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 dependence in patients who have achieved and sustained prolonged clinical stability on low to moderate doses (of transmucosal buprenorphine) for 3 months or longer.
For the management of severe pain that requires long term round the clock opioid treatment (for which alternative treatment options are not adequate)
Off Label Use of Buprenorphine in Adults include:
- For the treatment of Opioid withdrawal in heroin-dependent hospitalized patients
- 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:
- 0.3 mg Intramuscular or as a slow intravenous injection every 6 - 8 hours as needed
- The dose may be repeated every half to one hour if needed.

Use in the treatment of moderate to severe Chronic pain:

Buccal film:

Opioid-naive patients and opioid-non-tolerant patients:
- 75 mcg once a day or every 12 hours (if tolerated) for at least 4 days, then increase the dose to 150 mcg every 12 hours.

Conversion from other opioids to buprenorphine:

With the initiation of buprenorphine treatment, other round-the-clock opioids should be discontinued.
The patient's current opioids should be tapered to no more than 30 mg oral morphine sulfate equivalents daily.
Patients who were receiving a daily dose of less than 30 mg of oral morphine equivalents:
- 75 mcg once a day or every 12 hours
Patients who were receiving a daily dose of 30 - 89 mg of oral morphine equivalents:
- 150 mcg every 12 hours
Patients who were receiving a daily dose of 90 - 160 mg of oral morphine equivalents:
- 300 mcg every 12 hours
Patients who were receiving a daily dose of more than 160 mg of oral morphine equivalents:
- Consider the use of alternative analgesia as buprenorphine buccal film may not provide adequate analgesia.

Conversion from methadone:

Dose titration in opioid-naive or opioid-experienced patients:
- Individually titrate in increments of 150 mcg twice daily to a dose that provides adequate analgesia and minimizes adverse reactions.
- The dose should be titrated to no more than every 4th day.
- The maximum dose should not exceed 900 mcg twice daily.
Discontinuation of therapy:
- Abrupt discontinuation should be avoided.
- Gradual titration prevents withdrawal symptoms.
- Patients with oral mucositis should receive half the dose.

The Transdermal patch:

Opioid-naive patients:
- 5 mcg/hour applied once every 7 days

conversion from other opioids to buprenorphine:

All other around-the-clock opioid drugs should be discontinued when buprenorphine therapy is initiated.
Short-acting analgesics may be needed
Patients already receiving opioids may experience withdrawal symptoms.
Patients who were receiving a daily dose of less than 30 mg of oral morphine equivalents:
- 5 mcg/hour applied once every week
Patients who were receiving a daily dose of 30 - 80 mg of oral morphine equivalents:
- The opioid dose used as around-the-clock should be tapered to 30 mg/day or less for a week before initiating therapy.
- 10 mcg/hour applied once every week.
Patients who were receiving a daily dose of more than 80 mg of oral morphine equivalents:
- Alternative analgesics should be used as buprenorphine transdermal patch may not provide adequate analgesia even at the maximum dose of 20 mcg/hour applied weekly.
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:
- Taper the dose gradually every week to prevent withdrawal in the physically dependent patient.
- Treatment initiation with immediate-release opioids may be considered.

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

Immediate-release injection:
- 0.3 - 0.9 mg diluted in 50 to 100 mL of 0.9% saline infused intravenously over 20 - 30 minutes every 6 - 12 hours.

Use in the treatment of Opioid Dependence:

Extended-release injection:
- 300 mg subQ monthly for the first two months ( after treatment has been adjusted with 8 - 24 mg of a transmucosal buprenorphine-containing product for a minimum of one week).
- This is followed by a maintenance dose of 100 mg every month.
- The dose may be further increased to 300 mg monthly for patients who tolerate the 100 mg dose but do not demonstrate a satisfactory clinical response.
Subdermal implant:
- Insert 4 implants subdermally in the inner side of the upper arm.
- It should not be removed earlier than 6 months after the date of insertion.
- In case, the treatment is to be continued, 4 new implants may be inserted subdermally in the inner side of the contralateral arm.
Converting back to sublingual tablet:
- Sublingual buprenorphine treatment may be resumed at the previous sublingual doses on the day of implant removal.
Sublingual tablet:
- An induction dose of 2 - 4 mg.
- The dose may be increased in increments of 2 - 4 mg if no signs of precipitated withdrawal occur after 60 - 90 minutes.
- Buprenorphine treatment should begin after signs of mild to moderate opioid withdrawal appear.
- Withdrawal symptoms generally occur at least 6 - 12 hours after last use of short-acting opioids like heroin and oxycodone, and 24 - 72 hours after last use of long-acting opioids like methadone.
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:
- 200 - 300 mcg added to the local anesthetic like bupivacaine, mepivacaine, Tetracaine with or without epinephrine and administered as a single injection.

Buprenorphine Dose in Childrens

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 who were receiving a dose of fewer than 30 mg per day of oral morphine equivalents:
- 5 mcg/hour applied once a week.
Patients who were receiving a dose of 30 - 80 mg of oral morphine equivalents per day:
- Taper the current opioids for up to 7 days to 30 mg/day or less of oral morphine or equivalent before initiating therapy.
- 10 mcg/hour applied once a week.
Patients who were receiving a dose of more than 80 mg of oral morphine equivalents per day:
- Alternative preparations should be used as buprenorphine transdermal patch may not provide adequate analgesia even at the maximum dose of 20 mcg/hour applied once weekly.
Dose titration in opioid-naive or opioid-experienced patients:
- Titrate the dose in increments of 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour every 3rd day to a maximum dose of 20 mcg/hour applied every week (not more than two 5 mcg/hour patches)
- There is a risk of QTc prolongation associated with higher doses.
Discontinuation of therapy:
- The dose should be gradually tapered off weekly to prevent withdrawal symptoms in the physically dependent patient.

Use in the Opioid Dependence:

Note:
- Induction with buprenorphine should not be started until objective and clear signs of withdrawal are apparent.
- Buprenorphine and naloxone in combination is the preferred therapy over buprenorphine monotherapy for the treatment of short-acting opioid dependence.
- Buprenorphine treatment should begin after signs of mild to moderate opioid withdrawal appear.
- Withdrawal symptoms generally occur at least 6 - 12 hours after last use of short-acting opioids like heroin and oxycodone, and 24 - 72 hours after last use of long-acting opioids like methadone.

Induction therapy:
- 2 - 4 mg if no signs of precipitated withdrawal after 60 - 90 minutes.
- The dose may be increased in increments of 2 - 4 mg to a dose that is clinically effective to a maximum dose of 24 mg/day.

According to the manufacturer's labeling:

Adolescents older than 16 years:
- 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.

Subdermal implant:

Adolescents older than 16 years:
- Insert four implants subdermally in the inner side of the upper arm.
- The implants may be removed no later than 6 months after the date of insertion.
- Patients who desire continued treatment, insert 4 new implants subdermally in the inner side of the opposite arm.
- In case the sublingual tablets are to be resumed, treatment may be resumed at the previous sublingual dose on the day of implant removal.

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 in utero exposure, it crosses the placental barriers and can be detected in 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:

Adjustment in the dose has not been recommended by the manufacturer, however, it should be used with caution.

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 should be monitored for features suggestive of toxicity. If signs and symptoms of hepatic impairment are noted within two weeks of therapy, removal of the depot may be required.

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.
- Hypovolemia in patients with cardiovascular disease, including acute Myocardial Infarction (AMI), or the use of drugs such as anesthetics, phenothiazines, may cause 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.
- Buprenorphine should be avoided by patients with long QT syndrome, including those who have a family history or are taking concurrent class IA and III antiarrhythmics.
- Hypokalemia, hypomagnesemia or clinically unstable cardiovascular disease (including unstable hearts failure, atrial fibrillation or active MI) should not receive the drug.
Respiratory depression[US Boxed Warning]
- Severe, life-threatening respiratory depression can occur. Monitor your patient for signs of respiratory depression, particularly during dose adjustment and initiation.
- Buprenorphine can be ingested from the buccal film or transdermal patch and used in an uncontrolled manner, such as chewing, injecting, or swallowing.
- 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
- The dermal implant should not be used by patients who have a history of keloid or connective tissue disease such as scleroderma.
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 decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
CYP3A4 Inducers (Strong)	May decrease the serum concentration of Buprenorphine.
CYP3A4 Inhibitors (Moderate)	May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors).
CYP3A4 Inhibitors (Strong)	May increase the serum concentration of Buprenorphine.
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	May increase the serum concentration of Buprenorphine.
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir	May increase the serum concentration of Buprenorphine.
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)	QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
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 enhance the CNS depressant effect of Buprenorphine. Management: Advise patients receiving buprenorphine about the increased risk of CNS depression if they consume alcohol. Consider alternatives to buprenorphine for opioid addiction treatment in patients who are dependent on alcohol.
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 enhance the CNS depressant effect of Buprenorphine. Primidone may decrease the serum concentration of Buprenorphine. Management: Avoid use of buprenorphine and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased buprenorphine eﬃcacy and withdrawal if combined.
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 enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors.
Opioid Agonists	Opioids (Mixed Agonist / Antagonist) may diminish the analgesic effect of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Exceptions: Buprenorphine; Butorphanol; Meptazinol; Nalbuphine; Pentazocine.
Opioids (Mixed Agonist / Antagonist)	May diminish the therapeutic effect of Buprenorphine. This combination may also induce opioid withdrawal.
Orphenadrine	CNS Depressants may enhance the CNS depressant effect of Orphenadrine.
Oxomemazine	May enhance the CNS depressant effect of CNS Depressants.
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
Clinical features of toxicity or overdose especially in patients with hepatic impairment
Signs suggestive of infection or problems with wound healing one week after insertion of the subdermal implant.
Benefits and risks should be evaluated at one to four weeks of initiation of treatment and then at three months interval.
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
- Before applying the film, moisten the inside of your cheeks with water or tongue.
- After removing the packaging, apply the buccal film immediately with a dry thumb.
- Hold the yellow side of your film on the inside of your moistened cheek for five seconds.
- The film should be kept in place until it is completely dissolved (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:
- Place the tablet under your tongue
- It should not be swallowed or chewed.
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
- Only apply the patch to clean, dry skin.
- Apply to a dry area of skin.
- Before you apply, clean the site with water and let it dry completely.
- Avoid using soaps, alcohols, oils, lotions or abrasives because of the possibility of increased skin absorption.
- Use a patch that has been damaged, cut, or otherwise altered in no way.
- Before applying, remove the patch immediately from its protective pouch.
- 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:

Buprenorphine is an opioid derivative that is 25 - 40 times more potent and has a longer duration of action than morphine.
It acts by binding to the mu opioid receptors in central nervous system. It is also a weak kappa antagonist.
Buprenorphine acts as an antagonist and partial mu receptor agonist.
Subcutaneous injections of the extended-release formulation as a liquid form a solid depot precipitate that will slowly 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