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BUTORPHANOL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Butorphanol is a synthetically derived opioid agonist-antagonist of the phenanthrene series and exhibits analgesic effects from low intrinsic activity at receptors of the mu-opioid type (morphine-like) and agonist activity at kappa-opioid receptors.

Specific Substances

    1) levo-BC-2627 (butorphanol)
    2) CAS 42408-82-2 (butorphanol)
    3) CAS 58786-99-5 (butorphanol tartrate)
    1.2.1) MOLECULAR FORMULA
    1) BUTORPHANOL TARTRATE: C21H29NO2C4H6O6 (Prod Info butorphanol tartrate IV, IM injection, 2005)

Available Forms Sources

    A) FORMS
    1) Butorphanol tartrate is available as a solution for IM or IV injection in 1 mg/mL or 2 mg/mL 1 ml vials; 2 mg/mL, 2 ml vials; or 2 mg/mL, 10 ml multi-dose vials (Prod Info butorphanol tartrate IV, IM injection, 2005). Also, butorphanol tartrate is available in a 10 mg/mL, 2.5 mL nasal spray (Prod Info butorphanol tartrate nasal spray, 2009).
    2) Butorphanol tartrate is also formulated as a 1 mg, 5 mg or 10 mg tablet or a 2 mg/mL oral solution for veterinary use only (United States Food and Drug Administration, 2010; United States Food and Drug Administration, 2010).
    B) USES
    1) Butorphanol is a mixed agonist-antagonist of the Mu and Kappa opioid receptors indicated for the management of postoperative pain, labor pain and pre- and balanced anesthesia (Prod Info butorphanol tartrate IV, IM injection, 2005).
    2) Butorphanol is also used by veterinarians to treat major pain or post surgical pain in various animals, including cats and dogs (United States Food and Drug Administration, 2010; United States Food and Drug Administration, 2010).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Butorphanol is a mixed agonist-antagonist of the Mu and Kappa opioid receptors indicated for the management of postoperative pain, labor pain, and pre- and balanced anesthesia.
    B) PHARMACOLOGY: Butorphanol is a synthetically derived opioid agonist-antagonist of the phenanthrene series and exhibits analgesic effects from low intrinsic activity at receptors of the Mu-opioid type (morphine-like) and agonist activity at Kappa-opioid receptors.
    C) TOXICOLOGY: Therapeutic and toxic effects are mediated by different opioid receptors. Mu 1: Supraspinal and peripheral analgesia, sedation, and euphoria. Mu 2: Spinal analgesia, respiratory depression, physical dependence, GI dysmotility, bradycardia, and pruritus. Kappa 1: Spinal analgesia and miosis. Kappa 2: Dysphoria and psychotomimesis. Kappa 3: Supraspinal analgesia. Chronic opioid users develop tolerance to the analgesic and euphoric effects, but not to the respiratory depression effects.
    D) EPIDEMIOLOGY: Overdose with butorphanol is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Somnolence, dizziness, nausea and/or vomiting.
    2) LESS COMMON: Edema, chest pain, cough, dyspnea, blurred vision, syncope, and withdrawal symptoms.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Euphoria, drowsiness, constipation, nausea, vomiting, and pinpoint pupils. Mild bradycardia or hypotension may be present.
    2) SEVERE POISONING: Hypoventilation, cardiovascular insufficiency, coma, and death.
    0.2.20) REPRODUCTIVE
    A) Butorphanol is registered as FDA pregnancy category C. There are no adequate and well controlled trials in pregnant woman before 37 weeks of gestation. Butorphanol should only be used in pregnancy when the potential benefit of the medication justifies the risk to the infant.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer reports no carcinogenic studies have been done with butorphanol.

Laboratory Monitoring

    A) Monitor vital signs frequently, pulse oximetry, and continuous cardiac monitoring.
    B) Monitor for CNS and respiratory depression.
    C) Butorphanol plasma levels are not readily available or useful in guiding therapy. Urine toxicology screens may miss synthetic opioids such as butorphanol.
    D) Routine lab work is usually not indicated, unless it is helpful to rule out other causes or if the diagnosis of opioid toxicity is uncertain.
    E) Obtain a chest x-ray for persistent hypoxia. Consider a head CT and/or lumbar puncture to rule out an intracranial mass, bleeding or infection, if the diagnosis is uncertain.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Butorphanol is typically administered parenterally or intranasally; oral overdose is unlikely. See PARENTERAL EXPOSURE treatment section for further information.
    0.4.3) INHALATION EXPOSURE
    A) Due to the availability of butorphanol nasal spray, overdose due to inhalation may be possible. See the PARENTERAL EXPOSURE treatment section for further information.
    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Patients may only need observation.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Administer oxygen and assist ventilation for respiratory depression. Naloxone is the antidote indicated for severe toxicity (respiratory or CNS depression). Orotracheal intubation for airway protection should be performed early in cases of obtundation and/or respiratory depression that do not respond to naloxone, or in patients who develop severe acute lung injury.
    C) DECONTAMINATION
    1) PREHOSPITAL: Butorphanol is rapidly absorbed through parenteral or nasal administration, GI decontamination is unlikely to be of benefit and may cause aspiration and should be avoided. HOSPITAL: Butorphanol is rapidly absorbed through parenteral or nasal administration, GI decontamination is unlikely to be of benefit and may cause aspiration; it should be avoided.
    D) AIRWAY MANAGEMENT
    1) Administer oxygen and assist ventilation for respiratory depression. Orotracheal intubation for airway protection should be performed early in cases of obtundation and/or respiratory depression that do not respond to naloxone, or in patients who develop severe acute lung injury.
    E) ANTIDOTE
    1) NALOXONE, an opioid antagonist, is the specific antidote. Naloxone can be given intravascularly, intramuscularly, subcutaneously, intranasally or endotracheally. The usual dose is 0.4 to 2.0 mg IV. In patients with suspected opioid dependence incremental doses of 0.2 mg IV should be administered, titrated to reversal of respiratory depression and coma, to avoid precipitating acute opioid withdrawal. Doses may be repeated every 2 to 3 minutes up to 20 mg. Very high doses are rarely needed, but may be necessary in extreme overdoses. A CONTINUOUS infusion may be necessary in patients that have ingested a long-acting opioid, along with butorphanol. A suggested starting rate is two-thirds of the dose effective for initial reversal that is administered each hour; titrate as needed. DURATION of effect is usually 1 to 2 hours. Many opioids have a much longer duration of effect, so it may be necessary to observe the patient at least 3 to 4 hours after the last dose of naloxone to ensure that the patient does not have recurrent symptoms of toxicity. Naloxone can precipitate withdrawal in an opioid-dependent patients, which is usually not life-threatening; however it can be extremely uncomfortable for the patient.
    F) ACUTE LUNG INJURY
    1) Acute lung injury can develop in a small proportion of patients after an acute opioid overdose. The pathophysiology is unclear. Patients should be observed for 4 to 6 hours after overdose to evaluate for hypoxia and/or the development of acute lung injury. Continuous oxygen therapy, pulse oximetry, PEEP and mechanical ventilation may be necessary.
    G) HYPOTENSIVE EPISODE
    1) Hypotension is often reversed by naloxone. Initially treat with a saline bolus, if patient can tolerate a fluid load; then adrenergic vasopressors to raise mean arterial pressure.
    H) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis and hemoperfusion are not of value because of the large volume of distribution for butorphanol.
    I) INTRATHECAL INJECTION
    1) Limited experience. Treat seizures (benzodiazepines, barbiturates, propofol) and support blood pressure with fluids and pressors as needed. Naloxone infusion may be useful. Intubate and ventilate as needed. Cerebrospinal fluid drainage may accelerate recovery.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: Respiratory depression may occur at doses just above a therapeutic dose. Children should be evaluated in the hospital and observed as they are generally opioid naive and may develop respiratory depression. Adults should be evaluated by a health care professional if they have received a higher than recommended (therapeutic) dose, especially if opioid naive.
    2) OBSERVATION CRITERIA: Patients with deliberate ingestions and all children with ingestions should be sent to a health care facility for observation for at least 4 hours, as peak plasma levels and symptoms will likely develop within this time period. Patients who are treated with naloxone should be observed for 4 to 6 hours after the last dose, for recurrent CNS depression or acute lung injury.
    3) ADMISSION CRITERIA: Patients with significant persistent central nervous depression should be admitted to the hospital. Patients needing more than 2 doses of naloxone should be admitted as they may have taken a longer-acting opioid and may need additional doses. Patients with coma, seizures, dysrhythmias, or delirium or those needing a naloxone infusion or intubated patients should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    K) PITFALLS
    1) Patients may be discharged prematurely after mental status clears with a dose of naloxone. Naloxone's duration of effect may be much shorter than the duration of effect for many opioids. Other causes of altered mental status must be ruled out, such as hypoxia or hypoglycemia.
    A) PHARMACOKINETICS
    1) Butorphanol is rapidly absorbed after IM injection; peak plasma levels are reached in 20 to 40 minutes. Protein binding is approximately 80%. The volume of distribution varies from 305 to 901 liters. The duration of analgesia can be highly variable, but is generally 3 to 4 hours with IM and IV administration. Nasal administration of butorphanol 1 mg will cause peak serum levels of 0.9 to 1.04 ng/mL within 30 to 60 minutes. Oral bioavailability of butorphanol is approximately 5% to 17% due to extensive first pass metabolism.
    DIFFERENTIAL DIAGNOSIS
    2) Overdose with other sedating agents (eg, ethanol, benzodiazepine/barbiturate, antipsychotics); overdose with central alpha 2 agonists (eg, clonidine, tizanidine, imidazoline decongestants); CNS infection; intracranial hemorrhage; hypoglycemia or hypoxia.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established.
    B) THERAPEUTIC DOSE: IV or IM INJECTION: ADULT: Dosage for butorphanol will vary based on indication. For moderate to severe pain, doses range from 1 to 4 mg every 3 to 4 hours as needed. For balanced anesthesia, doses range from 4 to 12.5 mg, or approximately 0.06 to 0.18 mg/kg. Butorphanol 2 mg has a equivalent sedative effect of 10 mg of morphine or 80 mg meperidine. PEDIATRIC: The safety and effectiveness have not been established in patients less than 18 years of age for these formulations.
    C) THERAPEUTIC DOSE: NASAL SPRAY: ADULT: Moderate to severe pain: Dosage range from 1 to 2 mg intranasally, every 3 to 4 hours as needed. An increase in adverse effects is higher with the initial 2 mg dose.

Clinical Effects

Summary Of Exposure

    A) USES: Butorphanol is a mixed agonist-antagonist of the Mu and Kappa opioid receptors indicated for the management of postoperative pain, labor pain, and pre- and balanced anesthesia.
    B) PHARMACOLOGY: Butorphanol is a synthetically derived opioid agonist-antagonist of the phenanthrene series and exhibits analgesic effects from low intrinsic activity at receptors of the Mu-opioid type (morphine-like) and agonist activity at Kappa-opioid receptors.
    C) TOXICOLOGY: Therapeutic and toxic effects are mediated by different opioid receptors. Mu 1: Supraspinal and peripheral analgesia, sedation, and euphoria. Mu 2: Spinal analgesia, respiratory depression, physical dependence, GI dysmotility, bradycardia, and pruritus. Kappa 1: Spinal analgesia and miosis. Kappa 2: Dysphoria and psychotomimesis. Kappa 3: Supraspinal analgesia. Chronic opioid users develop tolerance to the analgesic and euphoric effects, but not to the respiratory depression effects.
    D) EPIDEMIOLOGY: Overdose with butorphanol is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Somnolence, dizziness, nausea and/or vomiting.
    2) LESS COMMON: Edema, chest pain, cough, dyspnea, blurred vision, syncope, and withdrawal symptoms.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Euphoria, drowsiness, constipation, nausea, vomiting, and pinpoint pupils. Mild bradycardia or hypotension may be present.
    2) SEVERE POISONING: Hypoventilation, cardiovascular insufficiency, coma, and death.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) BLURRED VISION
    a) Blurred vision occurred in greater than 1% of patients taking butorphanol (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) Butorphanol may increase the work of the heart during therapeutic use and should be used cautiously in patients with a history of acute myocardial dysfunction, ventricular dysfunction, or coronary insufficiency (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    2) WITH POISONING/EXPOSURE
    a) Cardiac insufficiency has been reported in acute exposure to butorphanol (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension has been reported less than 1% of patients receiving butorphanol. Syncope has also occurred with therapeutic use (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    C) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) Chest pain has been reported in less than 1% of patients with butorphanol use (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    D) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) In rare cases, severe hypertension has been reported with therapeutic use (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    E) EDEMA
    1) WITH THERAPEUTIC USE
    a) Edema has been reported in less than 1% of patients with butorphanol use (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HYPOVENTILATION
    1) WITH THERAPEUTIC USE
    a) Shallow breathing has been observed in less than 1% of patients receiving butorphanol (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    2) WITH POISONING/EXPOSURE
    a) Hypoventilation may develop with a significant overdose of butorphanol or based on individual variability, and likely appears similar to other opioids (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    B) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea has been reported in greater than 1% of patients using butorphanol (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    C) NASAL CONGESTION
    1) WITH THERAPEUTIC USE
    a) Nasal congestion was reported in 13% of patients taking butorphanol nasal spray (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    D) COUGH
    1) WITH THERAPEUTIC USE
    a) Cough has been reported in greater than 1% of patients using butorphanol (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) COMA
    1) WITH POISONING/EXPOSURE
    a) Coma has been reported in cases of acute overdose (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    B) DROWSY
    1) WITH THERAPEUTIC USE
    a) Somnolence was reported in 43% of patients taking butorphanol (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    2) WITH POISONING/EXPOSURE
    a) Drowsiness (Glasgow Coma Scale score of 13), sweating, and miosis were reported in a 26-year-old veterinarian, with severe dermatitis of both hands due to her occupation, following unintentional exposure of butorphanol and detomidine in an attempt to sedate a horse. The patient denied any needlestick injury, leading to speculation that poisoning was due to absorption of the sedatives through the patient's dermatitic hands (Hannah, 2010).
    C) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia has been reported in 11% of patients using butorphanol nasal spray (Prod Info butorphanol tartrate nasal spray, 2014).
    D) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness has been reported in 19% of patients using butorphanol (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009)
    E) SYNCOPE
    1) WITH THERAPEUTIC USE
    a) Syncope has been reported in less than 1% of patients with butorphanol use (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have been reported in 13% of patients taking butorphanol (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).

Reproductive

    3.20.1) SUMMARY
    A) Butorphanol is registered as FDA pregnancy category C. There are no adequate and well controlled trials in pregnant woman before 37 weeks of gestation. Butorphanol should only be used in pregnancy when the potential benefit of the medication justifies the risk to the infant.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) MICE, RABBITS, RATS: No evidence of teratogenicity was observed in mice, rabbits, or rats administered butorphanol during organogenesis (Prod Info butorphanol tartrate nasal spray, 2014; Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Butorphanol has been classified as FDA pregnancy category C (Prod Info butorphanol tartrate nasal spray, 2014; Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    2) Butorphanol should only be used during pregnancy if the potential maternal benefit outweighs the fetal risk (Prod Info butorphanol tartrate nasal spray, 2014; Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    3) During labor and delivery, use caution with IV or IM forms in neonates with an abnormal fetal heart rate pattern (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009) and the nasal form is not recommended (Prod Info butorphanol tartrate nasal spray, 2014).
    B) INFANT RESPIRATORY DISTRESS/APNEA
    1) There have been rare reports of infant respiratory distress/apnea when administered during labor and an increased risk if used within 2 hours of delivery, multiple doses, additional analgesic or sedative drug use, or preterm pregnancy use (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    C) TRANSIENT SINUSOIDAL FETAL HEART RATE PATTERNS
    1) Transient (10 to 90 minutes) sinusoidal fetal heart rate patterns were observed in a study of 119 patients when 1 mg IV doses were administered during labor; however, it was not associated with adverse neonatal outcomes. Use caution during delivery in neonates with an abnormal fetal heart rate pattern (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    D) ANIMAL STUDIES
    1) RABBITS: Increased incidences of post-implantation loss were observed in rabbits administered oral doses of 30 and 60 mg/kg (360 and 720 mg/m(2), respectively) (Prod Info butorphanol tartrate nasal spray, 2014; Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    2) RATS: A higher frequency of stillbirths was observed in rats administered subQ 1 mg/kg (5.9 mg/m(2)) doses (Prod Info butorphanol tartrate nasal spray, 2014; Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Injectable butorphanol has been measured in the breast milk of nursing mothers. A nursing mother receiving a 2 mg IM dose 4 times daily would likely result in a clinically insignificant dose in the infant of an estimated 4 mcg/L (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009). While no studies have been performed with nasal butorphanol, it should be assumed that exposures will be similar to that of the injectable form (Prod Info butorphanol tartrate nasal spray, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: Butorphanol showed reduced pregnancy rates in rats treated with 160 mg/kg/day (944 mg/m(2)) orally; however, a similar effect was not seen when rats were treated with 2.5 mg/kg/day (14.75 mg/m(2)) subcutaneously (Prod Info butorphanol tartrate nasal spray, 2014; Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer reports no carcinogenic studies have been done with butorphanol.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer reports no carcinogenic studies have been done with butorphanol (Prod Info butorphanol tartrate IV, IM injection, 2005; Prod Info butorphanol tartrate nasal spray, 2009).
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) Two year carcinogenicity studies revealed no evidence of carcinogenicity when mice and rats were given 60 mg/kg/day (180 mg/m(2) for mice and 354 mg/m(2) for rats) (Prod Info butorphanol tartrate IV, IM injection, 2005; Prod Info butorphanol tartrate nasal spray, 2009).

Genotoxicity

    A) Butorphanol was not genotoxic in S. typhimurium or E. coli assays or in unscheduled DNA synthesis and repair assays conducted in cultured human fibroblast cells (Prod Info butorphanol tartrate IV, IM injection, 2005; Prod Info butorphanol tartrate nasal spray, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs frequently, pulse oximetry, and continuous cardiac monitoring.
    B) Monitor for CNS and respiratory depression.
    C) Butorphanol plasma levels are not readily available or useful in guiding therapy. Urine toxicology screens may miss synthetic opioids such as butorphanol.
    D) Routine lab work is usually not indicated, unless it is helpful to rule out other causes or if the diagnosis of opioid toxicity is uncertain.
    E) Obtain a chest x-ray for persistent hypoxia. Consider a head CT and/or lumbar puncture to rule out an intracranial mass, bleeding or infection, if the diagnosis is uncertain.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with significant, persistent central nervous system depression should be admitted to the hospital. A patient needing more than 2 doses of naloxone should be admitted as a longer-acting opioid has likely been taken; additional doses may be needed. Patients with coma, seizures, dysrhythmias, delirium, and those needing a naloxone infusion or who are intubated should be admitted to an intensive care setting.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) Respiratory depression may occur at doses just above the therapeutic dose. Children should be observed and evaluated in the hospital as they are generally opioid naive and may develop respiratory depression. Adults should be evaluated by a health care professional if they have received a higher than recommended (therapeutic) dose, especially if opioid naive.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) SUMMARY: Patients with deliberate ingestions or a pediatric ingestion should be sent to a health care facility for observation for at least 4 hours, to ensure that peak plasma levels have been reached and there has been sufficient time for symptoms to develop. . Patients who are treated with naloxone should be observed for 4 to 6 hours after the last dose, for recurrent CNS depression or acute lung injury.
    B) Patients should be observed for return of respiratory depression and resedation after naloxone administration. The duration of action for naloxone is approximately 20 to 90 minutes, depending on the dose, route and the opioid agonist ingested (Howland, 2006).

Monitoring

    A) Monitor vital signs frequently, pulse oximetry, and continuous cardiac monitoring.
    B) Monitor for CNS and respiratory depression.
    C) Butorphanol plasma levels are not readily available or useful in guiding therapy. Urine toxicology screens may miss synthetic opioids such as butorphanol.
    D) Routine lab work is usually not indicated, unless it is helpful to rule out other causes or if the diagnosis of opioid toxicity is uncertain.
    E) Obtain a chest x-ray for persistent hypoxia. Consider a head CT and/or lumbar puncture to rule out an intracranial mass, bleeding or infection, if the diagnosis is uncertain.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital GI decontamination is generally not recommended because of the risk of CNS depression and subsequent aspiration.
    B) NALOXONE/SUMMARY
    1) Naloxone, a pure opioid antagonist, reverses coma and respiratory depression from all opioids. It has no agonist effects and can safely be employed in a mixed or unknown overdose where it can be diagnostic and therapeutic without risk to the patient.
    2) Indicated in patients with mental status and respiratory depression possibly related to opioid overdose (Hoffman et al, 1991).
    3) DOSE: The initial dose of naloxone should be low (0.04 to 0.4 mg) with a repeat dosing as needed or dose escalation to 2 mg as indicated due to the risk of opioid withdrawal in an opioid-tolerant individual; if delay in obtaining venous access, may administer subcutaneously, intramuscularly, intranasally, via nebulizer (in a patient with spontaneous respirations) or via an endotracheal tube (Vanden Hoek,TL,et al).
    4) Recurrence of opioid toxicity has been reported to occur in approximately 1 out of 3 adult ED opioid overdose cases after a response to naloxone. Recurrences are more likely with long-acting opioids (Watson et al, 1998)
    C) NALOXONE DOSE/ADULT
    1) INITIAL BOLUS DOSE: Because naloxone can produce opioid withdrawal in an opioid-dependent individual leading to severe agitation and hypertension, the initial dose of naloxone should be low (0.04 to 0.4 mg) with a repeat dosing as needed or dose escalation to 2 mg as indicated (Vanden Hoek,TL,et al).
    a) This dose can also be given intramuscularly or subcutaneously in the absence of intravenous access (Howland & Nelson, 2011; Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008; Maio et al, 1987; Wanger et al, 1998).
    2) Larger doses may be needed to reverse opioid effects. Generally, if no response is observed after 8 to 10 milligrams has been administered, the diagnosis of opioid-induced respiratory depression should be questioned (Howland & Nelson, 2011; Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008). Very large doses of naloxone (10 milligrams or more) may be required to reverse the effects of a buprenorphine overdose (Gal, 1989; Jasinski et al, 1978).
    a) Single doses of up to 24 milligrams have been given without adverse effect (Evans et al, 1973).
    3) REPEAT DOSE: The effective naloxone dose may have to be repeated every 20 to 90 minutes due to the much longer duration of action of the opioid agonist used(Howland & Nelson, 2011).
    a) OPIOID DEPENDENT PATIENTS: The goal of naloxone therapy is to reverse respiratory depression without precipitating significant withdrawal. Starting doses of naloxone 0.04 mg IV, or 0.001 mg/kg, have been suggested as appropriate for opioid-dependent patients without severe respiratory depression (Howland & Nelson, 2011). If necessary the dose may be repeated or increased gradually until the desired response is achieved (adequate respirations, ability to protect airway, responds to stimulation but no evidence of withdrawal) (Howland & Nelson, 2011). In the presence of opioid dependence, withdrawal symptoms typically appear within minutes of naloxone administration and subside in about 2 hours. The severity and duration of the withdrawal syndrome are dependant upon the naloxone dose and the degree and type of dependence.(Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008)
    b) PRECAUTION should be taken in the presence of a mixed overdose of a sympathomimetic with an opioid. Administration of naloxone may provoke serious sympathomimetic toxicity by removing the protective opioid-mediated CNS depressant effects. Arrhythmogenic effects of naloxone may also be potentiated in the presence of severe hyperkalemia (McCann et al, 2002).
    4) NALOXONE DOSE/CHILDREN
    a) LESS THAN 5 YEARS OF AGE OR LESS THAN 20 KG: 0.1 mg/kg IV/intraosseous/IM/subcutaneously maximum dose 2 mg; may repeat dose every 2 to 5 minutes until symptoms improve (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008)
    b) 5 YEARS OF AGE OR OLDER OR GREATER THAN 20 KG: 2 mg IV/intraosseous/IM/subcutaneouslymay repeat dose every 2 to 5 minutes until symptoms improve (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Krauss & Green, 2006). Although naloxone may be given via the endotracheal tube for pediatric resuscitation, optimal doses are unknown. Some experts have recommended using 2 to 3 times the IV dose (Kleinman et al, 2010)
    c) AVOIDANCE OF OPIOID WITHDRAWAL: In cases of known or suspected chronic opioid therapy, a lower dose of 0.01 mg/kg may be considered and titrated to effect to avoid withdrawal: INITIAL DOSE: 0.01 mg/kg body weight given IV. If this does not result in clinical improvement, an additional dose of 0.1 mg/kg body weight may be given. It may be given by the IM or subQ route if the IV route is not available (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008)
    5) NALOXONE DOSE/NEONATE
    a) The American Academy of Pediatrics recommends a neonatal dose of 0.1 mg/kg IV or intratracheally from birth until age 5 years or 20 kilograms of body weight (AAP, 1989; Kleinman et al, 2010).
    b) Smaller doses (10 to 30 mcg/kg IV) have been successful in the setting of exposure via maternal administration of narcotics or administration to neonates in therapeutic doses for anesthesia (Wiener et al, 1977; Welles et al, 1984; Fischer & Cook, 1974; Brice et al, 1979).
    c) POTENTIAL OF WITHDRAWAL: The risk of precipitating withdrawal in an addicted neonate should be considered. Withdrawal seizures have been provoked in infants from opioid-abusing mothers when the infants were given naloxone at birth to stimulate breathing (Gibbs et al, 1989).
    d) In cases of inadvertent administration of an opioid overdose to a neonate, larger doses may be required. In one case of oral morphine intoxication, 0.16 milligram/kilogram/hour was required for 5 days (Tenenbein, 1984).
    6) NALOXONE/ALTERNATE ROUTES
    a) If intravenous access cannot be rapidly established, naloxone can be administered via subcutaneous or intramuscular injection, intranasally, or via inhaled nebulization in patients with spontaneous respirations.
    b) INTRAMUSCULAR/SUBCUTANEOUS ROUTES: If an intravenous line cannot be secured due to hypoperfusion or lack of adequate veins then naloxone can be administered by other routes.
    c) The intramuscular or subcutaneous routes are effective if hypoperfusion is not present (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008). The delay required to establish an IV, offsets the slower rate of subcutaneous absorption (Wanger et al, 1998).
    d) Naloxone Evzio(TM) is a hand-held autoinjector intended for the emergency treatment of known or suspected opioid overdose. The autoinjector is equipped with an electronic voice instruction system to assist caregivers with administration. It is available as 0.4 mg/0.4 mL solution for injection in a pre-filled auto-injector (Prod Info EVZIO(TM) injection solution, 2014).
    e) INTRANASAL ROUTE: Intranasal naloxone has been shown to be effective in opioid overdose; bioavailability appears similar to the intravenous route (Kelly & Koutsogiannis, 2002). Based on several case series of patients with suspected opiate overdose, the average response time of 3.4 minutes was observed using a formulation of 1 mg/mL/nostril by a mucosal atomization device (Kerr et al, 2009; Kelly & Koutsogiannis, 2002). However, a young adult who intentionally masticated two 25 mcg fentanyl patches and developed agonal respirations (6 breaths per minute), decreased mental status and mitotic pupils did not respond to intranasal naloxone (1 mg in each nostril) administered by paramedics. After 11 minutes, paramedics placed an IV and administered 1 mg of IV naloxone; respirations normalized and mental status improved. Upon admission, 2 additional doses of naloxone 0.4 mg IV were needed. The patient was monitored overnight and discharged the following day without sequelae. Its suggested that intranasal administration can lead to unpredictable absorption (Zuckerman et al, 2014).
    1) Narcan(R) nasal spray is supplied as a single 4 mg dose of naloxone hydrochloride in a 0.1 mL intranasal spray (Prod Info NARCAN(R) nasal spray, 2015).
    2) FDA DOSING: Initial dose: 1 spray (4 mg) intranasally into 1 nostril. Subsequent doses: Use a new Narcan(R) nasal spray and administer into alternating nostrils. May repeat dose every 2 to 3 minutes. Requirement for repeat dosing is dependent on the amount, type, and route of administration of the opioid being antagonized. Higher or repeat doses may be required for partial agonists or mixed agonist/antagonists (Prod Info NARCAN(R) nasal spray, 2015).
    3) AMERICAN HEART ASSOCIATION GUIDELINE DOSING: Usual dose: 2 mg intranasally as soon as possible; may repeat after 4 minutes (Lavonas et al, 2015). Higher doses may be required with atypical opioids (VandenHoek et al, 2010).
    4) ABSORPTION: Based on limited data, the absorption rate of intranasal administration is comparable to intravenous administration. The peak plasma concentration of intranasal administration is estimated to be 3 minutes which is similar to the intravenous route (Kerr et al, 2009). In rare cases, nasal absorption may be inhibited by injury, prior use of intranasal drugs, or excessive secretions (Kerr et al, 2009).
    f) NEBULIZED ROUTE: DOSE: A suggested dose is 2 mg naloxone with 3 mL of normal saline for suspected opioid overdose in patients with some spontaneous respirations (Weber et al, 2012).
    g) ENDOTRACHEAL ROUTE: Endotracheal administration of naloxone can be effective(Tandberg & Abercrombie, 1982), optimum dose unknown but 2 to 3 times the intravenous dose had been recommended by some (Kleinman et al, 2010).
    7) NALOXONE/CONTINUOUS INFUSION METHOD
    a) A continuous infusion of naloxone may be employed in circumstances of opioid overdose with long acting opioids (Howland & Nelson, 2011; Redfern, 1983).
    b) The patient is given an initial dose of IV naloxone to achieve reversal of opioid effects and is then started on a continuous infusion to maintain this state of antagonism.
    c) DOSE: Utilize two-thirds of the initial naloxone bolus on an hourly basis (Howland & Nelson, 2011; Mofenson & Caraccio, 1987). For an adult, prepare the dose by multiplying the effective bolus dose by 6.6, and add that amount to 1000 mL and administer at an IV infusion rate of 100 mL/hour (Howland & Nelson, 2011).
    d) Dose and duration of action of naloxone therapy varies based on several factors; continuous monitoring should be used to prevent withdrawal induction (Howland & Nelson, 2011).
    e) Observe patients for evidence of CNS or respiratory depression for at least 2 hours after discontinuing the infusion (Howland & Nelson, 2011).
    8) NALOXONE/PREGNANCY
    a) In general, the smallest dose of naloxone required to reverse life threatening opioid effects should be used in pregnant women. Naloxone detoxification of opioid addicts during pregnancy may result in fetal distress, meconium staining and fetal death (Zuspan et al, 1975). When naloxone is used during pregnancy, opioid abstinence may be provoked in utero (Umans & Szeto, 1985).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Butorphanol is typically administered parenterally or intranasally; oral overdose is unlikely. See the PARENTERAL EXPOSURE treatment section for further information.

Enhanced Elimination

    A) LACK OF EFFECT
    1) Hemodialysis and hemoperfusion are not of value because of the large volume of distribution for butorphanol.

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established.
    B) THERAPEUTIC DOSE: IV or IM INJECTION: ADULT: Dosage for butorphanol will vary based on indication. For moderate to severe pain, doses range from 1 to 4 mg every 3 to 4 hours as needed. For balanced anesthesia, doses range from 4 to 12.5 mg, or approximately 0.06 to 0.18 mg/kg. Butorphanol 2 mg has a equivalent sedative effect of 10 mg of morphine or 80 mg meperidine. PEDIATRIC: The safety and effectiveness have not been established in patients less than 18 years of age for these formulations.
    C) THERAPEUTIC DOSE: NASAL SPRAY: ADULT: Moderate to severe pain: Dosage range from 1 to 2 mg intranasally, every 3 to 4 hours as needed. An increase in adverse effects is higher with the initial 2 mg dose.

Therapeutic Dose

    7.2.1) ADULT
    A) IV OR IM INJECTION
    1) The dosage for butorphanol will vary based on the indication. For moderate to severe pain, doses range from 1 to 4 mg every 3 to 4 hours as needed. For preoperative or preanesthetic medication, the usual dose is 2 mg IM administered 60 to 90 minutes prior to surgery (equivalent in sedative effect to 10 mg of morphine or 80 mg meperidine). For balanced anesthesia, doses range from 4 to 12.5 mg, or approximately 0.06 to 0.18 mg/kg (Prod Info butorphanol tartrate intramuscular injection solution, intravenous injection solution, 2009).
    B) NASAL SPRAY
    1) The recommended initial dose is 1 mg (1 spray) in ONE nostril; if pain is not relieved within 60 to 90 minutes, a repeat dose of 1 mg in ONE nostril may be used. After the second dose, the initial dose can be repeated every 3 to 4 hours as needed (Prod Info butorphanol tartrate nasal solution, 2011).
    2) Depending on the severity of pain, an initial dose of 2 mg (1 spray in each nostril) may be used every 3 to 4 hours; patients are to remain recumbent in the event that drowsiness or dizziness occurs (Prod Info butorphanol tartrate nasal solution, 2011).
    7.2.2) PEDIATRIC
    A) The safety and effectiveness have not been established in patients less than 18 years of age (Prod Info butorphanol tartrate IV, IM injection, 2005; Prod Info butorphanol tartrate nasal solution, 2011).

Minimum Lethal Exposure

    A) At the time of this review, a minimum lethal dose has not been established.

Maximum Tolerated Exposure

    A) At the time of this review, a maximum tolerated dose has not been established.

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Butorphanol is a mixed agonist-antagonist with low intrinsic activity at receptors of the Mu-opioid type (morphine-like). It is also an agonist at Kappa opioid receptors, which induces analgesia. Other CNS effects include depression of spontaneous respiratory activity and cough, stimulation of the emetic center, miosis and sedation. Possible non-CNS mediated mechanisms include alteration in cardiovascular resistance and capacitance, bronchomotor tone, gastrointestinal secretory and motor activity and bladder sphincter activity (Prod Info butorphanol tartrate IV, IM injection, 2005; Prod Info butorphanol tartrate nasal spray, 2009).

Physicochemical

Physical Characteristics

    A) BUTORPHANOL TARTRATE: A white crystalline powder with a melting point between 102.8 and 103.9 degrees C (217 and 219 degrees F) with decomposition; sparingly soluble in water, slightly soluble in methanol, insoluble in alcohol and chloroform, and soluble in dilute acids (Prod Info butorphanol tartrate injection, 2004).

Molecular Weight

    A) BUTORPHANOL TARTRATE: 477.55 (Prod Info butorphanol tartrate IV, IM injection, 2005)

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