Continuing Education Activity

Buprenorphine is a synthetic opioid developed in the late 1960s and is used to treat pain and opioid use disorder. This drug is a synthetic analog of thebaine—an alkaloid compound derived from the poppy flower. Buprenorphine is categorized as a Schedule III drug, which means it has a moderate-to-low potential for physical dependence or a high potential for psychological dependence. Buprenorphine is approved by the U.S. Food and Drug Administration (FDA) to treat acute and chronic pain and opioid dependence. This drug is used in agonist substitution treatment—a method for addressing addiction by substituting a more potent full agonist opioid, such as heroin, with a less potent opioid, such as buprenorphine or methadone. The substitute substance is then gradually tapered down by the prescriber, allowing the patient to withdraw from the opiate addiction with minimal discomfort. This activity reviews the FDA-approved indications, mechanism of action, administration, adverse event profile, toxicity, and management of buprenorphine therapy, pertinent for members of the interprofessional healthcare team involved in the treatment of patients with opioid misuse.

Objectives:

• Identify appropriate candidates for buprenorphine therapy based on a comprehensive assessment of opioid use disorders and patient history.

• Implement evidence-based buprenorphine treatment regimens, considering dosing, administration routes, and patient-specific factors.

• Select appropriate evidence-based treatment, adjunctive therapies, behavioral interventions, or counseling services to enhance the effectiveness of buprenorphine treatment.

• Collaborate with pharmacists, nurses, and other interprofessional healthcare professionals to ensure comprehensive and coordinated patient care on buprenorphine therapy.

Indications

Buprenorphine is a synthetic opioid developed in the late 1960s and is used to treat pain and opioid use disorders (OUDs). This drug is a synthetic analog of thebaine—an alkaloid compound derived from the poppy flower. Buprenorphine is categorized as a Schedule III drug, which means it has a moderate-to-low potential for physical dependence or a high potential for psychological dependence.[1][2][3][4][5]

FDA-Approved Indications

Buprenorphine is approved by the U.S. Food and Drug Administration (FDA) to treat acute and chronic pain and opioid dependence. This drug is used in agonist substitution treatment—a method for addressing addiction by substituting a more potent full agonist opioid, such as heroin, with a less potent opioid, such as buprenorphine or methadone. The substitute substance is then gradually tapered down by the prescriber, allowing the patient to withdraw from the opiate addiction with minimal discomfort.

Buprenorphine substitute treatment enables patients to focus on therapy rather than enduring uncomfortable withdrawals. The drug proves to be an effective choice for addressing opioid dependence by diminishing cravings and enhancing the overall quality of life during addiction treatment. By mitigating many distressing symptoms associated with opioid withdrawal, this approach facilitates the development of treatment plans that patients are more likely to adhere to, thereby reducing both morbidity and mortality rates.

Off-Label Uses

The off-label use of buprenorphine is limited to injection and includes perineural anesthesia, as well as withdrawal management in hospitalized patients dependent on heroin.[6][7]

Additional Uses of Buprenorphine

Buprenorphine shows promise in treating various addiction disorders beyond its established uses. Ongoing research is exploring a novel experimental formulation that combines buprenorphine and naltrexone, specifically examining its potential role in addressing cocaine addiction.[8] Naltrexone functions as an antagonist for mu- and kappa-opioid receptors. When combined with buprenorphine, naltrexone selectively activates kappa receptors without stimulating the opioid receptors. In theory, this combination is designed to reduce compulsive cocaine use without leading to opioid addiction.

The Drug Addiction Treatment Act (DATA) of 2016 allows physicians to provide office-based treatment for opioid addiction, as outlined by the Drug Enforcement Administration (DEA) in 2018. This federal legislation permits physicians the authority to prescribe Schedule III, IV, or V "narcotic" medications approved by the FDA, for patients dealing with opioid addiction. In 2002, the FDA approved both buprenorphine and a combination of buprenorphine-naloxone for the management of opioid dependence.[9]

Indications

• For the management of opioid-dependent patients with a contraindication to methadone.

• Methadone facilities and healthcare providers are currently unavailable, and there exists a waitlist exceeding 3 months for enrollment in a methadone clinic.

• For patients dependent on opioids who are intolerant to or have experienced treatment failure with methadone.

• Buprenorphine may also be beneficial for individuals with a brief history of opioid dependence and/or lower requirements for opioid agonists.

Federal Regulations for Buprenorphine Prescribing

Sublingual buprenorphine preparations are beneficial in the treatment of opioid dependence, including substances such as heroin, oxycodone, hydrocodone, and morphine. The utilization of buprenorphine as a replacement in opioid dependence management is subject to strict regulations and rigorous monitoring.

The Drug Addiction Treatment Act of 2000

Before January 2023, clinicians were required to obtain a DATA waiver, commonly known as an X-waiver, to prescribe buprenorphine for treating OUDs. This prerequisite was established under DATA 2000 to ensure clinicians had the necessary training and qualifications to prescribe buprenorphine for OUD treatment.[10][11][12] However, following the enactment of the Consolidated Appropriations Act of 2023, the X-waiver requirement was eliminated. This change enables clinicians with Schedule III authority on their DEA registration to prescribe buprenorphine for the treatment of OUD without the necessity of a DATA waiver. This change is intended to increase access to buprenorphine treatment for individuals with OUD and to address the ongoing opioid epidemic in the United States. However, clinicians are still required to have the appropriate authorization under applicable state law to prescribe buprenorphine for OUD treatment.

The Mainstreaming Addiction Treatment Act

The Mainstreaming Addiction Treatment (MAT) Act provision updates federal guidelines to expand the availability of evidence-based treatment to address the opioid epidemic. The MAT Act empowers all healthcare providers with a standard controlled substance license to prescribe buprenorphine for OUD, aligning it with the prescription of other essential medications. The MAT Act aims to destigmatize the standard of care for OUD and facilitate the integration of substance use disorder (SUD) treatment throughout healthcare settings. 

As of December 2022, the MAT Act has eliminated the DATA-waiver (X-waiver) program. All practitioners registered with the DEA and possessing Schedule III authority are now permitted to prescribe buprenorphine for OUD within their practice, contingent upon compliance with applicable state law, and SAMHSA encourages their active involvement. Prescribers previously registered as DATA-waiver prescribers will automatically receive a new DEA registration certificate reflecting this alteration, requiring no additional action on their part.

Currently, there are no restrictions on the number of patients with OUD that a provider may treat using buprenorphine. In addition, there is no longer a mandate for separate tracking of patients treated with buprenorphine or prescriptions written. Pharmacy staff is authorized to fill buprenorphine prescriptions using the prescribing authority's DEA number without requiring a DATA 2000 waiver from the prescriber. Notably, depending on the pharmacy, the dispensing software may still necessitate the X-waiver information for processing. Practitioners must still comply with applicable state limits regarding treating patients with OUD. Contact information for State Opioid Treatment Authorities can be found at https://www.samhsa.gov/medicationassisted-treatment/sota.

The Medication Access and Training Expansion Act

Although MAT effectively addresses OUD, numerous individuals still encounter obstacles in accessing this form of care. The Medication Access and Training Expansion (MATE) Act seeks to address these barriers by increasing the number of healthcare providers trained to provide MAT and reducing certain regulatory impediments. This is a one-time SUD CME requirement for DEA prescribers. Physicians board-certified in addiction medicine or addiction psychiatry are considered to have already satisfied this training requirement.

Mechanism of Action

Buprenorphine is a partial agonist at the mu receptor, which means it partially activates mu-opiate receptors. The drug also acts as a weak kappa receptor antagonist and delta receptor agonist. Buprenorphine is a potent analgesic acting on the central nervous system (CNS), which possesses a distinctive quality with its partial agonism at the mu receptor. This unique characteristic imparts several notable properties, including the plateauing of its analgesic effects at higher doses, where its effects transition into an antagonistic mode. Buprenorphine exhibits ceiling effects on respiratory depression, signifying its safety superiority over methadone in the context of agonist substitution treatment for addiction.[13]

Buprenorphine exhibits high-affinity binding to the mu-opioid receptors and slow-dissociation kinetics. In this way, it differs from other full-opioid agonists such as morphine and fentanyl, which results in milder and less uncomfortable withdrawal symptoms for the patient.

Pharmacokinetics

Absorption: When administered orally, buprenorphine experiences poor bioavailability due to the first-pass effect, where the liver and intestine extensively metabolize the drug. The preferred route of administration is sublingual, as it ensures rapid absorption and circumvents the first-pass effect. Placing the tablet under the tongue results in a slow onset of action, with the peak effect occurring approximately 3 to 4 hours after administration.

Distribution: Buprenorphine is highly lipophilic; therefore, it is extensively distributed and rapidly penetrates the blood-brain barrier. The drug's estimated volume of distribution is 188 to 335 L following IV administration. Buprenorphine is approximately 96% protein-bound. 

Metabolism: Buprenorphine undergoes metabolism by cytochrome CYP3A4 enzymes after it enters the body and forms an active metabolite, norbuprenorphine, with weak intrinsic activity. The average half-life of buprenorphine is approximately 38 hours, which ranges from 25 to 70 hours after sublingual administration. Substances that strongly inhibit the CYP3A4 enzyme can elevate buprenorphine levels, while inducers of this enzyme may lead to decreased levels.

Excretion: Most of the drug and its metabolite are eliminated through fecal excretion, with less than 20% excreted by the kidneys. Due to its slow onset of action and extended duration, buprenorphine proves effective in the treatment of opioid dependence. Once a patient has stabilized on a daily dose, prescribing buprenorphine on alternate days may be considered. Urine toxicology tests for patients taking buprenorphine often measure norbuprenorphine levels, which are highly concentrated in urine. This helps confirm patients are not manipulating tests by adding buprenorphine directly.[14]

Administration

Available Dosage Forms and Strengths

Buprenorphine can be administered through various methods. A transdermal patch is an option for chronic pain relief. In addition, there are buccal film and sublingual tablet formulations for oral administration. Parenteral routes include subdermal or subcutaneous implants and intravenous (IV) or intramuscular (IM) injections.

Oral formulations include buccal films and sublingual tablets, available in 2 mg and 8 mg strengths. The sublingual formula, widely used in treating opioid addiction, consists of buprenorphine and naloxone in a ratio of 4:1. Buprenorphine is available in sublingual formulations of 2 mg and 8 mg combined with naloxone at 0.5 mg and 2 mg respectively, to discourage misuse through injection. The drug formulation dissolves within 2 to 10 minutes when placed under the tongue.

Buprenorphine is also available in a sublingual tablet formulation combined with naloxone. As naloxone, an opioid antagonist, is not absorbed orally, the predominant effect is derived from buprenorphine when the combination drug is taken sublingually. Naloxone is added to buprenorphine to reduce the potential for its misuse when injected. If the tablet is dissolved and injected in an IV form, the absorbed naloxone blocks mu receptors, counteracting the euphoric effects of buprenorphine and potentially inducing withdrawal in opioid-dependent patients. Buprenorphine alone carries a higher potential for misuse compared to the buprenorphine-naloxone combination.[15][16][17]

The buccal film is available in various strengths for chronic pain relief, including 75 mcg, 150 mcg, 300 mcg, 450 mcg, 600 mcg, 750 mcg, and 900 mcg. An extended-release weekly transdermal patch is offered in strengths of 5 mcg/h, 7.5 mcg/h, 10 mcg/h, 15 mcg/h, and 20 mcg/h.

Parenteral routes, such as subdermal or subcutaneous implants and IM injections, are not commonly used. Buprenorphine is offered in various parenteral formulations, including a 0.3 mg/mL injection solution for IM use, a 100 mg/0.5 mL extended-release subcutaneous injection, and a 300 mg/1.5 mL extended-release subcutaneous injection. IV administration is not FDA-approved for managing opioid dependence except in exceptional circumstances and with proper authorization. Otherwise, IV use may be considered illegal.

Opioid Use Disorder 

When reducing, discontinuing, or tapering long-term opioid therapy, it is important to reduce the dose gradually. There is no established optimal tapering schedule, and the tapering should be individualized through discussions with the patient to minimize withdrawal symptoms. Factors such as the opioid's pharmacokinetics and the patient's goals should be considered during this personalized tapering approach. Recommended initial tapering schedules vary, ranging from a gradual 10% reduction weekly or monthly to a more accelerated 25% to 50% decrease every few days.

During the tapering process, patients may face an elevated risk of overdose if they revert to their original (or higher) opioid dose or resort to illicit opioids. Therefore, it is recommended to prescribe naloxone and vigilantly monitor for signs and symptoms of withdrawal. If a patient exhibits withdrawal symptoms, healthcare providers should contemplate slowing the taper schedule and incorporating adjunctive agents as necessary. Nonopioid analgesics should continue to be offered for pain management during the tapering process.[18]

Induction therapy: Induction therapy with buprenorphine is initiated when patients experience mild-to-moderate symptoms of opioid withdrawal. Typically, treatment is commenced 12 hours after using short-acting opioids or heroin or at least 24 hours or longer after using a long-acting opioid, for instance, morphine or oxycodone controlled-release formulations.[19] For patients using the fentanyl patch, it is advisable to wait at least 48 to 72 hours after discontinuation before initiating treatment.

• Naltrexone to buprenorphine: Transitioning from naltrexone to buprenorphine involves initiating buprenorphine approximately 1 day after the last oral naltrexone dose and around 28 days after the last IM naltrexone dose.

• Methadone to buprenorphine: For methadone maintenance patients opting for a switch to buprenorphine, it is recommended to wait typically for 24 to 48 hours or more after the last dose of methadone before initiating treatment. The methadone dose should be gradually tapered down to less than 30 mg and maintained for at least 7 days or longer before initiating buprenorphine treatment. This tapering strategy helps mitigate the risk of precipitating intense withdrawal symptoms.

During this period, the patient undergoes monitoring for withdrawal symptoms. Various tools, such as the Clinical Opiate Withdrawal Scale, can assist in evaluating the presence and intensity of withdrawal symptoms. For the symptomatic management of withdrawal symptoms, additional doses of buprenorphine may be required. Upon the patient's discharge, the induction can be rescheduled for the following day after the symptoms have subsided. Patients should be encouraged to abstain from opioids while at home.

According to the American Society of Addiction Medicine (ASAM), the recommended morphine milligram equivalents (MME) for chronic pain management cannot serve as a reference for drugs used in treating OUDs.[19] The recommendation is to use buprenorphine for managing opioid withdrawal instead of abruptly discontinuing opioid use. Suddenly stopping opioids may result in intense cravings and acute withdrawal, which can increase the risk of relapse, overdose, and death due to overdose.

Initial dosing: For the initial treatment dose of buprenorphine or naloxone, it is recommended to start at the lowest dose and gradually titrate every week until a response is observed. The minimum duration of treatment is 8 weeks. The patient should receive education on the potential for overdose, unintended dosing by others, diversion, and the consequences of careless storage.

Sublingual Tablet

Initial dosing: The recommended initial dose for buprenorphine or naloxone sublingual preparation for the treatment of OUD is typically between 2 mg and 4 mg. In patients with a history of OUD and a high risk of relapse but who are not currently dependent on opioids, an initial dose of 1 mg may be considered. Titration should proceed much more slowly in these patients than in opioid-tolerant individuals to prevent oversedation or overdose.

After the initial dose of buprenorphine, if no signs of precipitated withdrawal are observed after 1 to 2 hours and the dose is well-tolerated, it may be increased in increments of 2 mg to 4 mg. The objective of titration is to identify the lowest effective dose that ensures 24 hours of stabilization, aiming to reduce the risk of relapse and enhance treatment outcomes. The rate of titration may vary based on the patient's individual needs and the clinician's clinical judgment, emphasizing the importance of proceeding cautiously to avoid oversedation or overdose.

Maintenance dosage: The maintenance dosage during this phase involves gradually increasing the dose of buprenorphine based on the patient's physical and psychological needs. However, the dosage should not exceed a maximum of 24 mg/d.[20] According to ASAM, the efficacy of doses exceeding 24 mg/d is not well-established, and higher doses may increase the likelihood of diversion. Most patients typically respond well to doses ranging between 8 and 12 mg/d. The maintenance dose can be attained for most patients within 2 to 4 days. Once stabilized, the dosing frequency may be reduced, especially in reliable patients or those needing travel. Some patients may benefit from alternate dosing by doubling the dose at each visit.

Discontinuation of treatment: Discontinuation of sublingual buprenorphine should involve a gradual downward titration of the dose over several months to prevent withdrawal symptoms and avoid abrupt discontinuation.

Extended Release Injection (Subcutaneous)

Initial dosing: For initial dosing, a 300-mg extended-release injection is administered subcutaneously every month with intervals of at least 26 days for the first 2 months. This is done after the treatment has been inducted and titrated with 8 to 24 mg of sublingual buprenorphine product for at least 7 days. When transitioning from long-term buprenorphine transmucosal treatment (doses of 8 to 18 mg), the dose for the second month can be 100 mg or 300 mg as per clinical need.

Maintenance dosage: Maintenance dosage involves the administration of 100 mg extended-release injection monthly at intervals of at least 26 days. If patients tolerate the 100-mg dose but fail to exhibit a satisfactory clinical response, as indicated by self-reported use of illicit opioids or positive urine drug screenings for illicit opioids, the dosage may be escalated to 300 mg per month.

Patients with Pain

Although buprenorphine is classified as an opioid, it exhibits only partial analgesic activity at the mu-opioid receptor. Buprenorphine has limited use as an analgesic due to 2 primary reasons—it functions solely as a partial agonist and exhibits a ceiling effect. Buprenorphine tightly binds to the mu receptors, impeding the binding of full agonists at the mu receptor. Consequently, for patients managing pain with buprenorphine, alternative analgesic options such as nonsteroidal anti-inflammatory drugs are considered. If the patient is on a low dose of buprenorphine (2 mg to 8 mg), it can be increased to up to 24 mg daily. Alternative options for managing pain include regional anesthesia and nerve blocks. According to the Centers for Disease Control and Prevention (CDC) Practice Guidelines for prescribing opioids for pain (2022), treatment options for neuropathic pain include tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors (SNRIs), selected anticonvulsants (pregabalin, gabapentin, and oxcarbazepine), capsaicin, and lidocaine patches.[18]

Specific Patient Populations

Renal impairment: In patients with renal impairment, the dose of buprenorphine does not require alteration.[21][22] However, in individuals with liver dysfunction, the dose must be modified to prevent toxicity.[14][23][24]

Hepatic impairment: In individuals with hepatic impairment, including those with common comorbid conditions such as hepatitis B and C in opioid-dependent patients, vaccinations for hepatitis A and hepatitis B are recommended for seronegative patients, according to ASAM.[19] In addition, in patients with liver dysfunction, the dose of buprenorphine has to be modified to prevent toxicity.[14][23][24] As buprenorphine metabolism takes place in the liver, individuals with liver impairment should undergo close monitoring of their liver function and drug levels. Clinicians should caution patients with hepatitis about the correlation between IV use of buprenorphine and hepatotoxicity.[25]

For buccal film and sublingual tablets in patients with severe impairment (Child-Pugh class C), it is advisable to reduce the dose by 50% and closely monitor for signs and symptoms of toxicity. Subcutaneous injections are not recommended. If any liver impairment is diagnosed within 2 weeks of the depot injection, removal of the depot may be necessary. Manufacturers do not provide dosage adjustments for immediate-release injection solutions and transdermal patches.

Pediatric patients: For pediatric patients, using unit-dose packaging for all buprenorphine products is essential to prevent unintended exposure among young children. Adolescents should be provided with information on the risks of substance use and misuse, considering that suspected suicide accounted for 12% of adolescent exposures. Ensuring access to mental health services for this age group is crucial in addressing this issue.[26]

Older patients: Limited data exist on the use of buprenorphine in older patients. As geriatric patients may experience altered absorption, distribution, and metabolism, clinicians should exercise caution when prescribing buprenorphine to this population. In addition, the potential for drug interactions is heightened due to polypharmacy.

HIV-positive patients: Opioid addiction is a common comorbidity in HIV patients.[27] Although highly active antiretroviral therapy (HAART) can prolong life and improve the quality of life, the treatment of opioid dependency remains necessary. In one study, researchers found that buprenorphine-treated patients were more compliant with HAART compared to untreated patients, but the drug does not alter the effectiveness of HAART.

Due to the impact of many HAART drugs on liver microsomal enzymes, healthcare providers should closely monitor liver function and drug levels in patients prescribed buprenorphine simultaneously. In certain patients, buprenorphine dosages may need adjustments.

Pregnancy considerations: Exposure of infants to opioids in utero can lead to withdrawal symptoms after birth, known as neonatal abstinence syndrome (NAS). Buprenorphine is classified as an FDA pregnancy category C drug for use during pregnancy, indicating that the risk of adverse effects on the fetus cannot be ruled out.

Medication-assisted treatment (MAT), including opioid treatment programs (OTPs), is a combined therapeutic approach that integrates behavioral therapy and medications to address SUDs. Substantial evidence supports the positive impact of methadone maintenance on maternal and newborn outcomes in pregnant opioid-dependent patients. Similarly, evidence suggests that buprenorphine maintenance may also enhance fetal and maternal outcomes, potentially resulting in less intense NAS compared to methadone treatment.

Buprenorphine is categorized as an FDA pregnancy category C drug for use during pregnancy, whereas methadone holds an FDA pregnancy category B classification for pregnant patients. Buprenorphine crosses the placenta, and opioid use during pregnancy can cause neonatal withdrawal symptoms shortly after birth. Neonatal symptoms may encompass tremors, fever, irritability, sleep disturbances, tachypnea, excessive or high-pitched crying, heightened muscle tone, hyperreflexia, seizures, yawning, stuffy nose, sneezing, poor feeding, sucking, slow weight gain, vomiting, diarrhea, dehydration, and sweating.

Withdrawal symptoms in a neonate, resulting from maternal buprenorphine use during pregnancy, may manifest between the first and eighth day of life (Nguyen et al., 2018). The Substance Abuse and Mental Health Administration (SAMHSA) has provided the following recommendations:

• Women should be apprised that the impact of intrauterine exposure to methadone, buprenorphine, or buprenorphine-naloxone on ongoing infant development remains uncertain. Clinicians should additionally convey to their patients that the advantages of pharmacotherapy for OUD outweigh the risks.

• To date, evidence indicating that buprenorphine or methadone results in increased congenital disabilities does not exist, and their impact on neurological development is minimal.

• Experts do not unanimously agree on whether a woman in early pregnancy or expressing an intention to become pregnant with OUD should transition from a buprenorphine-naloxone combination to buprenorphine alone. Any decision to switch from the combination to the buprenorphine-only product should be made on a case-by-case basis, with the woman's full informed consent.

• Increasing evidence prevails that the combination product does not adversely affect newborn outcomes. The decision should be collaborative between the clinician and the patient, considering the balance between benefits and risks.

Breastfeeding considerations: Although research indicates that buprenorphine passes into breast milk, due to its low bioavailability, the extent to which it enters the systemic circulation in the breastfed infant is not well established. A few case reports indicate that buprenorphine does not suppress NAS, and the syndrome may not develop even after discontinuation of breastfeeding. Although the manufacturers of buprenorphine advise against using buprenorphine in breastfeeding women, limited evidence to date suggests that buprenorphine appears to be safe, and discontinuation of the medication may not be necessary. Infants should be observed for drowsiness and respiratory depression.[28]

Adverse Effects

Buprenorphine exerts some anticholinergic-like effects and may cause CNS depression, hypotension, QT prolongation, and lower seizure threshold. Additional adverse effects of buprenorphine include nausea, vomiting, drowsiness, dizziness, headache, memory loss, sweating, dry mouth, miosis, orthostatic hypotension, sexual adverse effects, and urinary retention.

Following buprenorphine treatment, a patient's tolerance to opioids may diminish, posing a potential risk if they resume their previous opioid dosage. Therefore, patients must recognize their heightened sensitivity to low opioid doses and promptly inform their healthcare provider of any unusual symptoms. Moreover, patients should be strongly advised against using opioids without prior consultation with their healthcare provider.

Patients should be cautioned about engaging in activities requiring mental alertness, such as operating machinery or driving, as buprenorphine may cause CNS depression.

Hepatitis and liver impairment, ranging from transient, asymptomatic transaminase elevations to liver failure, may occur, particularly in patients with preexisting hepatic impairment.[25] 

Hypersensitivity reactions have been reported, ranging from rash, hives, pruritus, and bronchospasm to anaphylactic shock.[29]

Buprenorphine may significantly lower blood pressure levels, which can result in orthostatic hypotension or syncope. Caution should be exercised when administering buprenorphine to individuals with hypovolemia, cardiovascular disorders, including recent myocardial infarction, or those concurrently using medications that may amplify hypotensive effects. Monitoring for signs of hypotension is advisable after initiating or adjusting the dosage. Buprenorphine is contraindicated for patients in circulatory shock.

Buprenorphine has been associated with the prolongation of the QTc interval.[30] The maximum recommended buprenorphine dosages are one 20 mcg/h transdermal patch or 900 mcg every 12 hours for the buccal film. Administration of buprenorphine should be avoided in patients with a history of long QT syndrome or those currently receiving class IA/III antiarrhythmic agents or other medications that may prolong the QT interval. Caution should be exercised in patients presenting with hypomagnesemia, hypokalemia, or unstable cardiac conditions, including symptomatic bradycardia, unstable atrial fibrillation, unstable heart failure, or active myocardial infarction.[31]

The potential for overdose leading to coma or death exists when opioid-naive individuals combine diverted buprenorphine with benzodiazepines, alcohol, or other centrally acting agents.[32] There is also a risk of severe, life-threatening, or fatal respiratory depression associated with extended-release and immediate-release injections, buccal film, and transdermal patch administration.

The sedative effects of opioids can be exacerbated by carbon dioxide retention due to opioid-induced respiratory depression.[33] In cases where discontinuation of the extended-release injection is necessary due to respiratory depression, it is imperative to closely monitor the patient for ongoing respiratory depression for several months due to the medication's extended-release properties. Patients and caregivers should be educated on identifying signs of respiratory depression and the critical importance of seeking immediate emergency assistance in the event of a suspected or known overdose.

Contraindications

Buprenorphine use is contraindicated only in patients with hypersensitivity reactions to it. Caution should be exercised in patients with respiratory depression and gastrointestinal obstruction. In addition, buprenorphine is not recommended for patients currently using full opioid agonists, such as heroin or morphine. Concurrent use of a full and partial agonist may result in acute withdrawal, defeating the purpose of buprenorphine administration (refer to the "Monitoring" section).[34]

Patients with known or suspected gastrointestinal obstruction, including paralytic ileus, are not recommended to use buprenorphine buccal film, immediate-release injection, and transdermal patch due to the risk of exacerbating the obstruction. Oral mucositis can accelerate absorption from buccal film and raise buprenorphine plasma levels. Healthcare providers should lower the dosage and carefully monitor for signs and symptoms of toxicity or overdose in patients experiencing oral mucositis.

Box Warnings

Accidental exposure to even a single dose of buprenorphine buccal film or transdermal patch, especially in children, can result in a fatal buprenorphine overdose.

Various forms of buprenorphine, such as buccal film, transdermal patch, or immediate-release injection, expose patients and other users to the risks of opioid addiction and substance use and misuse, which can result in overdose and death. Healthcare providers should evaluate the risk for each patient before prescribing buprenorphine and regularly monitor all patients for the emergence of such conditions or behaviors.

As part of the opioid analgesic risk evaluation and mitigation strategy (REMS) requirements, healthcare providers must participate in REMS-compliant education programs provided by drug companies with approved opioid analgesic products. Healthcare providers are responsible for completing REMS programs and counseling patients and caregivers on proper administration, safe use, storage, disposal, serious risks, and other tools to enhance patient safety with each prescription. Patients and caregivers should be reminded to read the medication guide provided by their pharmacist each time and be informed about the importance of the safe use of the product.[35]

Life-threatening respiratory depression is a potential risk associated with the use of buprenorphine buccal film, transdermal patch, and immediate-release injection. As respiratory depression can be severe, life-threatening, or fatal, careful monitoring for respiratory depression is essential, especially during the initiation of buprenorphine therapy or following a dose increase. Buprenorphine use or misuse, such as snorting, chewing, swallowing, or injecting the drug extracted from the buccal or transdermal formulation, can lead to uncontrolled delivery of buprenorphine, increasing the risk of overdose and death. The risk of respiratory depression is substantial in pediatric patients.[36]

Using buprenorphine in various forms, including buccal film, transdermal patch, and immediate-release injection, for an extended period during pregnancy can cause neonatal opioid withdrawal syndrome. If left unrecognized and untreated, this condition can be life-threatening to the newborn. If a pregnant woman needs to use opioids for an extended period, she should be informed of the risk of neonatal opioid withdrawal syndrome, and appropriate treatment should be made available. According to the American Academy of Pediatrics guidelines, infants exposed to buprenorphine should be observed for 4 to 7 days.[37]

Combining buprenorphine with CNS depressants such as benzodiazepines, alcohol, certain antidepressants, antihistamines, hypnotics, or sedatives can lead to life-threatening respiratory depression, coma, and even death. Buprenorphine and benzodiazepines or other CNS depressants should not be prescribed together unless alternative treatment options are inadequate. If necessary, the dosages and durations of treatment should be limited to the minimum requirements, and patients should be closely monitored for signs of respiratory depression and sedation.

IV administration of buprenorphine extended-release injection can lead to severe harm or death. If administered via IV, upon contact with body fluids, the extended-release injection forms a solid mass that can lead to occlusion and damage to local tissues and trigger thromboembolic events, such as life-threatening pulmonary emboli. For this reason, the drug is only accessible through a restricted program called the Sublocade REMS Program. Healthcare settings and pharmacies must be certified in the REMS program and adhere to its requirements to be eligible to order and dispense buprenorphine extended-release injections.

Warnings/Precautions

Clinicians should exercise caution when prescribing buprenorphine to patients with hepatic impairment, renal impairment, morbid obesity, thyroid dysfunction, a history of ileus or bowel obstruction, prostatic hyperplasia or urinary stricture, CNS depression or coma, delirium tremens, depression, anxiety disorders, posttraumatic stress disorder, and toxic psychosis. Frequent monitoring is recommended for patients with mental health conditions due to the increased risk of OUD and overdose. In addition, caution should be exercised in patients with acute pancreatitis or biliary tract dysfunction, as opioids may potentially cause constriction of the sphincter of Oddi.

Healthcare providers should exercise caution when administering opioids, including buprenorphine, to patients with adrenal insufficiency, such as Addison disease. Prolonged opioid use may lead to adrenal insufficiency, characterized by symptoms such as anorexia, nausea, vomiting, weakness, fatigue, dizziness, low blood pressure, and secondary hypogonadism.[38] In addition, caution should also be exercised when using buprenorphine in patients with elevated intracranial pressure (ICP), head injury, and intracranial lesions, as buprenorphine use may lead to an exaggerated elevation of ICP.[39] Caution is also necessary when administering the drug to patients with a history of seizure disorders, as buprenorphine may cause or worsen preexisting seizures.

Monitoring should be considered for patients with a substantially decreased respiratory reserve, hypercapnia, hypoxia, significant chronic obstructive pulmonary disease, and those with preexisting respiratory depression for signs of respiratory depression, particularly when initiating and titrating therapy with opioids. Respiratory depression may occur, even at therapeutic dosages.

Opioids should be avoided in patients with moderate-to-severe sleep-disordered breathing, according to the 2022 CDC guidelines. Caution should be exercised in patients with sleep-related disorders such as sleep apnea due to the increased risk of CNS and respiratory depression. Healthcare providers should consider monitoring such patients closely while treating them and titrating the dose carefully.[18]

Monitoring

When considering the use of buprenorphine, a partial agonist, it is important to understand its behavior when used in combination with other opioid receptor agonists. When taken with a full agonist, buprenorphine has a blocking effect and prevents the full agonist from producing a high. If administered too soon after a full agonist, the patient may experience withdrawal. A simple assessment, such as the Clinical Opiate Withdrawal Scale (COWS), is necessary before administering buprenorphine. Furthermore, it is recommended that patients exhibit at least mild-to-moderate withdrawal, translating to a score of at least 5 to 24 on the COWS. This step ensures that patients with opioid intoxication will not receive a partial agonist that may push them into withdrawal.[40][41]

Drug-Drug Interactions

Buprenorphine is metabolized in the liver by the CYP3A4 microsomal enzymes. If the patient is taking medications that induce these enzymes, such as carbamazepine, phenytoin, or rifampin, dosing may not achieve therapeutic levels of buprenorphine. On the other hand, if the patient is taking inhibitors of CYP3A4, such as fluvoxamine, ketoconazole, indinavir, erythromycin, or saquinavir, buprenorphine levels may remain elevated, posing a risk of potential toxicity.

Before prescribing buprenorphine, healthcare providers should thoroughly assess the patient's current medication regimen to identify potential severe drug interactions. Patients must be cautioned against combining buprenorphine with other opioids or alcohol.

Managing Missed Doses

When treating patients with opioid dependence, it is essential to anticipate missed doses. Currently, most pharmacists dispensing buprenorphine maintain records of the drug, dosage, time, and day, which is crucial for monitoring and ensuring compliance. This information is vital as it aids in ensuring compliance. If an individual misses a dose of buprenorphine, healthcare providers should be notified promptly, as it could be an initial indication of instability in the patient. Clinicians must develop a new treatment plan to maintain compliance and address any issues.

Follow-up

As with patients undergoing methadone treatment, individuals prescribed buprenorphine require vigilant monitoring from an interprofessional team of healthcare professionals within a comprehensive opioid dependence treatment protocol. In certain regions, pharmacists have assumed an active role in overseeing and monitoring patients receiving buprenorphine treatment. Pharmacists actively collaborate with healthcare providers and play an important role in dispensing take-home doses, also known as carries.

Cost and Availability of Buprenorphine

The average cost for a 30-day supply of buprenorphine is around $300 to $350 for two 2 mg or 8 mg tablets per day. Formulations containing naloxone are slightly more expensive, with a retail price ranging from $400 to $450 per month.

Toxicity

At each follow-up visit, healthcare providers should assess their patients for buprenorphine toxicity. Patients' vital signs must be obtained, and their overall physical and mental health status should be evaluated. Pharmacists should refrain from dispensing buprenorphine if the patient appears lethargic or intoxicated. In some cases, pharmacists may need to withhold the dose of buprenorphine. The prescriber must be notified of these plans and prioritize patient safety. Given buprenorphine's long half-life, the drug can typically be withheld for 1 day with minimal adverse effects. The patient can then be released the next day. If the patient exhibits signs of respiratory depression and/or hypotension, they should be promptly evaluated in the emergency room and treated as any other opioid overdose patient.

Difficulty in differentiating withdrawal symptoms is a problem when assessing buprenorphine's adverse effects. Opioid withdrawal symptoms may occur at any dose of buprenorphine and include nausea, vomiting, headache, diarrhea, flu-like symptoms, and diaphoresis. On the other hand, the adverse effects associated with buprenorphine treatment typically correlate with the dose—higher doses tend to result in more severe symptoms. Concurrent use of CNS depressants and alcohol can exacerbate adverse drug reactions associated with buprenorphine. Monitoring and adjusting the dosage are crucial considerations for managing these effects.

In the case of a buprenorphine overdose, patients may exhibit symptoms such as confusion, dizziness, pinpoint pupils, hallucinations, hypotension, respiratory depression, seizures, or coma. The risk of respiratory depression increases when combined with other CNS depressants, particularly benzodiazepines.[42] For instance, the concurrent use of buprenorphine and diazepam elevates the risk of respiratory and cardiovascular collapse. A retrospective analysis of 534 opioid-related drug overdose fatalities indicated that individuals with buprenorphine detected in toxicology tests typically had a history of polysubstance use.[43]

In the event of a buprenorphine overdose, a patient should receive a naloxone bolus dose ranging from 2 mg to 3 mg, followed by a continuous infusion of 4 mg/h. This protocol ensures a complete reversal of the overdose within 40 to 60 minutes, as a bolus dose is necessary to overcome buprenorphine's high affinity for the mu-opioid receptor.

Reports of rare cases of liver damage with jaundice exist with the use of buprenorphine. Regular monitoring of liver function is required for patients receiving buprenorphine. The most severe adverse reaction associated with buprenorphine use is respiratory depression, which can be fatal. This poses a unique challenge as there is no effective antidote for buprenorphine, distinguishing it from substances such as morphine. Respiratory depression associated with buprenorphine is more likely at high doses and is notably prolonged and challenging to reverse with naloxone due to buprenorphine's tight binding to opioid receptors. In severe cases, patients may necessitate mechanical ventilation to address respiratory depression.

Advantages of Buprenorphine Over Methadone

Buprenorphine use has proven to be more effective than detoxification in enhancing outcomes for individuals with opioid dependence. When compared to methadone, buprenorphine offers several advantages:

• The drug is safer even at high doses.
• Optional therapeutic doses can be achieved relatively quickly.
• There is a lower risk of substance misuse and diversion.
• The drug can be easily tapered.
• The drug is associated with less stigma than methadone.
• Patients can obtain the medication from any healthcare provider, eliminating the need for specialized methadone clinics.
• Due to its partial opioid receptor agonist activity, buprenorphine is less likely to cause euphoria compared to full agonists such as methadone or morphine, reducing the likelihood of misuse or diversion.
• Buprenorphine treatment typically lasts 3 to 6 months or even 1 to 2 years, whereas methadone treatment is often lifelong.

Patient Education

The success of buprenorphine-naloxone is dependent on patient education. Patients should receive counseling about the drug's addiction potential and be advised to avoid other CNS sedatives during each visit. Family members or caregivers should be educated about the signs and symptoms of buprenorphine toxicity. Patients should also be informed about appropriate actions to take in the event of lethargy or depressed respiration.

To ensure continuity in care, healthcare workers need to communicate all aspects of the treatment during weekly meetings to prevent omissions or overlaps in buprenorphine dosing. These meetings are particularly crucial when a patient is discharged from jail or a healthcare institution.

Pearls of Wisdom

• Buprenorphine acts as a partial agonist at the mu-opioid receptor and is generally considered safer than methadone. However, combining it with other CNS depressants, such as alcohol or benzodiazepines, can lead to respiratory depression and should be avoided.

• If an overdose occurs with buprenorphine, significantly higher doses of naloxone, along with other supportive measures, are necessary.

• Due to its partial opioid agonist nature, the drug has a lower potential for dependence and misuse compared to pure agonists such as heroin or morphine; however, it can still be misused.

• Incorporating naloxone into the formula is intended to further reduce the risk of substance misuse by injection but does not always eliminate the risk.

• Unlike methadone, the therapeutic dose of buprenorphine can be titrated to a stable dose within several days. In contrast, methadone often takes many weeks or even months to reach a therapeutic dose.

• In some cases, despite reaching the maximal dose of buprenorphine, it may not be sufficient to treat dependence. In such scenarios, consideration could be given to switching the patient to methadone.

• Buprenorphine can induce withdrawal symptoms in patients dependent on opioids if administered quickly after the last dose of a pure agonist such as fentanyl or oxycodone.

Enhancing Healthcare Team Outcomes

The success of buprenorphine-naloxone largely depends on patient education. Therefore, patients should be educated about the drug's addiction potential and the importance of avoiding other CNS sedatives at each visit. Family members or caregivers should also receive education about the signs and symptoms of buprenorphine toxicity. Patients and caregivers should be instructed on appropriate actions to take in the event of depressed respiration.

Pharmacists must collaborate with prescribers to ensure proper dosing, monitor drug interactions, and counsel patients on appropriate administration. Nursing staff should remain vigilant for signs of adverse effects or poor compliance. All interprofessional healthcare team members must be aware of the potential for diversion and promptly communicate any possible signs. Given the nature of buprenorphine therapy, effective coordination and communication among the interprofessional team are essential for driving improved patient outcomes. 

To ensure continuity in care, healthcare workers must communicate all aspects of the treatment with each other during the weekly meeting, preventing omissions or overlaps in the dosing of buprenorphine. This approach is crucial, especially after a patient's discharge from jail or a healthcare institution. The outcomes depend on compliance with therapy. However, due to the presence of other significant comorbidities in many patients with SUD, the overall effectiveness is poor, characterized by remissions and relapses.[44]

As with any drug, but perhaps even more so with buprenorphine, the regimen needs to be part of an interprofessional healthcare team approach to ensure optimal patient outcomes with minimal harm. Interprofessional coordination and collaboration among physicians, advanced practitioners, pharmacists, nurses, and public health professionals can enhance patient outcomes when prescribing buprenorphine and monitoring patients.