Butorphanol

Butorphanol is an Opioid Partial agonist-antagonist belonging to the analgesic class.

Butorphanol is an opioid agonist-antagonist used to treat moderate to severe pain.

Butorphanol is Rapidly and well absorbed. Bioavailability is 60-70% via nasal route. Time taken to reach peak plasma concentration is 0.5-1 hour via IM, IV- and 1-2-hour nasal route. It has volume of distribution of approximately 305 to 901 L. Plasma protein binding is approximately 80%. Butophanol is metabolized hepatically to hydroxybutorphanol as major metabolite. Butorphanol is extensively metabolized in the liver. Elimination occurs Via urine approximately 70-80% and 5% as unchanged and via faece (approximately 15%).

Butorphanol shows side effects like Excessive tiredness, difficulty falling asleep or staying asleep, unusual dreams, headache, constipation, stomach pain, feeling hot, flushing, pain, burning, numbness, or tingling in the hands or feet, uncontrollable shaking of a part of your body, nervousness, hostility, intense happiness, feeling of floating, sad mood, blurred vision, ringing in the ears, ear pain, unpleasant taste, dry mouth, difficulty urinating.

Butorphanol is available in the form of Injectable solution and nasal spray.

Butorphanol is available in India, US, Canada, France, Italy, Germany, Australia, and Spain.

Butorphanol is an Analgesic belonging to the class Opioid Partial agonist-antagonist.

Butorphanol interacts 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 may also be a result of other mechanisms. Butorphanol is a mixed agonist-antagonist that exerts antagonistic or partially antagonistic effects at mu opiate receptor sites but is thought to exert its agonistic effects principally at the kappa and sigma opiate receptors.

The onset of action can be observed within 15 minutes on nasal administration, 5-10 minutes on intramuscular administration, and less than 10 minutes on intravenous administration.

The Tmax of Butorphanol is about 20-40 minutes.

Butorphanol is available in the form of Injectable solution and nasal spray.

Butorphanol Injectable solution is given intramuscular and intravenous route.

Butorphanol is an opioid pain medication that is used to treat moderate to severe pain. It is also used as part of anesthesia for surgery, or during early labor.

Butorphanol is an Opioid Partial agonist-antagonist belonging to the analgesic class.

Butorphanol is used for the management of moderate to severe pain when the use of opioid analgesics is appropriate. It is used as anesthesia for surgeries, and also for the management of pain during early labor.

Butorphanol is approved for use in the following clinical indications

• Acute pain
• Pain during labor
• Preoperative sedation
• Supplement to balanced anesthesia

• Acute pain

IM Dose: Initial: 2 mg in patients who will be able to remain recumbent (in the event drowsiness or dizziness occurs); may repeat every 3 to 4 hours as needed; usual range: 1 to 4 mg every 3 to 4 hours as needed.

IV Dose: Initial: 1 mg; may repeat every 3 to 4 hours as needed; usual range: 0.5 to 2 mg every 3 to 4 hours as needed.

Intranasal (spray) Dose: Initial: One spray (1 mg per spray) in 1 nostril; if adequate pain relief is not achieved within 60 to 90 minutes, an additional 1 spray in 1 nostril may be given; may repeat initial dose sequence in 3 to 4 hours after the last dose as needed.

• Pain during labor

IM, IV Dose: 1 to 2 mg; may repeat in 4 hours.

• Preoperative sedation

IV Dose: 2 mg once; administer shortly before induction.

IM Dose: 2 mg once; administer 60 to 90 minutes before surgery.

• Supplement to balanced anesthesia

IV Dose: 2 mg shortly before induction; may be followed by incremental doses of 0.5 to 1 mg as needed during anesthesia (incremental dose dependent on previously administered sedative, analgesic, and hypnotic medications); usual total dose: 4 to 12.5 mg.

Butorphanol is available in various strengths as 2 mg/mL; 1 mg/mL; 10 mg/mL.

Butorphanol is available in the form of Injectable solution and nasal spray.

• Dosage Adjustment in Kidney Patient

IM: Initial: 1 mg; repeated dosing must be based on initial response rather than fixed intervals, but generally at least 6 hours from previous dose.

IV: Initial: 0.5 mg; repeated dosing must be based on initial response rather than fixed intervals, but generally at least 6 hours from previous dose.

Intranasal (spray): Initial: One spray (1 mg per spray) in 1 nostril; if adequate pain relief is not achieved within 90 to 120 minutes, an additional 1 spray in 1 nostril may be given. May repeat initial dose sequence as needed at intervals determined by patient response; usual interval: ≥6 hours between dosing sequences.

• Dosage Adjustment in Hepatic impairment Patient

IM: Initial: 1 mg; repeated dosing must be based on initial response rather than fixed intervals, but generally at least 6 hours from previous dose.

IV: Initial: 0.5 mg; repeated dosing must be based on initial response rather than fixed intervals, but generally at least 6 hours from previous dose.

Intranasal (spray): Initial: One spray (1 mg per spray) in 1 nostril; if adequate pain relief is not achieved within 90 to 120 minutes, an additional 1 spray in 1 nostril may be given. May repeat initial dose sequence as needed at intervals determined by patient response; usual interval: ≥6 hours between dosing sequences.

Butorphanol is contraindicated in patients with

• Butorphanol tartrate is contraindicated in patients hypersensitive to butorphanol tartrate or the preservative benzethonium chloride.

• CNS depression

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Hyperalgesia

Opioid-induced hyperalgesia (OIH) has occurred with short-term and prolonged use of opioid analgesics. Symptoms may include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily nonpainful stimuli; symptoms may be suggestive of OIH if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Consider decreasing the current opioid dose or opioid rotation in patients who experience OIH.

• Hypotension

May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute myocardial infarction [MI]), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Use with caution in patients with circulatory shock.

• Phenanthrene hypersensitivity

Use with caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (eg, codeine, hydromorphone, levorphanol, oxycodone, oxymorphone).

• Respiratory depression

Fatal respiratory depression may occur. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Patients and caregivers should be educated on how to recognize respiratory depression and the importance of getting emergency assistance immediately in the event of known or suspected overdose.

• Abdominal conditions

May obscure diagnosis or clinical course of patients with acute abdominal conditions.

• Adrenocortical insufficiency

Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis.

• Biliary tract impairment

Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; may cause constriction of sphincter of Oddi.

• Cardiovascular disease

Use extreme caution in patients with acute myocardial infarction, ventricular dysfunction, or coronary insufficiency; limit use to situations where the benefits clearly outweigh the risk.

• CNS depression/coma

Avoid use in patients with impaired consciousness or coma as these patients are susceptible to intracranial effects of CO₂ retention.

• Delirium tremens

Use with caution in patients with delirium tremens.

• Head trauma

Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.

• Hepatic impairment

Use with caution in patients with hepatic impairment. Dosage adjustments are recommended.

• Mental health conditions

Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to potential increased risk for opioid use disorder and overdose; more frequent monitoring is recommended.

• Obesity

Use with caution in patients who are morbidly obese.

• Prostatic hyperplasia/urinary stricture

Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Psychosis

Use with caution in patients with toxic psychosis.

• Renal impairment

Use with caution in patients with renal impairment. Dosage adjustments are recommended.

• Respiratory disease

Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Seizures

Use with caution in patients with a history of seizure disorders; may cause or exacerbate preexisting seizures.

• Serotonin syndrome

Potentially life-threatening serotonin syndrome (SS) has occurred with concomitant use of butorphanol and serotonergic agents (eg, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, St John's wort, tryptophan) or agents that impair metabolism of serotonin (eg, monoamine oxidase [MAO] inhibitors intended to treat psychiatric disorders, other MAO inhibitors [ie, linezolid and intravenous methylene blue]). Monitor patients closely for signs of SS such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis); neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures.

• Sleep-related disorders

Use with caution in patients with sleep-related disorders, including sleep apnea, due to increased risk for respiratory and central nervous system depression. Monitor carefully and titrate dosage cautiously in patients with mild sleep-disordered breathing. Avoid opioids in patients with moderate to severe sleep-disordered breathing.

• Thyroid dysfunction

Use with caution in patients with thyroid dysfunction.

• Benzodiazepines or other CNS depressants (intranasal)

Concomitant use may result in respiratory depression and sedation, which may be fatal. Consider prescribing naloxone for emergency treatment of opioid overdose in patients taking benzodiazepines or other CNS depressants concomitantly with opioids.

Consumption of alcohol is not recommended during treatment with this medicine due to the increased risk of severe side effects such as confusion, dizziness, nausea, vomiting, weakness, and fainting.

Pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

• Common

Drowsiness, dizziness, insomnia, Nausea and vomiting, Nasal congestion, Palpitations, vasodilation, Anxiety, burning sensation, confusion, euphoria, floating feeling, headache, lethargy, nervousness, paresthesia, Cold and clammy skin, diaphoresis, pruritus, Anorexia, constipation, stomach pain, unpleasant taste, xerostomia, Tremor, weakness, Blurred vision, Otalgia, tinnitus, Bronchitis, cough, dyspnea, epistaxis, nasal discomfort, pharyngitis, rhinitis, sinus congestion, sinusitis, upper respiratory tract infection

• Rare

Abnormal dreams, agitation, allodynia (opioid-induced hyperalgesia), apnea, chest pain, convulsions, delusions, depression, drug dependence, dysphoria, edema, hallucination, hostility, hypertension, hypogonadism, hypotension, respiratory depression, seizure, shallow respiration, skin rash, speech disturbance, syncope, tachycardia, urination disorder, urticaria, vertigo, withdrawal syndrome.

• Alizapride

May enhance the CNS depressant effect of CNS Depressants.

• Alvimopan

Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification

• Amphetamines

May enhance the analgesic effect of Opioid Agonists.

• Anticholinergic Agents

May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination.

• Azelastine (Nasal)

May enhance the CNS depressant effect of CNS Depressants.

• Blonanserin

CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin.

• Brimonidine (Topical)

May enhance the CNS depressant effect of CNS Depressants.

• Bromopride

May enhance the CNS depressant effect of CNS Depressants.

• Bromperidol

May enhance the CNS depressant effect of CNS Depressants.

• Buprenorphine

Opioids (Mixed Agonist / Antagonist) may diminish the therapeutic effect of Buprenorphine. This combination may also induce opioid withdrawal.

• Cannabinoid-Containing Products

CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products.

• Chlormethiazole

May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

• Chlorphenesin Carbamate

May enhance the adverse/toxic effect of CNS Depressants.

• CNS Depressants

May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification.

• CYP3A4 Inducers (Strong)

May decrease the serum concentration of Butorphanol.

• CYP3A4 Inhibitors (Strong)

May increase the serum concentration of Butorphanol.

• Daridorexant

May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended.

• Desmopressin

Opioid Agonists may enhance the hyponatremic effect of Desmopressin.

• Dexmedetomidine

CNS Depressants may enhance the CNS depressant effect of Dexmedetomidine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression.

• Difelikefalin

May enhance the CNS depressant effect of CNS Depressants.

• Dimethindene (Topical)

May enhance the CNS depressant effect of CNS Depressants.

• Diuretics

Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics.

• Droperidol

May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use.

• Eluxadoline

Opioid Agonists may enhance the constipating effect of Eluxadoline.

• Flunarizine

CNS Depressants may enhance the CNS depressant effect of Flunarizine.

• Flunitrazepam

CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available.

• Gastrointestinal Agents (Prokinetic)

Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic).

The common side effects of Butorphanol include the following

• Common side effects

Excessive tiredness, difficulty falling asleep or staying asleep, unusual dreams, headache, constipation, stomach pain, feeling hot, flushing, pain, burning, numbness, or tingling in the hands or feet, uncontrollable shaking of a part of your body, nervousness, hostility, intense happiness, feeling of floating, sad mood, blurred vision, ringing in the ears, ear pain, unpleasant taste, dry mouth, difficulty urinating.

• Rare side effects

Agitation, hallucinations (seeing things or hearing voices that do not exist), fever, sweating, confusion, fast heartbeat, shivering, severe muscle stiffness or twitching, loss of coordination, nausea, vomiting, or diarrhea, nausea, vomiting, loss of appetite, weakness, or dizziness, inability to get or keep an erection, irregular menstruation, decreased sexual desire, difficulty breathing, changes in heartbeat, fainting, rash, hives.

• Pregnancy

Pregnancy Category C

Reproduction studies in mice, rats, and rabbits during organogenesis did not reveal any teratogenic potential to butorphanol. However, pregnant rats treated subcutaneously with butorphanol at 1 mg/kg (5.9 mg/m2) had a higher frequency of stillbirths than controls. Butorphanol at 30 mg/kg/oral (360 mg/m2) and 60 mg/kg/oral (720 mg/m2) also showed higher incidences of post-implantation loss in rabbits. There are no adequate and well-controlled studies of Butorphanol in pregnant women before 37 weeks of gestation. Butorphanol should be used during pregnancy only if the potential benefit justifies the potential risk to the infant

• Nursing Mothers

Butorphanol has been detected in milk following administration of Butorphanol Injection to nursing mothers. The amount an infant would receive is probably clinically insignificant (estimated 4 µg/L of milk in a mother receiving 2 mg IM four times a day). Although there is no clinical experience with the use of Butorphanol NS in nursing mothers, it should be assumed that butorphanol will appear in the milk in similar amounts following the nasal route of administration.

• Pediatric Use

Butorphanol is not recommended for use in patients below 18 years of age because safety and efficacy have not been established in this population.

Symptoms: Resp depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary oedema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring.

Management: Supportive treatment. Immediate IV admin of an opiate antagonist (e.g. naloxone or nalmefene) as specific antidote. Administer oxygen, IV fluids and vasopressors as necessary.

• Pharmacodynamic
• Butorphanol is a synthetic opioid agonist-antagonist analgesic. The introduction of a transnasal formulation of butorphanol represents a new and noninvasive presentation of an analgesic for moderate to severe pain. This route of administration bypasses the gastrointestinal tract, and this is an advantage for a drug such as butorphanol that undergoes significant first-pass metabolism after oral administration. The onset of action and systemic bioavailability of butorphanol following transnasal delivery are like those after parenteral administration. Butorphanol blocks pain impulses at specific sites in the brain and spinal cord.

• Pharmacokinetics

Absorption

Butorphanol is Rapidly and well absorbed. Bioavailability is 60-70% via nasal route. Time taken to reach peak plasma concentration is 0.5-1 hr via IM, IV- and 1-2-hours nasal route.

Distribution

Butorphanol has volume of distribution of approximately 305 to 901 L. Plasma protein binding is approximately 80%.

Metabolism and Excretion

Butorphanol is metabolised hepatically to hydroxybutorphanol as major metabolite. Butorphanol is extensively metabolized in the liver. Elimination occurs by urine and fecal excretion.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19890s17lbl.pdf
• https://go.drugbank.com/drugs/DB00611
• https://medlineplus.gov/druginfo/meds/a682667.html#:~:text=Butorphanol injection is used to,medications called opioid agonist-antagonists
• https://reference.medscape.com/drug/butorphanol-343327
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