Buprenorphine - a very potent opioid analgesic

Buprenorphine is an opioid analgesic that is 25 to 40 times more potent and long-lasting than morphine. It is used to treat the following medical conditions:

  • Treatment of moderate to severe opioid use disorder

  • For the treatment of opioid dependency in patients who have maintained clinical stability for at least three months on low to moderate dosages (of transmucosal buprenorphine).

  • For the long-term, round-the-clock management of severe pain, opioid therapy (for which alternative treatment options are not adequate)

  • Off Label Use of Buprenorphine in Adults include:

    • To treat opioid withdrawal in hospitalised patients who are addicted to heroin
    • Perineural anesthesia

Buprenorphine Dose in Adults

 Note: Buprenorphine 8 mg sublingual tablet = buprenorphine/naloxone 8 mg/2 mg sublingual film = buprenorphine/naloxone 4.2 mg/0.7 mg buccal film = buprenorphine/naloxone 5.7 mg/1.4 mg sublingual tablet.

Dose in the treatment of moderate to severe Acute pain:

  • Immediate-release injection:
    • Every 6 to 8 hours, as needed, 0.3 mg intramuscularly or as a gradual intravenous injection
    • If necessary, the dose may be given again every 30 to 60 minutes.

  • Use in the treatment of moderate to severe Chronic pain:

Buccal film:

  • Opioid-naive patients and opioid-non-tolerant patients:

    • For at least 4 days, administer 75 mcg once daily or every 12 hours (if tolerated); after that, up the dosage to 150 mcg every 12 hours..

Conversion from other opioids to buprenorphine:

  • Buprenorphine treatment should begin with the cessation of other 24-hour opioids.
  • The amount of oral morphine sulphate equivalents from the patient's current opioids should be lowered to no more than 30 mg per day.
  • Patients taking a daily dose of less than 30 mg of oral morphine equivalents:
    • 75 mcg once a day or every 12 hours
  • Patients taking a daily dose of 30 - 89 mg of oral morphine equivalents:
    • 150 mcg every 12 hours
  • Patients taking a daily dose of 90 - 160 mg of oral morphine equivalents:
    • 300 mcg every 12 hours
  • Patients taking a daily dose of more than 160 mg of oral morphine equivalents:
    • Since that buprenorphine buccal film may not provide sufficient analgesia, take into account using different painkillers..

Conversion from methadone:

  • Dose titration in opioid-naive or opioid-experienced patients:
    • Individually titrate twice day in increments of 150 mcg to a dose that minimises side effects while delivering appropriate analgesia.
    • The dose should only be increased every fourth day or less.
    • The daily maximum dose shouldn't be more than 900 mcg.
  • Discontinuation of therapy:
    • Avoid abrupt termination whenever possible.
    • Withdrawal symptoms are avoided by gradual titration.
    • Half the dose should be given to patients with oral mucositis.

The Transdermal patch:

  • Opioid-naive patients:
    • Applying 5 mcg/hour once every seven days

conversion from other opioids to buprenorphine:

  • When buprenorphine therapy is started, all other 24-hour opioid medications should be stopped.
  • There may be a requirement for quick-acting analgesics.
  • Individuals who are already taking opioids can experience withdrawal.
  • Patients taking a daily dose of less than 30 mg of oral morphine equivalents:
    • 5 mcg/hour applied once every week
  • Patients taking a daily dose of 30 - 80 mg of oral morphine equivalents:
    • Before beginning therapy, the opioid dose that is taken continuously should be decreased to 30 mg/day or less for a week.
    • once-weekly application of 10 mcg/hour.
  • Patients taking a daily dose of more than 80 mg of oral morphine equivalents:
    • Although the buprenorphine transdermal patch may not offer sufficient analgesia even at the maximal dose of 20 mcg/hour given weekly, alternative analgesics should be employed.
  • Dose titration in opioid-naive or opioid-experienced patients:
    • The dose may be increased in increments of 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour based on patient's requirements, with a minimum titration interval of 72 hours.
    • The maximum dose is 20 mcg/hour applied once every week.
    • The risk for QTc prolongation increases with doses of more than 20 mcg/hour patch.
  • Discontinuation of therapy:
    • To keep the physically dependent patient from going into withdrawal, taper the dose progressively every week.
    • It might be thought of starting the treatment with opioids with immediate release.

Off label use in the treatment of Opioid withdrawal in heroin-dependent hospitalized patients:

  • Immediate-release injection:
    • Every 6 to 12 hours, 0.3 to 0.9 mg dissolved in 50 to 100 mL of 0.9% saline is administered intravenously over 20 to 30 minutes.

Use in the treatment of Opioid Dependence:

  • Extended-release injection:
    • During the first two months, take 300 mg subQ monthly ( after treatment has been adjusted with 8 - 24 mg of a transmucosal buprenorphine-containing product for a minimum of one week).
    • A maintenance dose of 100 mg is then given once a month after that.
    • For individuals who tolerate the 100 mg dose but do not show an acceptable clinical response, the dose may be increased further to 300 mg once a month.
  • Subdermal implant:
    • Subdermally place 4 implants on the inside side of the upper arm.
    • It should not be taken out before six months have passed since the date of insertion.
  • Converting back to sublingual tablet:
    • On the day of implant removal, sublingual buprenorphine medication may be continued at the previous sublingual doses.
  • Sublingual tablet:
    • A  2 to 4 mg induction dosage.
    • If after 60 to 90 minutes there are no signs of precipitated withdrawal, the dose may be increased in increments of 2 to 4 mg.
    • Once there are indications of mild to moderate opioid withdrawal, buprenorphine treatment should start.
    • For short-acting opioids like heroin and oxycodone, withdrawal symptoms often start 6–12 hours after the last dose, but for long-acting opioids like methadone, they start 24–72 hours after the last dose.
  • Manufacturer's labeling:
    • Induction:
      • Day 1: 8 mg
      • Day 2 and subsequent induction days: Increase in increments of 2 - 4 mg every 3 - 4 days.
    • Maintenance:
      • Target dose: 16 mg/day.

Off label use in the treatment of Perineural anesthesia:

  • Immediate-release perineural injection:
    • A single injection of 200–300 mcg is given along with a local anaesthetic such as bupivacaine, mepivacaine, or tetracaine, with or without epinephrine.

Buprenorphine Dose in Children

Dose in the treatment of moderate to severe Acute pain: .

  • Children 2 - 12 years:
    • Intramuscular or slow Intravenous injection:
      • Opioid-naive patients:
        • 2 - 6 mcg/kg/dose every 4 - 6 hours.
  • Adolescents:
    • Intramuscular or slow Intravenous injection:
      • Opioid-naive patients:
        • 0.3 mg every three or four times a day as needed

Use in the treatment of moderate to severe Chronic pain:

  • Transdermal patch in Adolescents 18 years of age or older:
    • Opioid-naive patients:
      • 5 mcg/hour applied once a week.

Conversion from other opioids to buprenorphine patch in Opioid-experienced patients:

(When buprenorphine therapy is initiated, all the other opioids should be discontinued).

  • Patients taking a dose of fewer than 30 mg per day of oral morphine equivalents:
    • Single weekly application of 5 mcg/hour.
  • Patients taking a dose of 30 - 80 mg of oral morphine equivalents per day:
    • Before beginning therapy, taper the current opioids for up to 7 days to 30 mg/day or less of oral morphine or an equal dose.
    • Single weekly application of 10 mcg/hour.
  • Patients taking dose of more than 80 mg of oral morphine equivalents per day:
    • Buprenorphine transdermal patches should not be utilised since even at the maximal dose of 20 mcg/hour given once per week, they may not provide sufficient analgesia.
  • Dose titration in opioid-naive or opioid-experienced patients:
    • Increase the dosage by 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour increments every third day, up to a weekly maximum dose of 20 mcg/hour (no more than two 5 mcg/hour patches).
    • A QTc prolongation risk is connected to larger doses.
  • Discontinuation of therapy:
    • To avoid the physically dependent patient experiencing withdrawal symptoms, the dose should be taken off gradually over the course of a week.

Use in the Opioid Dependence:

  • Note:
    • Buprenorphine induction shouldn't begin unless there are obvious, objective indicators of withdrawal.
    • The ideal therapy for the management of short-acting opioid dependency is a combination of buprenorphine and naloxone.
    • Once there are indications of mild to moderate opioid withdrawal, buprenorphine treatment should start.
    • For short-acting opioids like heroin and oxycodone, withdrawal symptoms often start 6–12 hours after the last dose, but for long-acting opioids like methadone, they start 24–72 hours after the last dose.

  • Induction therapy:

    • if no signs of precipitated withdrawal appear after 60 to 90 minutes, give 2 to 4 mg.
    • The dose may be raised in 2–4 mg increments up to a daily maximum of 24 mg until it is clinically effective.

According to the manufacturer's labeling:

  • Adolescents older than 16 years:
    • Induction:
      • Day 1: 8 mg
      • Day 2 and subsequent induction days: Increase every 3–4 days in increments of 2–4 mg.
    • Maintenance:
      • Target dose: 16 mg/day.

Subdermal implant:

  • Adolescents older than 16 years:
    • Subdermally place four implants on the inside side of the upper arm.
    • No later than six months following the date of implantation, the implants may be withdrawn.
    • If a patient wants to continue receiving therapy, 4 additional implants are placed subdermally on the inner side of the other arm.
    • On the day of implant removal, if the sublingual pills are to be restarted, the treatment may be started at the previous sublingual dose.

Pregnancy Risk Factor: C

  • [US Boxed Warning]
    • Pregnancy may lead to neonatal opioid withdrawal syndrome.
    • In the first week of life, neonates may experience withdrawal symptoms.
    • The neonate may experience withdrawal symptoms such as agitation and bradycardia. Convulsions, hypertonia. myoclonus, tremors and convulsions are some of the other symptoms.
    • After being exposed in pregnancy, it passes through the placenta and can be found in the serum, urine, and meconium.
    • It has not been proven that teratogenic effects can be produced.
    • It is an alternative treatment for pregnant opioid addicts.
    • Subdermal implants should not be used during pregnancy. It should also not be used to treat labor pains.
    • Buprenorphine should be taken at the same dose for those suffering from opioid dependence.
    • Buprenorphine should not be given to patients on methadone during labor.
    • Amenorrhea can occur in patients who have been addicted to substances. Buprenorphine therapy may be used to induce pregnancy. Therapy should include effective contraception.
    • Long-term opioid use in men can lead to secondary hypogonadism, which can cause infertility or sexual dysfunction.

Buprenorphine use during breastfeeding:

  • Breast milk contains buprenorphine.
  • It is not advised to breastfeed when pain management is being done (e.g., with the immediate-release injection or the subdermal patch).
  • You can use the extended-release buprenorphine and sublingual tablets during breastfeeding. However, you should be cautious about opioid addiction.
  • Breastfeeding infants should be monitored for sedation and apnea.

Buprenorphine Dose in Renal Disease:

  • The manufacturer has not advised changing the dosage, but it should still be done carefully.

Buprenorphine Dose in Liver Disease:

Buprenorphine Buccal film:

  • Mild impairment (Child-Pugh class A):
    • Adjustment in the dose is not necessary.
  • Moderate impairment (Child-Pugh class B):
    • Adjustment in the dose is not necessary, however, use it with caution and monitor the patient for signs & symptoms of toxicity and overdose.
  • Severe impairment (Child-Pugh class C):
    • Initiate with a lower dose and titrate the dose by 50% of the usual dose.

Buprenorphine Extended-release injection for Subcutaneous administration:

  • Mild impairment:
    • Adjustment in the dose is not necessary.
  • Moderate to severe impairment:
    • Avoid its use.
    • The patient needs to be watched for symptoms of poisoning. The depot may need to be removed if hepatic impairment signs and symptoms appear within two weeks of therapy.

Buprenorphine Immediate-release intramuscular or intravenous injection:

  • Mild or moderate impairment:
    • Adjustment in the dose is not necessary.
  • Severe impairment:
    • Adjustment in the dose is not necessary, however, it should be used with caution.

Buprenorphine Subdermal implant:

  • Mild impairment:
    • Adjustment in the dose is not necessary.
  • Moderate or severe impairment:
    • Avoid its use

Sublingual tablets:

  • Mild impairment:
    • Adjustment in the dose is not necessary.
  • Moderate impairment:
    • Adjustment in the dose is not necessary.
    • Use with caution and monitor the patient for clinical features of toxicity or overdose.
  • Severe impairment:
    • Initiate with a lower dose and titrate the dose by 50% of the usual dose.
    • Monitor the patient for toxicity.

Buprenorphine Transdermal patch:

  • Mild to moderate impairment:
    • Adjustment in the dose is not necessary.

Buccal film:

Common Side Effects of Buprenorphine Include:

  • Cardiovascular:
    • Hypertension
    • Peripheral Edema
  • Central Nervous System:
    • Fatigue
    • Headache
    • Dizziness
    • Drowsiness
    • Anxiety
    • Depression
    • Falling
    • Insomnia
    • Opioid Withdrawal Syndrome
  • Dermatologic:
    • Hyperhidrosis
    • Pruritus
    • Skin Rash
  • Endocrine & Metabolic:
    • Hot Flash
  • Gastrointestinal:
    • Nausea
    • Diarrhea
    • Xerostomia
    • Vomiting
    • Constipation
    • Abdominal Pain
    • Decreased Appetite
    • Gastroenteritis
  • Genitourinary:
    • Urinary Tract Infection
  • Hematologic & Oncologic:
    • Anemia
    • Bruise
  • Neuromuscular & Skeletal:
    • Back Pain
    • Muscle Spasm
  • Respiratory:
    • Upper Respiratory Tract Infection
    • Bronchitis
    • Nasopharyngitis
    • Oropharyngeal Pain
    • Paranasal Sinus Congestion
    • Sinusitis
  • Miscellaneous:
    • Fever

Subdermal Implant:

Common Side Effects Of Buprenorphine Include:

  • Central Nervous System:
    • Headache
  • Local:
    • Local Pain
    • Local Pruritus

Less Common Side Effects Of Buprenorphine Include:

  • Cardiovascular:
    • Chest Pain
  • Central Nervous System:
    • Depression
    • Dizziness
    • Pain
    • Drowsiness
    • Fatigue
    • Chills
    • Migraine
    • Paresthesia
    • Sedation
    • Sensation Of Cold
  • Dermatologic:
    • Localized Erythema
    • Skin Rash
    • Excoriation
    • Skin Lesion
  • Gastrointestinal:
    • Constipation
    • Nausea
    • Vomiting
    • Toothache
    • Upper Abdominal Pain
    • Flatulence
  • Hematologic & Oncologic:
    • Local Hemorrhage
  • Local:
    • Localized Edema
    • Local Swelling
  • Neuromuscular & Skeletal:
    • Back Pain
    • Limb Pain
    • Asthenia
  • Respiratory:
    • Oropharyngeal Pain
    • Cough
    • Dyspnea
  • Miscellaneous:
    • Fever
    • Laceration

Buprenorphine Injection:

Common Side Effects Of Buprenorphine Include:

  • Central Nervous System:
    • Sedation

Less Common Side Effects Of Buprenorphine Include:

  • Cardiovascular:
    • Hypotension
  • Central Nervous System:
    • Vertigo
    • Dizziness
    • Headache
    • Fatigue
    • Drowsiness
  • Dermatologic:
    • Injection Site Pruritus
    • Diaphoresis
  • Endocrine & Metabolic:
    • Increased Gamma-Glutamyl Transferase
  • Gastrointestinal:
    • Nausea
    • Constipation
    • Vomiting
  • Hepatic:
    • Increased Serum Aspartate Aminotransferase
    • Increased Serum Alanine Aminotransferase
  • Local:
    • Pain At Injection Site
    • Erythema At Injection Site
    • Bruising At Injection Site
    • Induration At Injection Site
    • Swelling At Injection Site
  • Neuromuscular & Skeletal:
    • Increased Creatine Phosphokinase
  • Ophthalmic:
    • Miosis
  • Respiratory:
    • Hypoventilation

Sublingual Tablet:

Common Side Effects Of Buprenorphine Include:

  • Central Nervous System:
    • Headache
    • Insomnia
  • Dermatologic:
    • Diaphoresis
  • Gastrointestinal:
    • Nausea
    • Abdominal Pain
  • Infection:
    • Infection

Less Common Side Effects Of Buprenorphine Include:

  • Gastrointestinal:
    • Constipation
    • Vomiting

Transdermal Patch:

Common Side Effects Of Buprenorphine Include:

  • Central Nervous System:
    • Dizziness
    • Headache
    • Drowsiness
  • Gastrointestinal:
    • Nausea
    • Constipation
  • Local:
    • Application-Site Pruritus

Less Common Side Effects Of Buprenorphine Include:

  • Cardiovascular:
    • Chest Pain
    • Hypertension
    • Peripheral Edema
  • Central Nervous System:
    • Fatigue
    • Insomnia
    • Anxiety
    • Depression
    • Falling
    • Hypoesthesia
    • Migraine
    • Pain
    • Paresthesia
  • Dermatologic:
    • Pruritus
    • Hyperhidrosis
    • Skin Rash
  • Gastrointestinal:
    • Vomiting
    • Xerostomia
    • Anorexia
    • Diarrhea
    • Dyspepsia
    • Upper Abdominal Pain
    • Stomach Discomfort
  • Genitourinary:
    • Urinary Tract Infection
  • Infection:
    • Influenza
  • Local:
    • Application Site Erythema
    • Application Site Rash,
    • Application Site Irritation
  • Neuromuscular & Skeletal:
    • Arthralgia
    • Asthenia
    • Back Pain
    • Joint Swelling
    • Limb Pain
    • Muscle Spasm
    • Musculoskeletal Pain
    • Myalgia
    • Neck Pain
    • Tremor
  • Respiratory:
    • Bronchitis
    • Cough
    • Dyspnea
    • Nasopharyngitis
    • Pharyngolaryngeal Pain
    • Sinusitis
    • Upper Respiratory Tract Infection
  • Miscellaneous:
    • Fever

Contraindication to Buprenorphine include:

  • Allergy reactions to buprenorphine and any component of this formulation
  • Respiratory depression
  • Acute severe asthma
  • Gastrointestinal obstruction.
  • Hypercapnia
  • Cor pulmonale
  • Acute alcoholism/alcohol dependence
  • Delirium tremens
  • Convulsive disorders
  • Severe CNS depression
  • Increased intracranial pressure
  • Head injury
  • Hepatic insufficiency severe
  • Mild pain can be managed with non-opioid pain medication
  • Obstructive airway disease
  • Status asthmaticus
  • Use within 14 days of MAOIs
  • Myasthenia gravis
  • Pregnancy and during labor
  • Breastfeeding
  • Oral mucositis (buccal films only)
  • Congenital long QT prolongation or QTc prolongation
  • Hypokalemia uncorrected
  • Hypomagnesemia
  • Hypocalcemia

Warnings and Precautions

  • CNS depression:
    • It can cause CNS depression, which may lead to impairment of mental or physical abilities.
    • The drug should be used with caution in patients who are skilled at using heavy machinery or for tasks that require mental alertness.
  • Hepatic impairment
    • It has been linked to liver toxicity and even hepatic failure.
    • Preexisting liver disease, alcoholics and drug addicts are all factors that could lead to hepatic impairment.
    • If liver dysfunction signs and symptoms are present, treatment may be stopped.
  • Hypersensitivity reactions
    • Anaphylactic shock, bronchospasm and angioneurotic swelling may all occur. However, the most common reactions are a rash and hives.
  • Hypotension
    • Hypotension can be caused by its use, manifested as syncope or orthostatic hypotension.
    • The use of medications such anaesthetics, phenothiazines, or hypovolemia in patients with cardiovascular illness, especially acute myocardial infarction (AMI), may result in hypotension.
  • Infection
    • Subdermal implant removal or insertion site infection can occur.
    • After one week, or if there are signs and symptoms that suggest infection, the site should be checked.
  • Extension of QT
    • It prolongs the QTc interval.
    • Do not exceed 900 mg per 12 hours for buccal film, or 20 mg/hour transdermal patches.
    • Patients with long QT syndrome, including those with a family history or those who are taking class IA and III antiarrhythmics concurrently, should refrain from taking buprenorphine.
    • The medication should not be used to patients with hypokalemia, hypomagnesemia, or clinically unstable cardiovascular illness (including unstable heart failure, atrial fibrillation, or active MI).
  • Respiratory depression[US Boxed Warning]
    • Keep an eye out for respiratory depression symptoms in your patient, especially during dose commencement and adjustment.
    • Buprenorphine can be used in an uncontrolled way, including chewing, injecting, or swallowing, by ingesting it from the transdermal patch or buccal film.
    • Injecting buprenorphine by yourself, especially with concomitant buprenorphine, can lead to coma or death.
    • Patients with chronic respiratory conditions such as cor pulmonale, chronic obstructive lung disease, cor pulmonale or decreased respiratory reserve should be cautious about taking the drug.
  • Conditions abdominales:
    • Patients with acute abdominal conditions may not be diagnosed or treated appropriately.
  • Adrenocortical Insufficiency
    • Patients with adrenal insufficiency (Addison disease) should be cautious.
    • Long-term opioid abuse can cause adrenal insufficiency (nausea and vomiting, anorexia and fatigue, weakness and low blood pressure), or secondary hypogonadism (Brennan 2013,). This could lead to infertility, sexual dysfunction, mood disorders and osteoporosis.
  • Insufficiency of the biliary tract:
    • Patients suffering from biliary dysfunction, including acute pancreatitis, should not take the drug. It may cause constriction in the sphincter.
  • Bowel obstruction
    • Patients who have had a history of bowel obstruction or ileus should be cautious about taking the drug.
  • Delirium tremens:
    • Patients with delirium-tremens should be advised to avoid the drug.
  • Dermatological conditions
    • Those with a history of keloid or connective tissue disease, such as scleroderma, shouldn't utilise the dermal implant.
  • Head trauma
    • It can cause an increase in intracranial pressure. Patients with intracranial injuries, intracranial lesions or elevated intracranial tension (ICP) should not use it.
    • It can also lead to miosis or changes in consciousness, which may affect patient evaluation.
  • Obesity:
    • Patients suffering from morbid obesity should be advised to take the drug with caution.
  • Oral mucositis
    • Patients with oral mucositis might be able to absorb the buccal film more quickly and have higher plasma levels.
    • Overdose should be checked and the patient should be treated with caution.
  • Prostatic hyperplasia, urinary stricture
    • Patients with prostatic hyperplasia or urinary strictures should not use it.
  • Psychosis:
    • Patients suffering from psychosis should be cautious when taking the drug.
  • Renal impairment
    • Patients with impaired renal function should be cautious when taking the drug.
  • Respiratory disease
    • Opioid analgesics should be used with caution in patients at high risk for respiratory depression.
    • These include:
      • Chronic obstructive lung disease
      • Cor-pulmonale
      • Patients with hypoxemia, hypercapnia, and preexisting respiratory depression should be notified before initiating or titrating treatment.
    • These patients may benefit from non-opioid painkillers.
  • Seizure:
    • It may cause or exacerbate a pre-existing seizure disorder. Please use with caution.
  • Sleep-disordered breathing
    • Patients with sleep-disordered breathing risk factors, such as HF or obstructive sleeping apnea, should be advised to use opioids cautiously for chronic pain.
  • Thyroid dysfunction:
    • Thyroid disease patients should be cautious when using the drug.

Buprenorphine: Drug Interaction

Risk Factor C (Monitor therapy)

Alizapride

May enhance the CNS depressant effect of CNS Depressants.

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.

Aprepitant

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Bosentan

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Brimonidine (Topical)

May enhance the CNS depressant effect of CNS Depressants.

Bromopride

May enhance the CNS depressant effect of CNS Depressants.

Cannabidiol

May enhance the CNS depressant effect of CNS Depressants.

Cannabis

May enhance the CNS depressant effect of CNS Depressants.

Chlorphenesin Carbamate

May enhance the adverse/toxic effect of CNS Depressants.

Clofazimine

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Cobicistat

May increase the serum concentration of Buprenorphine.

CYP3A4 Inducers (Moderate)

May lower the serum level of CYP3A4 substrates (High risk with Inducers).

CYP3A4 Inducers (Strong)

May lower the level of buprenorphine in the blood.

CYP3A4 Inhibitors (Moderate)

May slow down CYP3A4 substrate metabolism (High risk with Inhibitors).

CYP3A4 Inhibitors (Strong)

Buprenorphine serum concentration might rise.

Daclatasvir

May increase the serum concentration of Buprenorphine.

Deferasirox

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Desmopressin

Opioid Agonists may enhance the adverse/toxic effect of Desmopressin.

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.

Dronabinol

May enhance the CNS depressant effect of CNS Depressants.

Duvelisib

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Efavirenz

May decrease serum concentrations of the active metabolite(s) of Buprenorphine. Efavirenz may decrease the serum concentration of Buprenorphine.

Etravirine

May decrease the serum concentration of Buprenorphine.

Fosaprepitant

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Fosnetupitant

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Gastrointestinal Agents (Prokinetic)

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

Ivosidenib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Kava Kava

May enhance the adverse/toxic effect of CNS Depressants.

Larotrectinib

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Lofexidine

May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.

Magnesium Sulfate

May enhance the CNS depressant effect of CNS Depressants.

MetyroSINE

CNS Depressants may enhance the sedative effect of MetyroSINE.

Minocycline

May enhance the CNS depressant effect of CNS Depressants.

Nabilone

May enhance the CNS depressant effect of CNS Depressants.

Netupitant

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Ombitasvir, Paritaprevir, and Ritonavir

Buprenorphine serum concentration might rise.

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir

Buprenorphine serum concentration might rise.

Palbociclib

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Pegvisomant

Opioid Agonists may diminish the therapeutic effect of Pegvisomant.

Piribedil

CNS Depressants may enhance the CNS depressant effect of Piribedil.

Pramipexole

CNS Depressants may enhance the sedative effect of Pramipexole.

QT-prolonging Agents (Highest Risk)

The QTc-prolonging action of QT-prolonging Agents may be enhanced by QT-prolonging Agents (Indeterminate Risk - Avoid) (Highest Risk). When using these medications together, watch out for cardiac arrhythmias and a prolonged QTc interval. Individuals may be considerably more at risk for QTc prolongation if they have additional risk factors.

Ramosetron

Opioid Agonists may enhance the constipating effect of Ramosetron.

ROPINIRole

CNS Depressants may enhance the sedative effect of ROPINIRole.

Rotigotine

CNS Depressants may enhance the sedative effect of Rotigotine.

Rufinamide

May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced.

Sarilumab

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Selective Serotonin Reuptake Inhibitors

CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced.

Serotonin Modulators

Opioid Agonists may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline.

Siltuximab

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Simeprevir

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Succinylcholine

May enhance the bradycardic effect of Opioid Agonists.

Tetrahydrocannabinol

May enhance the CNS depressant effect of CNS Depressants.

Tetrahydrocannabinol and Cannabidiol

May enhance the CNS depressant effect of CNS Depressants.

Tocilizumab

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Risk Factor D (Consider therapy modification)

Alcohol (Ethyl)

May intensify Buprenorphine's CNS depressive effects. Treatment: Inform buprenorphine users that drinking alcohol increases their risk of CNS depression. While treating patients with opioid addiction who are also alcohol dependent, take into account alternatives to buprenorphine.

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.

Blonanserin

CNS Depressants may enhance the CNS depressant effect of Blonanserin.

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.

CNS Depressants

May enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants.

Dabrafenib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects).

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. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs.

Enzalutamide

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring.

Flunitrazepam

CNS Depressants may enhance the CNS depressant effect of Flunitrazepam.

Lorlatinib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.

Methotrimeprazine

CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established.

MiFEPRIStone

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus.

Mitotane

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane.

Nalmefene

May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of nalmefene and opioid agonists. Discontinue nalmefene 1 week prior to any anticipated use of opioid agonistss. If combined, larger doses of opioid agonists will likely be required.

Naltrexone

May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations.

Perampanel

May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination.

PHENobarbital

May enhance the CNS depressant effect of Buprenorphine. PHENobarbital may decrease the serum concentration of Buprenorphine. Management: Avoid use of buprenorphine and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased buprenorphine efficacy and withdrawal if combined.

Pitolisant

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant.

Primidone

May intensify Buprenorphine's CNS depressive effects. Buprenorphine's serum concentration may drop if you take primidone. Management: When at all feasible, refrain from using buprenorphine and primidone. Check for sedation or respiratory depression. If primidone is used with buprenorphine, keep an eye out for decreased efficacy and withdrawal because primidone is also a potent CYP3A4 inducer.

Sincalide

Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction.

Sodium Oxybate

May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated.

St John's Wort

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling.

Stiripentol

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring.

Suvorexant

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

Zolpidem

CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol.

Risk Factor X (Avoid combination)

Atazanavir

Buprenorphine may decrease the serum concentration of Atazanavir. Atazanavir may increase the serum concentration of Buprenorphine. Management: Avoid this combination in patients un-boosted atazanavir due to possible decreased atazanavir concentrations. This combination is not contraindicated in patients also receiving ritonavir, but monitoring for buprenorphine toxicity is recommended.

Azelastine (Nasal)

CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal).

Bromperidol

May enhance the CNS depressant effect of CNS Depressants.

Conivaptan

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Eluxadoline

Opioid Agonists may enhance the constipating effect of Eluxadoline.

Fusidic Acid (Systemic)

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Idelalisib

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Monoamine Oxidase Inhibitors

Buprenorphine may make monoamine oxidase inhibitors more harmful or poisonous.

Opioid Agonists

The analgesic action of opioid antagonists may be reduced by opioids (Mixed Agonist/Antiagonist). Management: If patients are given mixed agonist/antagonist opioids instead of pure opioid agonists, look for alternatives and keep an eye out for withdrawal symptoms in patients who are opioid-dependent or signs of therapeutic failure/high dose requirements.

Opioids (Mixed Agonist / Antagonist)

Buprenorphine, butorphanol, meptazinol, nalbuphine, and pentazocine are exceptions. May impair the therapeutic impact of Buprenorphine. This combination may also trigger opioid withdrawal.

Orphenadrine

The CNS depressing action of orphenadrine may be enhanced by CNS depressants.

Oxomemazine

CNS depressants may have an enhanced CNS depressant impact.

Paraldehyde

CNS Depressants may enhance the CNS depressant effect of Paraldehyde.

Thalidomide

CNS Depressants may enhance the CNS depressant effect of Thalidomide.

Monitor:

  • Pain relief
  • Respiratory and mental status
  • CNS depression especially with concomitant use of other CNS depressants
  • Blood pressure
  • Liver function tests prior to initiating therapy and during the treatment.
  • Signs of abuse, addiction, or misuse
  • Clinical features of withdrawal
  • Application site reactions in patients using the transdermal patch
  • Clinical features of hypogonadism or hypoadrenalism
  • Particularly in patients with hepatic impairment, clinical signs of toxicity or overdose
  • One week after the subdermal implant was placed, symptoms of infection or poor wound healing may appear.
  • Benefits and dangers should be assessed between one and four weeks after therapy begins and again after three months.
  • Urine drug testing should be done yearly.

How to administer Buprenorphine?

  • Intramuscular Buprenorphine:

    • Apply the immediate-release injection by deep intramuscular injection.

  • Intravenous buprenorphine

    • Slowly administer the immediate-release injection for at least 2 minutes.
    • In heroin-dependent patients hospitalized for opioid withdrawal, administration should not exceed 20-30 minutes.

  • Film:Buprenorphine Buccal

    • Use water or your tongue to wet the inside of your cheeks before putting the film.
    • Apply the buccal film as soon as the packaging is removed with a dry thumb.
    • Hold the yellow side of the film for five seconds on the inside of your wet cheek.
    • Keep the film in place until it dissolves entirely (usually within 30 mins of application).
    • After placement, it should not be chewed or swallowed.
    • Do not eat or drink until the film is gone.
    • Avoid applying it to open sores and lesions.
    • You can dispose of the film by removing the foil wrap from all unused and unneeded films.

  • Sublingual tablet:

    • Sublingually ingest the pill.
    • It must not be eaten or consumed.

  • Subcutaneous injection:

    • Use only the safety needle and syringe provided with the product to administer the extended-release injection subcutaneously.
    • Do not inject the drug intravenous.
    • Between injections, rotate the injection site.
    • The solid depot gradually releases buprenorphine through subsequent injections.
    • A lump may be noticed by the patient, which may last for several weeks.
    • You should not rub or massage the injection site.

  • Implants subdermal:

    • It is placed under local anesthesia by skilled health care professionals.

  • Transdermal patch

    • Apply the patch only to dry, clean skin.
    • Apply to a spot of dry skin.
    • Clean the area with water and let it to thoroughly dry before applying.
    • Because of the potential for enhanced skin absorption, avoid using abrasives, oils, lotions, soaps, and alcohols.
    • Use a patch that has not been cut, damaged, or otherwise modified.
    • Remove the patch right away from its protective pouch before application.
    • Take off the protective backing. Apply the sticky side to one of eight possible application locations.
      • Upper outer arm
      • Upper chest
      • Upper back
      • To either side of your chest
      • Two patches cannot be applied simultaneously at one application site.
      • Press the patch into place for approximately 15 seconds.
      • Rotate the site and change the patch every week.
      • After 21 days, the patch can be applied to the same spot.
      • If the patch is not attached, an adhesive tape can be applied to the sides.
      • It is not recommended to dispose of the patch in trash.

Mechanism of action of Buprenorphine:

  • An opioid derivative called buprenorphine is 25–40 times more effective than morphine and acts for a longer period of time.
  • It works by attaching to the central nervous system's mu opioid receptors.
  • As a mild kappa antagonist, it is also.
  • Buprenorphine acts as an antagonist and partial mu receptor agonist.
  • When the liquid extended-release formulation is injected subcutaneously, a solid depot precipitate is created. This solid depot precipitate will gradually release buprenorphine through diffusion and biodegradation.

The analgesic effect is seen in about 15 minutes and the peak effect in about one hour after an intramuscular injection. The immediate-release formulation lasts for approximately 6 hours, while the depot injection takes 28 days.

After intramuscular or subcutaneous administration, 30-40% of the immediate-release formula is absorbed. It is high protein-bound (96%), and is metabolized primarily in the liver by the enzyme CYP3A4.

Compared to the intravenous administration, the bioavailability is as follows:

  • Transdermal Patch: 15%
  • Sublingual tablet: 29%
  • Immediate-release intramuscular: 70%
  • Buccal film: 46 - 65%

The half-life elimination in different age-groups is as follows:

  • Immediate-release intravenous formulation:
    • Premature neonates: 20 ± 8 hours
    • Children 4 - 7 years: 1 hour
  • Intravenous:
    • 2.2 - 3 hours
  • Buccal film:
    • 27.6 +/- 11.2 hours
  • Sublingual tablets:
    • 37 hours
  • Transdermal patch:
    • 26 hours

The time to peak plasma concentration of the buccal film is 2.5 - 3 hours, the extended-release subcutaneous formulation is 24 hours (steady state achieved after 4 - 6 months). The time to reach peak plasma concentration after the subdermal implant is 12 hours (steady-state achieved by 4 weeks), sublingual tablets is 30 minutes to one hour, and the steady-state after the transdermal patch is achieved by day 3. It is excreted primarily via feces.    

Buprenorphine international brand names:

  • Belbuca
  • BuTrans 10
  • BuTrans 15
  • BuTrans 20
  • BuTrans 5
  • Probuphine
  • Subutex
  • Belbuca
  • Buprenex
  • Butrans
  • Probuphine Implant Kit
  • Sublocade
  • Acron
  • Addictex
  • Addnok
  • Bignanto
  • Brospina
  • Bugesic
  • Bupainx
  • Bupensan
  • Bupine
  • Buprefarm
  • Bupren
  • Buprex
  • Buprotec
  • Dorfene
  • Feliben
  • Gabup
  • Hapoctasin
  • Nalgesic
  • Norphin
  • Norspan
  • Norspan Patch
  • Norspan Tape
  • Pentorel
  • Restiva
  • Shumeifen
  • Sovenor
  • Suboxone
  • Subutex
  • Tidigesic
  • Transtec

Buprenorphine brands in Pakistan:

Buprenorphine (HCl) [Inj 0.3 mg/ml]
Benorine Brookes Pharmaceutical Laboratories (Pak.) Ltd.
Buprenwan Swan Pharmaceuticals(Pvt) Ltd
Isbup Isis Pharmaceutical
Norphine Helix Pharma (Printravenousate) Lintramuscularited

Buprenorphine (HCl) [Inj 0.324 mg/ml]
Brucipin Shifa Laboratories.(Pvt) Ltd.
Buepron Sami Pharmaceuticals (Pvt) Ltd.
Bunorfin Atco Laboratories Lintramuscularited
Bupregesic Popular Chemical Works (Pvt) Ltd.
Dorfene Pharmedic (Pvt) Ltd.
Dorgesic Dosaco Laboratories
Gesnor P.D.H. Pharmaceuticals (Pvt) Ltd.
Medibunor Medicraft Pharmaceuticals (Pvt) Ltd.
Opinor Global Pharmaceuticals
Orgesic Obs
Prenor Amson Vaccines & Pharma (Pvt) Ltd.
Prenor Amson Vaccines & Pharma (Pvt) Ltd.
Temfin Ceicil Laboratories Ltd.
Temgesic Reckitt Benckiser Pakistan Ltd.
Zonor Pharmatec Pakistan (Pvt) Ltd.

Buprenorphine (HCl) [Tabs 0.2 mg]
Bepnor Panacea Pharmaceuticals
Brucipin Shifa Laboratories.(Pvt) Ltd.
Bunorfin Atco Laboratories Lintramuscularited
Buper Rakaposhi Pharmaceutical (Pvt) Ltd.
Bupredan Danas Pharmaceuticals (Pvt) Ltd
Bupri-U Unintravenousersal Pharmaceuticals (Pvt) Ltd
Gesic Unexo Labs (Pvt) Ltd.
Mommi Xenon Pharmaceuticals (Pvt) Ltd.
Norphine Helix Pharma (Printravenousate) Lintramuscularited
Opinor Global Pharmaceuticals
Prozem Valor Pharmaceuticals
Rukgasee Reko Pharmacal (Pvt) Ltd.
Temgesic Sublingual Reckitt Benckiser Pakistan Ltd.
Temgo Aries Pharmaceuticals (Pvt) Ltd
Zonor Pharmatec Pakistan (Pvt) Ltd.
Zurofin Plintravenousa Pakistan (Pvt) Lintramuscularited

Buprenorphine (HCl) [Tabs 216 mg]
Segesic Saydon Pharmaceutical Industries (Pvt) Ltd.

Buprenorphine (HCl) [Tabs 400 mg]
Semoxin Semos Pharmaceuticals (Pvt) Ltd.

Buprenorphine (HCl) [Tabs 0.216 mg]
Oproniex Wilshire Laboratories (Pvt) Ltd.
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