Buprenorphine

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

Buprenorphine is a partial opioid agonist used for management of severe pain that is not responsive to alternative treatments. Also used for maintenance treatment of opioid addiction.

Buprenorphine is Rapidly absorbed (approximately 40-90%) following IM admin; readily absorbed (approximately 55%) following sublingual administration. Absolute bioavailability of approximately 15% (transdermal). Time taken to reach to peak plasma concentration is 90 min for sublingual and approximately 60 hours for transdermal. Buprenorphine is highly lipophilic, and therefore extensively distributed, with rapid penetration through the blood-brain barrier. The estimated volume of distribution is 188 - 335 L when given intravenously. Buprenorphine is approximately 96% protein bound. Buprenorphine Undergoes hepatic metabolism via oxidation by CYP3A4 isoenzyme to the pharmacologically active metabolite N-dealkylbuprenorphine (norbuprenorphine) and via conjugation to glucuronide metabolites. It is primarily eliminated via feces (as free forms of buprenorphine and norbuprenorphine) while 10 - 30% of the dose is excreted in urine (as conjugated forms of buprenorphine and norbuprenorphine).

Buprenorphine shows side effects like Dizziness and Drowsiness, Headache, Difficulty in breathing, Nausea and vomiting, Itching, redness or irritation at application site, Anxiety and nervousness, Watery eyes, Back pain, Irregular heartbeat, Decreased blood pressure.

Buprenorphine is available in the form of Injectable solution, sublingual tablets, transdermal film, extended release, subcutaneous solution, buccal film.

Buprenorphine is available in India, US, UK, UK, China, Europe and Australia, Canada, France, Singapore, Germany.

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

Buprenorphine is a partial agonist at the mu receptor, meaning that it only partially activates opiate receptors. It is also a weak kappa receptor antagonist and delta receptor agonist. It is a potent analgesic that acts on the central nervous system (CNS). The partial agonism at the mu receptor is a unique quality of buprenorphine.

The effect of Buprenorphine can be observed within 15 minutes after intramuscular administration and 1 hour after intravenous administration of the dose.

The effect of Buprenorphine lasts for an average duration of 6 hours after intramuscular administration of the dose.

Buprenorphine is available in the form of Injectable solution, sublingual tablets, transdermal film, extended release, subcutaneous solution, buccal film.

Buprenorphine Injectable solution is given via intravenous and intramuscular route, tablets and buccal film are taken sublingually and transdermal film applied on skin to different site.

Buprenorphine is used in the treatment of severe opioid responsive pain conditions in patients who have not adequately responded to non-opioid analgesics. It is also be used to treat opioid dependence or opioid addiction and prevent the withdrawal symptoms that patients may experience when opioid medications are stopped.

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

Buprenorphine, a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor.

Buprenorphine is approved for use in the following clinical indications

• Buprenorphine is indicated for the treatment of opioid dependence and is preferred for induction.
• Buprenorphine should be used as part of a complete treatment plan to include counseling and psychosocial support.

• Moderate to severe pain

Adult Sublingual Dose: 200-400 mcg repeated 6-8 hourly as needed.

Adult Parenteral Dose: 300-600 mcg by IM or slow IV inj repeated 6-8 hourly if needed.

Adult Transdermal Dose:

Non-malignant pain: Initial: 5 mcg/hour. Replace patch every 7 days and apply new patch to a different site. Avoid using the same area of the skin for the next 3-4 wk.

Cancer pain: Initial: Opioid-naive patient: 35 mcg/hour; patient receiving a strong opioid analgesic: Base dose on previous 24-hr opioid requirement. Replace patch every 96 hr at the latest and apply new patch to a different site. Avoid using the same area of the skin for at least the next 2 applications.

Child Sublingual Dose: 6-12 years 16-25 kg: 100 mcg; >25-37.5 kg: 100-200 mcg; >37.5-50 kg: 200-300 mcg. Doses to be given 6-8 hourly.

Child Parenteral Dose: 6 months to 12 years 3-6 mcg/kg 6-8 hourly. Refractory cases: Up to 9 mcg/kg.

• Premedication before anesthesia

Adult Sublingual Dose: 400 mcg.

Adult Parenteral Dose: 300mcg.

• Opioid dependence

Adult Sublingual Dose: Initially, 0.8-4 mg once daily, may increase as necessary. Maintenance: ≤32 mg daily. Once the patient is stabilised, gradually reduce dose and may stop treatment if appropriate. Opioid-dependent addicts who have not undergone withdrawal: 1st dose should not be given until 1st signs of craving appear or until at least 6 hours after last opioid use. Patients receiving methadone: Reduce methadone dose to max 30 mg daily before starting therapy.

Child Sublingual Dose: ≥16 yr Same as adult dose.

Buprenorphine is available in various strengths as 0.3 mg/mL; 2 mg; 8 mg; 7.5 mcg/hr; 5 mcg/hr; 10 mcg/hr; 15 mcg/hr; 20 mcg/hr; 100 mg/0.5 mL; 300 mg/1.5 mL; 74.2 mg; 8 mg/0.16 mL; 16 mg/0.32 mL; 24 mg/0.48 mL; 128 mg/0.36 mL; 32 mg/0.64 mL; 64 mg/0.18 mL; 96 mg/0.27 mL; 75 mcg; 150 mcg; 300 mcg; 450 mcg; 600 mcg; 750 mcg; 900 mcg.

Buprenorphine is available in the form of Injectable solution, sublingual tablets, transdermal film, extended release, subcutaneous solution, buccal film.

• Dosage Adjustment in Kidney Patient

No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine.

• Dosage Adjustment in Hepatic impairment Patient

For patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.

Avoid grapefruit products. Grapefruit inhibits the metabolism of buprenorphine through CYP3A4, which increases the serum levels buprenorphine.

Buprenorphine is contraindicated in patients with

• Buprenorphine is contraindicated in patients with a history of hypersensitivity to buprenorphine, as serious adverse reactions, including anaphylactic shock, have been reported.

• Accidental opioid overdose: Patients who had been treated with buprenorphine may respond to lower opioid doses than previously used. This could result in potentially life-threatening opioid intoxication. Patients should be aware that they may be more sensitive to lower doses of opioids after treatment with buprenorphine, after a missed dose, or near the end of the dosing interval.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• Hepatic events: Hepatitis has been reported; hepatic events ranged from transient, asymptomatic transaminase elevations to hepatic failure; in many cases, patients had preexisting hepatic impairment. Remove buprenorphine subdermal implant if signs and symptoms of buprenorphine toxicity develop concurrent with hepatic impairment. If signs and symptoms of toxicity or overdose occur within 2 weeks of extended-release injection (Sublocade), removal of the depot may be required.
• Hypersensitivity reactions: Hypersensitivity, including bronchospasm, angioneurotic edema, and anaphylactic shock, have been reported. The most common symptoms include rash, hives, and pruritus.
• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute myocardial infarction [MI]), or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.
• Infection: Subdermal implant: Infection may occur at site of insertion or removal, with excessive palpation shortly after insertion and improper removal increasing the risk.
• QT prolongation: Buprenorphine has been observed to cause QTc prolongation. Do not exceed a dose of 900 mcg every 12 hours buccal film or one 20 mcg/hour transdermal patch. Avoid using in patients with a personal or family history of long QT syndrome or in patients taking concurrent class IA or III antiarrhythmics or other medications that prolong the QT interval. Use with caution in patients with hypokalemia, hypomagnesemia, or clinically unstable cardiac disease, including unstable heart failure, unstable atrial fibrillation, symptomatic bradycardia, or active MI.
• Respiratory depression: Buccal film, ER and IR injection, transdermal patch: Serious, life-threatening, or fatal respiratory depression may occur. Misuse by self-injection of buprenorphine or the concomitant use of buprenorphine and benzodiazepines (or other CNS depressants, including alcohol) may result in coma or death. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. If the ER injection is discontinued due to respiratory depression, monitor the patient for ongoing respiratory depression for several months due to its ER characteristics (Sublocade) or for ~1 month for weekly Brixadi and ~4 months for monthly Brixadi. Patients and caregivers should be educated on how to recognize respiratory depression and the importance of getting emergency assistance immediately in the event of a known or suspected overdose.
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause adrenal insufficiency (nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low BP) or secondary hypogonadism, which may lead to mood disorders and osteoporosis.
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; opioids may cause constriction of sphincter of Oddi.
• Bowel obstruction: Use with caution in patients with a history of ileus or bowel obstruction; buccal film, IR injection, and transdermal patch are contraindicated in patients with known or suspected GI obstruction, including paralytic ileus.
• CNS depression/coma: Avoid use in patients with impaired consciousness or coma because these patients are susceptible to intracranial effects of CO₂ retention.
• Delirium tremens: Use with caution in patients with delirium tremens.
• Dermatological conditions: Subdermal implant: Use subdermal implants with caution in patients with a history of keloid formation, connective tissue disease (ie, scleroderma), or history of recurrent MRSA infections.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.
• Hepatic impairment: Use buccal film and sublingual tablet with caution in patients with moderate hepatic impairment; dosage adjustment recommended in severe hepatic impairment. Use IR injection with caution in patients with severe impairment. Subdermal implants should not be used in patients with preexisting moderate to severe hepatic impairment. Transdermal patch should not be used in patients with severe hepatic impairment; consider alternative therapy with more flexibility for dosing adjustments. Patients with preexisting moderate or severe hepatic impairment are not candidates for the ER injection. If moderate or severe hepatic impairment develops during treatment with the ER injection, continue with caution and monitor for toxicity for several months.
• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, posttraumatic stress disorder) due to potential increased risk for opioid use disorder and overdose; more frequent monitoring is recommended.
• Obesity: Use with caution in patients who are morbidly obese.
• Oral mucositis: Buccal film: Oral mucositis may lead to more rapid absorption and higher buprenorphine plasma levels; reduce dose in patients with oral mucositis and monitor closely for signs and symptoms of toxicity or overdose.
• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.
• Psychosis: Use with caution in patients with toxic psychosis.
• Renal impairment: Use with caution in patients with renal impairment.
• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.
• Seizure: Use with caution in patients with a history of seizure disorders; may cause or exacerbate preexisting seizures.
• Sleep-related disorders: Use with caution in patients with sleep-related disorders, including sleep apnea, due to increased risk for respiratory and CNS depression. Monitor carefully and titrate dosage cautiously in patients with mild sleep-disordered breathing. Avoid opioids in patients with moderate to severe sleep-disordered breathing.
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
• Benzodiazepines and other CNS depressants: Concomitant use may result in respiratory depression and sedation, which may be fatal. Consider prescribing naloxone for emergency treatment of opioid overdose in patients taking benzodiazepines or other CNS depressants concomitantly with opioids.

Consumption of alcohol is not recommended during treatment with buprenorphine due to the increased risk of side effects such as dizziness, lightheadedness, and fainting. It is advised that you do not perform any activities that require high mental alertness such as driving a vehicle or operating machinery if you consume alcohol during treatment with buprenorphine.

Buprenorphine can pass into breast milk and may cause drowsiness and breathing problems in a nursing baby.

If you use buprenorphine while you are pregnant, your baby could become dependent on the drug. This can cause life-threatening withdrawal symptoms in the baby after it is born. Babies born dependent on habit-forming medicine may need medical treatment for several weeks.

Avoid grapefruit products. Grapefruit inhibits the metabolism of buprenorphine through CYP3A4, which increases the serum levels buprenorphine.

Common

CNS depression, including somnolence, dizziness, alterations in judgment and levels of consciousness, including coma; sedation, dizziness, sweating, vertigo, headache; nausea, vomiting, dry mouth, constipation, dyspepsia, abdominal cramps, flatulence, diaphoresis; rash, urticaria, pruritus; miosis, blurred vision, hallucinations, and other psychotomimetic effects; hypotension leading to syncope, HTN, tachycardia, bradycardia, ECG abnormalities.

• Benzodiazepines or other Central Nervous System (CNS) Depressants

Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.

• Inhibitors of CYP3A4

The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Buprenorphine is achieved.

• CYP3A4 Inducers

The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine, potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine.

• Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delavirdine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.

• Antiretrovirals: Protease inhibitors (PIs)

Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir concomitantly with and without ritonavir.

• Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)

Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.

• Serotonergic Drugs

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.

• Monoamine Oxidase Inhibitors (MAOIs)

MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

• Muscle Relaxants

Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

• Diuretics

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone

• Anticholinergic Drugs

The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

The common side effects of Buprenorphine include the following

Common side effects

Dizziness and Drowsiness, Headache, Difficulty in breathing, Nausea and vomiting, Itching, redness or irritation at the application site, Anxiety and nervousness, Watery eyes, Back pain, Irregular heartbeat, and Decreased blood pressure.

• Pregnancy

Pregnancy Category C

The data on the use of buprenorphine, the active ingredient in Buprenorphine, in pregnancy, is limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. There are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations. Observational studies have reported on congenital malformations among buprenorphine-exposed pregnancies but were also not designed appropriately to assess the risk of congenital malformations specifically due to buprenorphine exposure.

• Nursing Mothers

Advise breastfeeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties.

• Pediatric Use

The safety and effectiveness of Buprenorphine has not been established in pediatric patients.

• Geriatric Use

Due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe Buprenorphine should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose.

Symptoms: Respiratory depression, sedation, somnolence, nausea, vomiting, CV collapse, and marked miosis.

Management: Supportive treatment. May use naloxone or resp stimulants if appropriate.

• Pharmacodynamic

Buprenorphine interacts predominately with the opioid mu-receptor. These mu-binding sites are discreetly distributed in the human brain, spinal cord, and other tissues. In clinical settings, buprenorphine exerts its principal pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation. In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Buprenorphine depresses the respiratory centers, depresses the cough reflex, and constricts the pupils.

• Pharmacokinetics

Absorption

Buprenorphine is Rapidly absorbed (approximately 40-90%) following IM admin; readily absorbed (approximately 55%) following sublingual administration. Absolute bioavailability of approximately 15% (transdermal). Time taken to reach to peak plasma concentration is 90 min for sublingual and approximately 60 hours for transdermal.

Distribution

Buprenorphine is highly lipophilic, and therefore extensively distributed, with rapid penetration through the blood-brain barrier. The estimated volume of distribution is 188 - 335 L when given intravenously. Buprenorphine is approximately 96% protein-bound.

Metabolism and Excretion

Buprenorphine Undergoes hepatic metabolism via oxidation by CYP3A4 isoenzyme to the pharmacologically active metabolite N-dealkylbuprenorphine (norbuprenorphine) and via conjugation to glucuronide metabolites. It is primarily eliminated via feces (as free forms of buprenorphine and norbuprenorphine) while 10 - 30% of the dose is excreted in urine (as conjugated forms of buprenorphine and norbuprenorphine).

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