Probuphine

Opioid Use Disorder Treatment

Probuphine is used to treat opioid dependence, which includes addiction to prescription pain medications or illegal opioids like heroin. It is intended for use as part of a complete treatment program that includes counseling and psychosocial support. The medication works by providing a steady level of buprenorphine to help suppress withdrawal symptoms and reduce cravings.

Maintenance and Stability

This medication is specifically for patients who are already in a stable phase of recovery. It is not used to start treatment or for patients who are still actively using opioids. To be eligible for Probuphine, patients must have achieved and sustained clinical stability on low-to-moderate doses of other buprenorphine products, such as sublingual tablets or films.

Long-Term Delivery

Probuphine consists of small implants placed under the skin, usually in the upper arm. This delivery method is used to provide continuous medication for six months. It may be prescribed for patients who prefer a long-term option over daily dosing or for those who have difficulty adhering to a daily medication schedule.

How Buprenorphine Works

Probuphine contains buprenorphine, which is a partial opioid agonist. This means it binds to the same receptors in the brain as other opioids, such as heroin or prescription painkillers, but it does not activate them as strongly. By occupying these receptors, the medication helps the body in several ways:

• Reducing Cravings: It satisfies the brain's physical need for opioids, which helps decrease the urge to use other substances.
• Easing Withdrawal: It provides enough stimulation to the receptors to prevent or significantly lessen the physical symptoms of withdrawal.
• Blocking Effects: Because buprenorphine sticks tightly to the brain's receptors, it can block other opioids from attaching. This can prevent a person from feeling the "high" of other opioids if they are used during treatment.

The Ceiling Effect

Buprenorphine has a "ceiling effect," meaning that its effects do not continue to increase after a certain dose is reached. This makes it less likely to cause dangerous respiratory depression (slowed breathing) compared to full opioids.

Continuous Delivery System

Probuphine is unique because it is an implant that releases a constant, low level of medication into the bloodstream for six months. This steady delivery avoids the daily peaks and valleys in medication levels that can occur with oral or sublingual treatments, helping to maintain a stable state in the brain and body.

Common Side Effects

Many people using Probuphine experience mild side effects. These often include:

• Pain, itching, swelling, or redness at the site of the implant
• Headache
• Nausea, vomiting, or constipation
• Dizziness or drowsiness
• Tooth decay or other dental problems

Serious Side Effects

Seek medical attention immediately if you experience any of the following serious symptoms:

• Respiratory depression: Slow, shallow, or difficult breathing.
• Severe allergic reactions: Hives, swelling of the face, lips, or tongue, or difficulty swallowing.
• Liver problems: Dark urine, light-colored stools, or yellowing of the skin and eyes.
• Implant site complications: Numbness or weakness in the arm, or if the implant migrates or pokes through the skin.
• Adrenal insufficiency: Extreme tiredness, muscle weakness, or loss of appetite.
• Serotonin syndrome: Agitation, hallucinations, fever, or shivering (usually when taken with certain other medications).

Boxed Warning: Insertion and Removal Risks

The surgical procedures required to insert and remove Probuphine implants are associated with risks of serious complications. These include nerve injury, migration of the implant, protrusion through the skin, or accidental expulsion. Because of these risks, Probuphine is only available through a restricted distribution program called the Probuphine REMS Program. Only healthcare providers who have been certified in the program may perform the insertion and removal procedures.

Respiratory and Central Nervous System Depression

Buprenorphine can cause severe, life-threatening breathing problems. This risk is significantly increased if the medication is used in combination with alcohol, benzodiazepines, or other central nervous system depressants. Monitoring for signs of slowed or shallow breathing is essential, especially during the initial period after insertion.

Liver Health

Cases of moderate to severe liver injury have been reported in individuals using buprenorphine. Healthcare providers typically perform blood tests to check liver function before starting treatment and continue to monitor liver health periodically while the implants are in place.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of buprenorphine during pregnancy can lead to neonatal opioid withdrawal syndrome in the newborn. This condition may be life-threatening if not recognized and treated according to protocols developed by neonatology experts.

Additional Precautions

• Adrenal Insufficiency: Chronic use of opioids may lead to adrenal insufficiency, a condition where the adrenal glands do not produce enough cortisol. Symptoms may include nausea, vomiting, dizziness, and fatigue.
• Allergic Reactions: Severe hypersensitivity reactions, including anaphylaxis and swelling of the face or throat (angioedema), have been reported.
• Heart Rhythm Changes: Buprenorphine may cause QT prolongation, which affects the heart's electrical cycle. This risk is higher in individuals with certain pre-existing heart conditions or those taking other medications that affect heart rhythm.
• Abuse and Misuse: As a Schedule III controlled substance, buprenorphine carries risks of addiction, abuse, and misuse.

Pregnancy

Limited data are available regarding the use of buprenorphine implants specifically during pregnancy. However, prolonged use of buprenorphine during pregnancy can cause neonatal opioid withdrawal syndrome (NOWS). This is a condition where the newborn experiences withdrawal symptoms such as irritability, tremors, and difficulty feeding. NOWS is treatable but requires medical management in a hospital setting.

Healthcare providers often consider the risks of untreated opioid use disorder, which can also harm the fetus, when deciding whether to continue buprenorphine treatment during pregnancy. It is important to discuss the risks and benefits of treatment with a healthcare professional.

Breastfeeding

Buprenorphine passes into breast milk in small amounts. While many individuals continue treatment while breastfeeding, it is important to monitor the infant for signs of excessive sleepiness or breathing difficulties. If these symptoms occur, seek medical help immediately.

The decision to breastfeed while using Probuphine should be made in consultation with a doctor to ensure the safety of the baby and the health of the parent.

Dosage Forms

Probuphine is supplied as a small, rod-shaped implant. It is designed for subdermal insertion, where it is placed under the skin of the upper arm by a healthcare provider.

• Subdermal implant

FDA Approval and Indication

The FDA approved Probuphine in 2016 as the first subdermal implant for the maintenance treatment of opioid dependence. It is specifically indicated for patients who have achieved clinical stability on a daily dose of 8 mg or less of oral or sublingual buprenorphine.

Boxed Warning

Probuphine carries a boxed warning due to risks associated with the surgical procedures required for its insertion and removal. Potential complications include:

• Nerve damage or injury to the arm where the implant is placed.
• Migration of the implant, which could lead to embolism if it enters the bloodstream.
• Protrusion or accidental expulsion of the implant.

REMS Program

Because of the risks associated with the insertion and removal process, Probuphine is only available through a restricted distribution program called the Probuphine REMS (Risk Evaluation and Mitigation Strategy) Program. Healthcare providers who prescribe, insert, or remove the implants must complete specific training and certification.

Controlled Substance Status

Buprenorphine, the active ingredient in Probuphine, is classified as a Schedule III controlled substance. This classification is due to its potential for abuse and the risk of physical or psychological dependence.

Safety Communications

The FDA has issued communications urging healthcare providers to use caution when considering withholding opioid addiction medications from patients who are also taking benzodiazepines or other central nervous system depressants. While combined use increases the risk of serious side effects, the FDA notes that the benefits of continuing addiction treatment often outweigh these risks.

Withdrawal Symptoms

Stopping Probuphine or removing the implants can cause opioid withdrawal. Because the medication stays in your system for some time, withdrawal symptoms may not start right away. Symptoms often include:

• Nausea, vomiting, or diarrhea
• Muscle aches and joint pain
• Anxiety, irritability, or sleep problems
• Sweating, chills, or goosebumps
• Runny nose or watery eyes

Discontinuing Treatment

The implants provide a steady dose of buprenorphine for six months. If they are removed and not replaced with another form of treatment, withdrawal is likely. Healthcare providers usually monitor patients closely after removal to manage any physical or psychological symptoms that arise.

Neonatal Withdrawal

Long-term use of buprenorphine during pregnancy can lead to neonatal opioid withdrawal syndrome in the newborn. This requires medical management shortly after birth to address symptoms such as irritability, abnormal sleep patterns, and tremors.