol) may result in profound sedation, respiratory depression, hypotension, coma, and death.416,417,418,700,701,702,703,704 Opiate analgesics frequently are implicated as contributing to fatal overdoses involving other CNS depressants, and epidemiologic studies have shown that a substantial proportion of fatal opiate overdoses involve the concurrent use of benzodiazepines, alcohol, or other CNS depressants.416,417,418,435,700,701,702 Whenever possible, concomitant use of opiates and benzodiazepines should be avoided.410,411,415,435 Alcohol also should be avoided in patients receiving opiates.700 Concomitant use of opiate analgesics and benzodiazepines or other CNS depressants should be reserved for patients in whom alternative treatment options are inadequate; the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.700,703

If a benzodiazepine or other CNS depressant is required for any indication other than epilepsy in a patient receiving butorphanol, the drug should be initiated at a lower dosage than indicated in the absence of opiate therapy and titrated based on clinical response.700,703 In patients receiving a CNS depressant, butorphanol, if required, should be initiated at a reduced dosage and titrated based on clinical response.700,703 Clinicians should consider prescribing the opiate antagonist naloxone for patients receiving opiates who are at increased risk of opiate overdosage, including those receiving benzodiazepines or other CNS depressants concomitantly.411,431,750 (See Cautions: Precautions and Contraindications.)

Drugs Associated with Serotonin Syndrome

Serotonin syndrome may occur in patients receiving opiate partial agonists concomitantly with other serotonergic drugs, including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists (“triptans”), selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants, antiemetics that are 5-HT₃ receptor antagonists, buspirone, cyclobenzaprine, dextromethorphan, lithium, St. John's wort ( Hypericum perforatum ), tryptophan, other serotonin modulators (e.g., mirtazapine, nefazodone, trazodone, vilazodone), and monoamine oxidase (MAO) inhibitors (both those used to treat psychiatric disorders and others, such as linezolid, methylene blue, and selegiline).400 Serotonin syndrome may occur within the recommended dosage ranges for these drugs.400 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.400

If concomitant use of other serotonergic drugs is warranted, patients should be monitored for serotonin syndrome, particularly during initiation of therapy and dosage increases.400 If serotonin syndrome is suspected, treatment with butorphanol, other opiate agonist or partial agonist therapy, and/or any concurrently administered serotonergic agents should be discontinued.400

For further information on serotonin syndrome, including manifestations and treatment, see Drug Interactions: Serotonergic Drugs, in Fluoxetine Hydrochloride 28:16.04.20.

Other Drugs

Concomitant administration of butorphanol and pancuronium reportedly may cause an increase in conjunctival changes. In patients receiving a nasal vasoconstrictor (e.g., oxymetazoline), the rate of absorption of intranasal butorphanol may be decreased while the extent of absorption appears to be unchanged; therefore, a slower onset of analgesic action may occur in patients receiving butorphanol nasal solution immediately following or concomitantly with oxymetazoline.113

Since it is not known if drugs that affect hepatic microsomal enzymes (e.g., cimetidine, erythromycin, theophylline) may interfere with the metabolism of butorphanol, the manufacturer suggests that clinicians consider decreasing doses and increasing intervals between doses of butorphanol in patients receiving such drugs.113

Acute Toxicity

No instances of butorphanol overdosage have been reported, but expected symptoms would be respiratory depression, cardiovascular effects, and other CNS effects. Treatment consists of immediate IV administration of naloxone. Respiratory and cardiac status should be constantly evaluated, and appropriate supportive measures such as administration of oxygen, IV fluids and vasopressors, and assisted or controlled respiration should also be used if necessary.

Chronic Toxicity

Tolerance and psychological and physical dependence may occur in patients receiving butorphanol.105,106,107,108,109,128,129 Although episodes of drug abuse have been reported by all routes of administration, the potential for abuse of butorphanol tartrate is reportedly less than that of codeine or propoxyphene. In addition, butorphanol has been misused in combination with diphenhydramine by drug abusers in a manner similar to the parenteral use of pentazocine and tripelennamine (known as T's and blues), since the combination's effects are purported to be similar to those of IV heroin (diacetylmorphine).106

Following abrupt discontinuance after prolonged use of butorphanol, withdrawal symptoms, which are similar to but more intense than those produced by morphine, have occurred and may include nausea, vomiting, gastric distress, decreased caloric intake, abdominal cramping, diarrhea, increased temperature, flu-like symptoms, diaphoresis, mydriasis, visual changes (including alteration of color perception), malaise, myalgia, rhinorrhea, itching, tachycardia, and “electric shocks” usually associated with a feeling of faintness.105,107,110,128,129 Acute withdrawal has been reported to develop within 4-24 hours after discontinuance of the drug in individuals who are dependent.105,107 Clonidine hydrochloride has been used in the management of acute butorphanol withdrawal in at least one individual.105

The manufacturer states that more cases of drug abuse have been reported in patients receiving butorphanol tartrate nasal solution than in those receiving butorphanol tartrate injection.128,129 Results of a randomized, double-blind, placebo-controlled, crossover study in 7 men with a history of opiate dependence indicate that the psychopharmacologic profile of butorphanol tartrate injection is similar to that of the nasal solution.129 Therefore, it has been suggested that butorphanol's abuse potential may be independent of the route of administration, but might be dependent on nonpharmacologic factors (e.g., pattern of usage, alteration of the formulation).129

In clinical studies, less than 1% of patients using butorphanol tartrate nasal solution had experiences suggestive of development of physical dependence or tolerance; however, patients in these studies did not receive prolonged continuous administration of the nasal solution.128,129 In 1 controlled clinical study in patients with chronic pain secondary to nonmalignant disease who were receiving butorphanol tartrate nasal solution or placebo for up to 6 months, overuse (probably associated with development of tolerance) was reported in 2.9% of patients receiving the drug, while tolerance reportedly did not occur in patients receiving placebo.128 In this study, following abrupt discontinuance of the nasal solution, withdrawal symptoms (e.g., anxiety, agitation, tremulousness, diarrhea, chills, diaphoresis, insomnia, confusion, incoordination, hallucinations) occurred in about 2.6% of patients, most of whom discontinued the drug after prolonged use or administration of high dosages.128,129 Such withdrawal symptoms were not reported in patients receiving placebo.128,129

Prolonged continuous use of butorphanol tartrate injection also may result in physical dependence or tolerance and abrupt discontinuance of the injection in patients physically dependent on butorphanol may result in withdrawal symptoms.105,107,129

The manufacturer states that to minimize the risk of abuse and physical dependence associated with butorphanol tartrate, careful patient selection, dosage and prescription limitations for the drug, appropriate directions for use, and frequent monitoring are important.128,129 Butorphanol tartrate should be used carefully in patients with a history of drug abuse or in those receiving the drug repeatedly for extended periods of time.128,129

Pharmacology

Butorphanol tartrate has analgesic and opiate antagonistic effects. The exact mechanisms of actions of the drug are not known. However, the analgesic effect is believed to result from an interaction with an opiate receptor site in the CNS (probably in or associated with the limbic system); the opiate antagonistic effect may result from competitive inhibition at the opiate receptor, but other mechanisms probably also are involved. The drug exerts antagonistic114,115,126 or partially antagonistic113 effects at µ opiate receptor sites, while it is thought that butorphanol exerts its agonistic effects principally at the κ and Σ opiate receptors.101,102,103,104 On a weight basis, the analgesic activity of IM butorphanol tartrate is approximately 4-7 times that of IM morphine, 15-30 times that of IM pentazocine, and 30-50 times that of IM meperidine. Studies in animals indicate that, on a weight basis, subcutaneous butorphanol has 30 times the opiate antagonist activity of subcutaneous pentazocine and ¹/₄₀ that of subcutaneous naloxone.

Like opiate agonists, butorphanol produces respiratory depression, sedation, miosis and, in animals, antitussive effects. In adults, a single 2-mg IV dose of butorphanol tartrate (about 0.03 mg/kg) decreases respiration to the same degree as 10 mg of morphine sulfate IV or 70 mg of meperidine hydrochloride IV. In contrast to morphine, respiratory depression in healthy adults plateaus with a 2-mg IV dose of butorphanol tartrate. However, the duration of respiratory depression produced by butorphanol is increased with increasing dosage (i.e., respiratory depression persists 1 hour after 2 mg IV and at least 90 minutes after 4 mg IV).

In one study, IV administration of butorphanol tartrate 0.025 mg/kg slightly increased pulmonary artery pressure, pulmonary wedge pressure, left ventricular end-diastolic pressure, systemic arterial pressure, pulmonary vascular resistance, and cardiac index.

In animals, butorphanol tartrate inhibits GI motility slightly, causes little increase in duodenal smooth muscle activity, and has little or no effect on bile duct flow. In dogs, butorphanol causes very little systemic histamine release as compared to equianalgesic doses of morphine. In contrast to morphine, butorphanol transiently increases urine output and decreases urine osmolality and sodium and potassium excretion in rats. These effects are caused by inhibition of release of vasopressin from the hypothalamus.

IV administration of 0.2-0.8 mg of naloxone hydrochloride reverses the respiratory depressant effects of 2-4 mg of IV butorphanol tartrate. Naloxone also reverses the analgesic, antitussive, and GI motility inhibiting effects of butorphanol; the diuretic response to butorphanol in animals is not reversed by naloxone.

Pharmacokinetics

Absorption

Butorphanol tartrate is completely absorbed from the GI tract in healthy, fasting individuals and from IM injection sites. However, orally administered butorphanol tartrate undergoes first-pass metabolism and only 17% of a dose reaches systemic circulation unchanged. The absolute bioavailability of butorphanol following nasal inhalation may vary with age and gender; the absolute bioavailability of the nasal solution is about 50, 70, and 75% in geriatric women, young individuals, and geriatric men, respectively.113,114,118 Absolute bioavailability of nasally inhaled butorphanol appears to be unchanged in patients with allergic rhinitis.113 However, in patients receiving a nasal vasoconstrictor (e.g., oxymetazoline), rate of absorption of intranasal butorphanol may be decreased while extent of absorption appears to be unchanged.113,114,119 When intranasal butorphanol was administered in patients receiving oxymetazoline, peak plasma concentrations of butorphanol were reduced by about 50%.113,119

Following oral administration of a single 8-mg dose of butorphanol tartrate to healthy, fasting individuals, peak plasma butorphanol concentrations of 0.7 ng/mL are achieved within 1-1.5 hours. Peak plasma butorphanol concentrations of approximately 2.2 ng/mL occur 30-60 minutes after IM administration of a single 2-mg dose. Peak plasma concentrations of 1.5 ng/mL occur almost immediately after a single 1-mg IV dose. Following nasal inhalation of a single 1-mg dose of butorphanol tartrate solution, mean peak blood butorphanol concentrations of 0.9-1.04 ng/mL are achieved in about 30-60 minutes.113,114 Butorphanol tartrate appears to exhibit dose-proportional, linear pharmacokinetics following inhalation of 1-4 mg of nasal solution of the drug every 6 hours for 5 days;113,114,121 peak plasma concentrations and the area under the plasma concentration-time curve (AUC) increased in a dose-dependent fashion, while time to achieve peak plasma concentrations remained relatively constant.114,121 Steady-state plasma concentrations of nasally inhaled butorphanol were reached within 48 hours and were about 1.8 times those reported following administration of single doses of the nasal solution;113,114,121 therefore, modest accumulation of the drug appears to occur.114 After an initial absorption/distribution phase, single-dose pharmacokinetics of butorphanol are similar following IV, IM, or intranasal administration.113

After IV administration of 1 or 2 mg of butorphanol tartrate in postoperative patients, the onset of analgesic activity occurs in 1 minute, peak analgesia occurs in 4-5 minutes, and the duration of action is 2-4 hours. Following IM administration of 1 or 2 mg of butorphanol tartrate in postoperative patients, analgesic activity occurs within 10-30 minutes, peak analgesia occurs within 30-60 minutes, and duration of analgesia is 3-4 hours; after 4 mg IM, analgesic effects usually persist at least 4 hours. After nasal inhalation of 1 or 2 mg of butorphanol tartrate solution in postoperative patients, onset of analgesia occurs within 15 minutes, peak analgesia occurs in about 1-2 hours, and duration of analgesia is approximately 2.5-5 hours.113,114,125 In one study, oral administration of 8 or 16 mg of butorphanol tartrate produced analgesic effects within 1-2 hours and analgesia persisted 5-6 hours.

Distribution

Animal studies indicate that highest concentrations of butorphanol and its metabolites are found in the liver, kidneys, and intestine; drug concentrations are higher in the lungs, spleen, heart, endocrine tissues, blood cells, and fat tissue than in plasma; brain concentrations are lower than plasma concentrations. In concentrations of 1-7 ng/mL, about 80% of butorphanol is bound to plasma proteins. Following IV administration, the mean volume of distribution of butorphanol is 487 (range: 305-901 L) and 552 L (range: 305-737 L) in young (20-40 years of age) and geriatric individuals (older than 65 years of age), respectively.113

Butorphanol rapidly crosses the placenta, and neonatal serum concentrations are 0.4-1.4 times maternal concentrations. The drug is distributed into milk.

Elimination

Plasma elimination half-life of butorphanol is similar following intranasal and IV administration;113,114,120 the plasma elimination half-life of butorphanol is about 4.6 (range: 2-8.7 hours)113 and 4.7 hours (range: 2.9-8.8 hours) after IV and intranasal administration, respectively.113,114 Plasma elimination half-life of butorphanol may be increased in geriatric individuals following IV and intranasal administration; elimination half-life reportedly was about 5.6 (range 3.3-8.8 hours) and 6.6 hours (range: 3.8-9.2 hours) following IV and intranasal administration, respectively.113 Plasma elimination half-life also may be increased in patients with renal impairment (creatinine clearance less than 30 mL/minute);113,114 elimination half-life reportedly was 10.5 hours in such patients.113

Butorphanol is extensively metabolized in the liver, principally by hydroxylation to form hydroxybutorphanol, the major metabolite; N -dealkylation and conjugation of butorphanol and its metabolites also occur. Metabolites of butorphanol have no analgesic activity. Butorphanol and its metabolites are excreted mainly by the kidneys as unconjugated hydroxybutorphanol (60-80% of a dose), and less than 5% of a dose is excreted unchanged in urine. In 72-96 hours, 62% of a 1-mg IV dose, 72% of a 2-mg IM dose, and 75% of an 8-mg oral dose can be recovered in the urine. Glucuronides of butorphanol and/or hydroxybutorphanol are excreted in bile and undergo enterohepatic recycling. About 11-14% of a parenteral dose is excreted in feces. Following IV administration of butorphanol tartrate, mean total body clearance of butorphanol is 1650 (range: 1167-2567 mL/minute) and 1367 mL/minute (range: 867-2383 mL/minute) in young (20-40 years of age) and geriatric (older than 65 years of age) individuals, respectively.113 Body clearance of butorphanol also may be decreased in patients with renal impairment.113 Following administration of butorphanol tartrate nasal solution, total body clearance of butorphanol is about 4333 and 2500 mL/minute in healthy individuals and in patients with renal impairment (those with creatinine clearance less than 30 mL/minute), respectively.113,123

Chemistry and Stability

Chemistry

Butorphanol tartrate is a synthetic opiate partial agonist analgesic. The drug is structurally related to morphine but pharmacologically similar to pentazocine and nalbuphine. Butorphanol tartrate occurs as a white powder with a bitter taste and is sparingly soluble in water and insoluble in alcohol. The pK_a of the drug is 8.6.

Butorphanol tartrate is commercially available as an injection and as a solution for nasal inhalation.113 Butorphanol tartrate injection is a sterile solution of the drug in water;113 the injection contains sodium citrate and has a pH of 3-5.5.100,113 For intranasal use, butorphanol tartrate is available as a solution of the drug in purified water; sodium hydroxide and/or hydrochloric acid are added to adjust pH to 5.113 Butorphanol tartrate injection and nasal solution contain sodium chloride to adjust tonicity and citric acid; the multiple-dose vials of the injection and nasal solution also contain benzethonium chloride as a preservative.113 Butorphanol tartrate nasal solution is administered by a spray pump which, after initial priming, delivers metered sprays containing 1 mg of butorphanol tartrate per spray.113

Stability

Butorphanol tartrate injection should be protected from light and stored at temperatures below 30°C; freezing should be avoided. Butorphanol tartrate nasal solution should be stored at temperatures below 30°C.113

Butorphanol tartrate reportedly is physically and chemically compatible for at least 24 hours with atropine sulfate, hydroxyzine hydrochloride, or promethazine hydrochloride. Specialized references should be consulted for specific compatibility information.

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