buprenorphine, long-acting injection

Action and Spectrum

Actions and Spectrum: 

Mechanism of Action 

• buprenorphine is a partial opioid agonist, which binds to and activates opioid receptors in the brain but with less intensity than full opioid agonists like heroin or oxycodone. It has a high affinity for the mu-opioid receptors, which are responsible for the analgesic and euphoric effects of opioids. However, buprenorphine also acts as an antagonist at these receptors, blocking the effects of other opioids. 
• The partial agonist properties of buprenorphine produce a dual mechanism of action. It relieves opioid withdrawal symptoms and cravings by partially activating the opioid receptors. Simultaneously, its antagonist activity prevents the full activation of these receptors by other opioids, thereby blocking their effects and reducing the potential for misuse and overdose. 

Spectrum of Activity 

buprenorphine has a broad spectrum of activity, primarily in managing opioid dependence and chronic pain. Some critical aspects of its spectrum of activity include: 

• Opioid Dependence Treatment: buprenorphine is used as a substitution therapy for individuals with opioid dependence, including addiction to heroin or prescription opioids. It helps to suppress withdrawal symptoms and cravings, allowing individuals to transition from full agonist opioids to a more stable state of opioid dependence or to taper off opioids entirely eventually. 
• Maintenance Therapy: buprenorphine can be prescribed as a maintenance therapy for opioid dependence over the long term. It helps to stabilize individuals, reduces the risk of relapse, and improves overall treatment outcomes. 
• Pain Management: buprenorphine is also utilized for chronic pain management, mainly when other opioids may not be suitable or practical. It can provide analgesia while minimizing the risk of respiratory depression and other adverse effects associated with full opioid agonists. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Sublocade 

Injection site reactions (5.3-11.6%)  

1 to 10% 

Brixadi 

Constipation (7.5%) 

Nausea (7%) 

Injection site pruritus (6.1%) 

Urinary tract infection (5.2%) 

Upper respiratory tract infection (4.2%) 

Injection site pain (9.9%) 

Headache (7.5%) 

Injection site erythema (6.6%) 

Insomnia (5.6%) 

Injection site swelling (4.7%) 

Injection site reaction (4.2%)  

Sublocade 

Constipation (8-9.4%) 

Nausea (8-8.9%) 

CPK increased (2.5-5.4%) 

Somnolence (2-4.9%) 

Headache (8.5-9.4%) 

Vomiting (5.5-9.4%) 

Fatigue (3.9-6%) 

ALT increased (1-5%) 

AST increased (3.4-4.5%)  

Post-marketing reports 

Anaphylaxis 

Injection site necrosis 

Adrenal insufficiency with use >1 month 

Androgen deficiency with long-term opioid use 

Black Box Warning

Black box warning: 

• Serious Harm or Death with IV Administration: buprenorphine long-acting injection should never be administered intravenously (IV). Intravenous administration can lead to severe harm or even death. The drug can solidify upon contact with body fluids, causing blockages, tissue damage, and potentially life-threatening blood clot events, including pulmonary emboli. 
• Long-Acting Delivery and Depot: The long-acting delivery of buprenorphine is achieved through biodegradable depots. These depots are designed to release buprenorphine at a controlled rate over a specific duration, usually two weeks or one month, depending on the formulation. 
• Sublocade REMS Program: To mitigate the risk of IV self-administration and ensure the safe use of buprenorphine long-acting injection, a Risk Evaluation and Mitigation Strategy (REMS) program called Sublocade REMS exists. This program restricts access to the medication and involves certification for healthcare settings and pharmacies that order and dispense the injection. 

Contraindication / Caution

Contraindications/caution: 

Contraindications: 

• Hypersensitivity: buprenorphine long-acting injection is contraindicated in individuals with known hypersensitivity or allergy to buprenorphine or any of the components of the formulation. Allergic reactions can range from mild to severe and may include symptoms such as rash, itching, swelling, dizziness, or difficulty breathing. 
• Significant Respiratory Depression: buprenorphine is a potent opioid agonist and can cause significant respiratory depression. Therefore, buprenorphine long-acting injection is contraindicated in individuals with severe respiratory insufficiency, acute or severe bronchial asthma, or hypercapnia (increased carbon dioxide levels in the blood). 
• Acute or Severe Hepatic Impairment: buprenorphine is metabolized by the liver, and hepatic impairment can affect its clearance and increase the risk of adverse effects. Thus, buprenorphine long-acting injection is contraindicated in individuals with acute or severe hepatic impairment. 
• Paralytic Ileus: buprenorphine can cause gastrointestinal motility disturbances, including paralytic ileus, a condition characterized by the inability of the intestine to propel its contents forward. buprenorphine long-acting injection is contraindicated in individuals with known or suspected gastrointestinal obstruction, including paralytic ileus. 

Caution: 

• Dependence and withdrawal: buprenorphine itself is an opioid, and the use of long-acting buprenorphine can lead to dependence. Abrupt discontinuation or rapid tapering of buprenorphine can result in withdrawal symptoms.  
• Abuse Potential and Addiction: buprenorphine is a Schedule III controlled substance with a potential for abuse and addiction. Caution is required when prescribing buprenorphine long-acting injections to individuals with a history of substance abuse or addiction, as they may be at increased risk of misusing or diverting the medication. 
• Central Nervous System (CNS) Depression: buprenorphine can cause CNS depression, resulting in sedation, dizziness, and impaired cognitive and physical abilities. Caution should be exercised when using buprenorphine long-acting injection in individuals taking other CNS depressants, such as benzodiazepines, alcohol, or other opioids, as it can potentiate the depressant effects. 
• Respiratory Depression: buprenorphine can cause respiratory depression, particularly in opioid-naive individuals with compromised respiratory function or taking other respiratory depressants. Close monitoring of respiratory function is necessary, especially during initiation and dose adjustments. 
• Hepatic impairment: buprenorphine is metabolized by the liver, and caution is advised when using buprenorphine long-acting injection in individuals with mild to moderate hepatic impairment. Dose adjustments may be necessary, and close monitoring is recommended. buprenorphine long-acting injection is contraindicated in individuals with acute or severe hepatic impairment. 
• Injection Site Reactions: buprenorphine long-acting injection is administered subcutaneously, and injection site reactions, including pain, pruritus, erythema, swelling, or nodule formation, may occur. Proper administration techniques and regular assessment of injection sites are necessary to minimize potential complications. 
• Pediatric and Geriatric Use: The safety and efficacy of buprenorphine long-acting injections have not been well established in pediatric and geriatric populations. When considering its use in these populations, caution and individualized dosing should be exercised. 

Pregnancy / Lactation

Pregnancy consideration: Insufficient data available 

Lactation: Excretion of the drug in human breast milk is known in low quantities 

Pregnancy category: 

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

buprenorphine long-acting injection, such as Sublocade or Buvidal, exhibits pharmacological properties consistent with buprenorphine, the active ingredient. Here are the critical pharmacological aspects of buprenorphine: 

• Opioid Receptor Interaction: buprenorphine is a partial opioid agonist, meaning it binds to and activates the opioid receptors in the brain, predominantly the mu-opioid receptors. However, it has a lower intrinsic activity than full agonists like heroin or oxycodone. This property allows buprenorphine to produce analgesic and euphoric effects but with a diminished potential for abuse and respiratory depression. 
• Partial Agonist/Antagonist Activity: buprenorphine acts as a partial agonist at the mu-opioid receptors, producing a ceiling effect. This means that beyond a specific dose, increasing the dosage does not result in a proportional increase in opioid effects. buprenorphine also acts as an antagonist at the same receptors, displacing and blocking the effects of other opioids. This aggressive action helps prevent the full activation of opioid receptors by other opioids, reducing the potential for misuse and overdose. 

Pharmacodynamics: 

• Respiratory Depression: buprenorphine has a lower risk of respiratory depression compared to full opioid agonists. It produces less respiratory depression due to its partial agonist activity and ceiling effect. However, it is essential to note that respiratory depression can still occur, especially at higher doses or when used with other central nervous system depressants. 
• Analgesic Effects: buprenorphine provides analgesia by acting on the mu-opioid receptors in the central nervous system. Its analgesic properties make it helpful in managing chronic pain, particularly in situations where full opioid agonists may be associated with higher risks or adverse effects. 

Pharmacokinetics: 

Absorption 

buprenorphine long-acting injection is administered via subcutaneous (SC) injection, which allows for the slow and controlled release of buprenorphine over an extended period. The injected formulation forms a biodegradable depot, gradually releasing the drug into the surrounding tissues. From the injection site, buprenorphine is absorbed into the bloodstream, providing sustained therapeutic levels over weeks. 

Distribution 

buprenorphine has high protein binding (approximately 96%) to plasma proteins, primarily albumin. The bound portion of buprenorphine is not pharmacologically active. The unbound (free) fraction is responsible for the drug’s therapeutic effects. Buprenorphine distributes widely throughout the body, crossing the blood-brain barrier, and is found in various tissues. 

Metabolism 

buprenorphine undergoes extensive metabolism, primarily in the liver. It is primarily metabolized by hepatic enzymes, such as cytochrome P450 3A4 (CYP3A4), to norbuprenorphine, an active metabolite with lower potency. Other minor metabolic pathways include glucuronidation, leading to the formation of buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide. These metabolites are primarily inactive or exhibit fragile opioid activity. 

Elimination and Excretion 

buprenorphine and its metabolites are excreted mainly through feces and urine. Approximately 30% of the dose is excreted in the urine, primarily as conjugated metabolites, while the remaining percentage is eliminated through feces. The elimination half-life of buprenorphine is relatively long, ranging from 20 to 73 hours, contributing to its extended duration of action. 

Adminstartion

Administration: 

The general guidelines for the administration of buprenorphine long-acting injection: 

• Certified Healthcare Provider: buprenorphine long-acting injection should only be administered by a certified healthcare provider who has completed the necessary training and is authorized to perform the injection. The certification is part of the Risk Evaluation and Mitigation Strategy (REMS) program for buprenorphine long-acting injection. 
• Injection Site: The injection is typically administered in the abdominal area, either in the abdominal wall’s subcutaneous tissue or on the lateral side of the abdomen. Other suitable injection sites may include the upper arm or the lateral thigh. 
• Preparation: The buprenorphine long-acting injection is supplied as a prefilled syringe or delivery system. The healthcare provider should carefully inspect the syringe or device for any visible particles or discoloration. If any abnormalities are noted, the injection should not be used. 
• Injection Technique: The following steps are generally involved in the administration of buprenorphine long-acting injection: 

1. Clean the injection site with an appropriate antiseptic solution. 
2. Allow the injection site to dry before proceeding. 
3. Use an aseptic technique while handling the injection and related materials.
4. Remove the needle cap or safety device from the prefilled syringe or device. 
5. Pinch the skin at the injection site to create a fold. 
6. Insert the needle into the subcutaneous tissue at a 45 to 90-degree angle, depending on the depth of the subcutaneous tissue.
7. Inject the medication slowly and steadily, applying gentle pressure on the plunger. 
8. Once the injection is complete, remove the needle from the injection site. 
9. i. If necessary, apply gentle pressure to the injection site with a sterile gauze pad.

• Post-Injection Care: The healthcare provider should discard the used syringe or device in an appropriate sharps container after the injection. Proper disposal procedures should be followed to ensure safety. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: buprenorphine, long-acting injection 

Why do we use buprenorphine, long-acting injection? 

buprenorphine long-acting injection is primarily used for the treatment of opioid dependence and, in some cases, for the management of chronic pain. The primary uses of buprenorphine long-acting injection: 

• Opioid Dependence Treatment: buprenorphine long-acting injection is indicated for the maintenance treatment of opioid dependence in adults. It is part of a comprehensive treatment program with counseling and psychosocial support. The injection provides a sustained release of buprenorphine over an extended period, helping to reduce withdrawal symptoms, cravings, and the risk of relapse. 
• Opioid Detoxification: buprenorphine long-acting injection may also be used for the detoxification phase of opioid dependence treatment. It can help ease the transition from full opioid agonists to buprenorphine by providing a gradual withdrawal and stabilization process. It supports the management of withdrawal symptoms and reduces the discomfort associated with opioid cessation. 
• Chronic Pain Management: In some cases, buprenorphine long-acting injection may be used to manage chronic pain. buprenorphine’s unique pharmacological profile, including its partial agonist activity and ceiling effect, allows for analgesic effects while minimizing the risk of respiratory depression and other adverse effects associated with full opioid agonists.