Buprenorphine

Mechanism of Action

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 feature gives its many unique properties, specifically that its analgesic effects plateau at higher doses, and then its effects become antagonistic. Buprenorphine exhibits ceiling effects on respiratory depression, which means that it is safer than methadone for agonist substitution treatment in addiction.

Buprenorphine has high-affinity binding to the mu-opioid receptors and slow-dissociation kinetics. In this way, it differs from other full-opioid agonists like morphine and fentanyl, allowing withdrawal symptoms to be milder and less uncomfortable for the patient.

When administered orally, buprenorphine has poor bioavailability because of the first-pass effect. The liver and intestine break down the majority of the drug. Sublingual administration is the preferred route of administration. The absorption is fast, and this route also avoids the first-pass effect. Upon placing the tablet under the tongue, it has a slow onset of action, with the peak effect occurring 3 to 4 hours after administration.

Once in the body, buprenorphine is broken down by the cytochrome CYP 34A enzymes to an active metabolite (norbuprenorphine) with weak intrinsic activity. The average half-life of buprenorphine is about 38 hours (25 to 70 hours) following sublingual administration. Potent inhibition of the 3A4 enzyme by drugs (such as ketoconazole or protease inhibitors) may cause increased levels of buprenorphine, while inducers of this enzyme (such as carbamazepine, topiramate, phenytoin, or barbiturates) may cause lower levels.

The majority of the drug and the metabolite get excreted in the feces, and the kidneys excrete less than 20%. Because of the slow onset of action and prolonged duration of action, the drug is useful in treating opioid dependence. It may be prescribed on alternate days once the patient has stabilized on the daily dose.

Administration

Buprenorphine administration is possible via many means. For chronic pain relief, a transdermal patch is an option. Oral forms include a buccal film and sublingual tablets. Parenteral routes include a subdermal or subcutaneous implant and intravenous (IV) or intramuscular (IM) injections.

Buprenorphine is also available combined with naloxone in a sublingual tablet. Naloxone is not absorbed orally, so the effect is predominantly from buprenorphine when taking the combination drug. Naloxone is added to buprenorphine to reduce its abuse potential when injected. When taking the combination in an IV form, the naloxone is also absorbed and works to prevent the high of buprenorphine and may even precipitate a withdrawal; this is why buprenorphine alone has a higher potential for misuse than buprenorphine/naloxone.[6][7][8]

Federal Regulations for Prescribing Buprenorphine

Sublingual buprenorphine preparations are helpful in the management of opioid dependence (such as heroin, oxycodone, hydrocodone, and morphine). The use of buprenorphine replacement therapy in the management of opioid dependence is regulated and highly monitored. 

Mainstreaming Addiction Treatment (MAT) 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 health care providers with a standard controlled substance license to prescribe buprenorphine for opioid use disorder (OUD), just as they prescribe other essential medications. The MAT Act is intended to help destigmatize a standard of care for OUD and will integrate substance use disorder treatment across healthcare settings. 

As of December 2022, the MAT Act has eliminated the DATA-Waiver (X-Waiver) program. All DEA-registered practitioners with Schedule III authority may now prescribe buprenorphine for OUD in their practice if permitted by applicable state law, and SAMHSA encourages them to do so. Prescribers who were registered as DATA-Waiver prescribers will receive a new DEA registration certificate reflecting this change; no action is needed on the part of registrants.

There are no longer any limits on the number of patients with OUD that a practitioner may treat with buprenorphine. Separate tracking of patients treated with buprenorphine or prescriptions written is no longer required. 

Pharmacy staff can now fill buprenorphine prescriptions using the prescribing authority's DEA number and does not need a DATA 2000 waiver from the prescriber. However, depending on the pharmacy, the dispensing software may still require the X-Waiver information in order to proceed. Practitioners are still required to comply with any applicable state limits regarding the treatment of patients with OUD.  Contact information for State Opioid Treatment Authorities can be found here: https://www.samhsa.gov/medicationassisted-treatment/sota.  

Drug Addiction Treatment Act of 2000

Unlike methadone, which requires dispensing from a specialized clinic, buprenorphine/naloxone can be prescribed in an outpatient setting, as permitted by the Drug Addiction Treatment Act of 2000. However, healthcare workers who wish to prescribe buprenorphine to treat their opioid-dependent patients must undertake some training or extra education to know more about this agent. Further, most insurers also recommend that healthcare workers who prescribe this drug must have completed an approved course of buprenorphine treatment for opioid dependence.[9][10][11]

Just like the prescription of other opioids like morphine, the healthcare worker should maintain good medical records when prescribing buprenorphine. Each time a clinician prescribes the drug, the medical notes should contain the following:

• Reason for prescribing
• Start and end date
• Which pharmacy will dispense the drug?
• Who will supervise the administration?
• Will the drug be taken at home or at the pharmacy?
• What type of follow-up and who will be in charge of follow up
• How will compliance be monitored?

Further, the prescriber must comply with all the DEA requirements and actively monitor the patient.

Buprenorphine Dose Routes

The parenteral formula is not FDA-approved for the management of opioid dependence, and hence intravenous use is not permitted, except under extraordinary circumstances and with permission; otherwise, such use can be illegal, and the prescriber can lose his or her DEA number and ability to write any future prescriptions for controlled substances.

Buprenorphine has multiple routes of administration. For chronic pain relief, a transdermal patch can be used (this formula is only available in Europe). Oral forms include a buccal film and sublingual tablets. Parenteral routes include a subdermal or subcutaneous implant and IV or IM injections but are not routinely used. The sublingual formula has extensive use in the treatment of opioid addiction; it contains buprenorphine and naloxone in a 4 to 1 ratio. Buprenorphine is available in 2 mg and 8 mg sublingual formulas combined with naloxone 0.5 mg and 2 mg, respectively, to deter drug abuse by injection.

Once placed underneath the tongue, the drug formula dissolves in 2 to 10 minutes.

Naloxone is an opioid antagonist, and its use in the formula is to prevent injection of the liquid obtained by dissolving the pills; this may help decrease the misuse of buprenorphine and limit diversion. Because naloxone is poorly absorbed sublingually, its systemic effects when patients take buprenorphine properly are minimal. However, if the tablet is dissolved and injected, the naloxone blocks mu receptors and prevents receptor activation or precipitates withdrawal in opioid-dependent patients.

Initial Dosing

The initial treatment dose of buprenorphine/naloxone should be at the lowest dose and gradually titrated every week until noting a response. The minimum duration of treatment is eight weeks. In the majority of cases, the drug is administered under supervision by a pharmacist, except when the pharmacy is not open on the weekends, then the patient can receive a take-home dose. Take-home doses are only suitable for compliant patients who are clinically motivated to treat their opioid dependence. However, before agreeing on take-home dosing, the patient must receive education on the consequences of the following:

• Potential for overdose
• Unintended dosing by others
• Diversion
• Consequences of careless storage

If take-home dosing is agreed upon, initially, it should be limited to weekend doses only and then gradually increased as the patient shows more reliability. At all times, the patient requires monitoring for compliance.

Induction Therapy 

Induction with buprenorphine initiates when the patient is experiencing mild to moderate symptoms of opioid withdrawal. The treatment is usually started 6 to 12 hours after the use of short-acting opioids (e.g., heroin, oxycodone) or at least 24 hours or longer after using a long-acting opioid (e.g., morphine or oxycodone controlled-release formulations. For those methadone maintenance patients who prefer a switch to buprenorphine, the recommendation is that one waits at least 72 hours or more after the dose of methadone before initiating treatment. The dose of methadone should be tapered down to less than 30 mg before buprenorphine treatment to decrease the risk of precipitating intense withdrawal symptoms.

For patients on the fentanyl patch, at least 48 to 72 hours is necessary after discontinuation before starting treatment.

In most patients with opioid dependence, the initial dose is 2 to 4 mg. For those on high doses of opioids or potent agents like oxycodone, an additional dose of 2 to 4 mg may be necessary on the same day. After the supervised dosing, the healthcare provider in the clinic will monitor the patient.

During this time, the patient undergoes monitoring for withdrawal symptoms. Tools like the Clinical Opiate Withdrawal Scale can help to determine the presence and intensity of withdrawal symptoms. Additional doses of buprenorphine may be necessary for the symptomatic management of the withdrawal symptoms. Once the symptoms have subsided and the patient is discharged, the induction can be rescheduled for the following day. The patient should be encouraged to abstain from opioids while at home.

Maintenance Phase

During this phase, the dose of buprenorphine is gradually increased according to the patient’s physical and psychological needs but should not exceed a maximum of 24 mg in one day. Most patients respond to doses between 8 to 12 mg per day. In most patients, the maintenance dose is attainable within 2 to 4 days. Once stabilized, the dosing frequency may be reduced, especially in reliable patients or those who need to travel. Some patients may benefit from alternate dosing by doubling the dose at each visit.

Adverse Effects

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

Potential for Buprenorphine Abuse

Even though buprenorphine is only a partial opioid agonist and has mild addictive potential, some people still misuse the drug. Buprenorphine tablets are misused by crushing them and either snorting the powder or dissolving the power and using it as an intravenous solution. Also, in the US, where buprenorphine is also available in a sublingual formula, concerns have been raised about diversion and abuse; thus, the sublingual formulation is combined with naloxone to prevent IV abuse. Further, most patients undergo supervised daily dosing for the first two months of treatment to help lower the risk of diversion. Pharmacists also pay close attention to the patient’s compliance to ensure that double doctoring and lost or stolen ‘carries’ do not occur frequently.

There is always the potential of overdose from the diverted buprenorphine in opioid-naive individuals when combined with benzodiazepines, alcohol, or other centrally acting agents.

Contraindications

The only true contraindication to buprenorphine use is a hypersensitivity reaction to it. Its use requires caution in patients with respiratory depression and gastrointestinal obstruction.

Buprenorphine is also not a recommended agent for patients currently using full opioid agonists, such as heroin or morphine, because the concurrent use of a full and partial agonist may result in acute withdrawal (see "Monitoring"), thus defeating the purpose of buprenorphine administration.

In patients with renal impairment, the dose of buprenorphine does not require alteration. However, in patients with liver dysfunction, the dose has to be modified to prevent toxicity.[12][13][14]

Buprenorphine Use in Special Populations

Pregnant Patients

It is well-known that in-utero exposure of infants to opioids can result in withdrawal symptoms after birth, referred to as neonatal abstinence syndrome (NAS). Buprenorphine is classified as category C for use during pregnancy, which means that the risk of adverse effects on the fetus cannot be ruled out. Buprenorphine does cross the placenta, and the use of opioids during pregnancy may result in neonatal withdrawals soon after birth. Symptoms of this may include irritability, apnea, increased tone, tremor, convulsions, or respiratory depression in the neonate. The onset of withdrawal in a neonate whose mother has taken buprenorphine during the pregnancy could be from the first day of life to the eighth day of life.

Medication-assisted treatment (MAT), including opioid treatment programs (OTPs), is a combined therapeutic approach using behavioral therapy and medications to treat substance use disorders. There is ample evidence indicating that methadone maintenance does improve maternal and newborn outcomes in pregnant opioid-dependent patients. Similarly, evidence suggests that maintenance with buprenorphine may also improve fetal and maternal outcomes. The resultant NAS may be less intense than that observed after methadone. At present, buprenorphine is listed as a category C drug in pregnancy, whereas methadone is category B in pregnant patients. Buprenorphine is classified as category C for use during pregnancy, which means that the risk of adverse effects on the fetus cannot be ruled out. Buprenorphine does cross the placenta, and the use of opioids during pregnancy may result in neonatal withdrawals soon after birth. Symptoms of this in the neonate may include any of the following:

• Tremors (trembling)

• Fever

• Irritability

• Sleep problems

• Tachypnea

• Excessive and/or high-pitched crying

• Increased muscle tone

• Hyperreflexia

• Seizures

• Yawning, stuffy nose, and sneezing

• Poor feeding and sucking, slow weight gain

• Vomiting

• Diarrhea

• Dehydration

• Sweating

The onset of withdrawal in a neonate whose mother has taken buprenorphine during the pregnancy could be anywhere from the first day of life to the eighth day of life (Nguyen et al., 2018). According to the Substance Abuse and Mental Health Administration (SAMHSA), the following are the recommendations:

• The woman should understand that experts are undecided about whether intrauterine exposure to methadone, buprenorphine, or buprenorphine/naloxone leads to lasting developmental issues for the infant. The clinician should further inform her that the benefits of pharmacotherapy for opioid use disorder outweigh the risks.
• There is no evidence to date showing buprenorphine or methadone result in increased birth defects, and it has a minimal long-term impact on neurological development.
• Experts are not in agreement whether a woman in early pregnancy or who states her intention to become pregnant with opioid use disorder should be switched from a buprenorphine/naloxone combination to buprenorphine alone and that any switch from the combination to the buprenorphine-only product should only be made based on the specifics of the case, with the woman's full informed consent.
• There is increasing evidence that newborn outcomes are not adversely affected by the combination product; the decision should remain with the clinician and the patient based on the benefit vs. risk.

Breastfeeding Women

Research has shown that buprenorphine does pass into breast milk. Still, because it has low bioavailability, it is not well established how much enters the systemic circulation in the breastfed infant. A few case reports indicate that buprenorphine does not suppress NAS and that the syndrome doesn't develop even after discontinuation of breastfeeding. While the manufacturers of buprenorphine advise against the use of buprenorphine in breastfeeding women, the limited evidence to date reveals that buprenorphine appears to be safe, and discontinuation may not be necessary.

Elderly

So far, there is very little data on the use of buprenorphine in elderly patients. Because geriatric patients do have altered absorption, distribution, and metabolism, one should exercise caution when prescribing buprenorphine to this population. Plus, the potential for drug interactions also exists.

HIV Patients

Common comorbidity in HIV patients is opioid addiction. While highly active antiretroviral therapy (HAART) can prolong life and improve the quality of life, opioid dependency still needs to be treated. In one study, researchers found that buprenorphine-treated patients were more compliant with HAART compared to untreated patients, but the drug does not change the effectiveness of HAART.

Since many HAART drugs also affect the liver microsomal enzymes, healthcare workers should closely monitor liver function and drug levels in patients who have buprenorphine prescribed simultaneously. In some patients, the dose of buprenorphine may require alteration.

Hepatitis

Both hepatitis B and C are common comorbid conditions in opioid-dependent patients. Since buprenorphine breakdown occurs in the liver, these patients should have their liver function and drug levels closely monitored. Clinicians should caution patients with hepatitis that intravenous use of buprenorphine has correlations with liver damage.

Patients with Pain

Even though buprenorphine is an opioid, it only has partial analgesic activity at the mu-opioid receptor. The two reasons why buprenorphine has limited use as an analgesic are it is only a partial agonist and has a ceiling effect. It binds tightly to the mu receptors and will prevent the binding of full agonists at the mu receptor. Thus, in patients with pain managed with buprenorphine, the other options for analgesics include the use of non-steroidal anti-inflammatory drugs. If the patient is on a low dose of buprenorphine (2 to 8 mg), this can be increased to up to 24 mg every day. Other options include regional anesthesia, nerve blocks, or the use of anticonvulsants.

Monitoring

One must consider how buprenorphine, a partial agonist, behaves when administered with other opioid receptor agonists. When in the presence of a full agonist, buprenorphine use results in a blockade effect and doesn’t allow the high of the full opioid agonist to occur. If taken too soon after a full agonist, the patient may enter into withdrawals, which is why it is important to perform a simple assessment, such as the Clinical Opiate Withdrawal Scale, or COWS, before giving buprenorphine. Suggestions are that the patient is in at least mild to moderate withdrawal, which translates to a score of at least 5 to 24 on the COWS. This step ensures that a patient with opioid intoxication will not receive a partial agonist that may push them into withdrawal.[15][16]

Before prescribing buprenorphine, one should closely examine all the medications; the patient is taking because serious drug interactions can occur. Combining buprenorphine with CNS depressants like benzodiazepines, alcohol, certain antidepressants, antihistamines, hypnotics, or sedatives, can lead to life-threatening respiratory depression, coma, and even death. The patient should be warned not to combine buprenorphine with other opioids or alcohol.

Buprenorphine is broken down in the liver by the CYP3A4 microsomal enzymes. Hence if the patient is on medications that induce these enzymes (e.g., carbamazepine, phenytoin, or rifampin), therapeutic levels of buprenorphine may not be reached. On the other hand, if the patient is on inhibitors of CYP3A4 (e.g., fluvoxamine, ketoconazole, indinavir, erythromycin, saquinavir), levels of buprenorphine will remain elevated, and there is potential for toxicity.

At each clinic visit, there should be a reconciliation of the patient’s drug list to ensure no new drug additions.

Managing Missed Doses

When dealing with opioid-dependent patients and their treatment, one must prepare to deal with missed doses. Today most pharmacists who dispense buprenorphine keep track of the drug, the dosage, time, and day. This information is vital as it helps with compliance. Anytime the individual misses a dose of buprenorphine, the healthcare provider must receive notification since it may be the first sign of instability in the patient. To prevent loss of compliance, the clinician must develop a new treatment plan.

Follow up

As with patients treated with methadone, patients prescribed buprenorphine also need close monitoring from an interprofessional group of healthcare professionals as part of a comprehensive opioid dependence treatment protocol. In some parts of the country, pharmacists have also taken an active role in the supervision and monitoring of patients treated with buprenorphine. The pharmacist further communicates with the healthcare providers and plays an active role in dispensing take-home doses (carries).

Cost and Availability of Buprenorphine

The average cost for a 30-day supply of buprenorphine (two 2 or 8 mg tablets per day) is about $300 to $350. Formulas that contain naloxone are slightly more expensive, retailing at $400 to $450 a month.

Toxicity

At each visit to the pharmacy, the patient must undergo an assessment for buprenorphine toxicity. The vital signs should be obtained, and the patient's overall physical and mental health status evaluated. The clinician should not dispense buprenorphine if the patient appears lethargic or intoxicated. In some cases, the pharmacist may have to withhold the dose of buprenorphine may. The healthcare provider must be notified of these plans, as patient safety is paramount. Because buprenorphine has a long half-life, the drug can be withheld for one day without any adverse effects. The patient should then be released the next day. If the patient has signs of respiratory depression and/or hypotension, he or she should be evaluated in the emergency room and treated like any other opioid overdose patient.

One of the problems when trying to determine the adverse effects of buprenorphine is the difficulty in differentiating the withdrawal symptoms. The typical withdrawal symptoms after opioid withdrawal includes nausea, vomiting, headache, diarrhea, flu-like symptoms, and diaphoresis. These withdrawal symptoms may occur at any dose of buprenorphine. On the other hand, the adverse effects associated with buprenorphine treatment usually relate to the dose. The higher the dose, the more severe the symptoms are. Also, the side effects of buprenorphine can worsen with other CNS depressants and alcohol.

If a patient overdoses on buprenorphine, they may experience confusion, dizziness, pinpoint pupils, hallucinations, hypotension, respiratory depression, seizures, or coma. Respiratory depression is a possibility when using other central nervous depressants, especially benzodiazepines. For example, when using buprenorphine and diazepam together increased the risk of respiratory and cardiovascular collapse.

When a patient overdoses on buprenorphine, they must be given a naloxone bolus dose of 2 mg to 3 mg followed by continuous infusion of 4 mg per hour; this will cause a full reversal of the overdose within 40 to 60 minutes. A bolus dose is needed to overcome the high affinity that buprenorphine has to the mu-opioid receptor.

Reports exist of rare cases of liver damage with jaundice with the use of buprenorphine. For those who receive buprenorphine, liver functions require regular monitoring. The most severe and serious adverse reaction associated with buprenorphine use is respiratory depression, which can be fatal. This situation is particularly problematic with buprenorphine because, unlike morphine, there is no effective antidote. The respiratory depression associated with buprenorphine tends to occur at high doses and is much more prolonged and difficult to reverse with naloxone, as the binding of buprenorphine to the opioid receptors is very tight. In some cases, the patient may require mechanical ventilation to manage respiratory depression.

Benefits of Buprenorphine Compared to Methadone

The use of buprenorphine has been demonstrated to be more effective than detoxification in improving outcomes in patients with opioid dependence. When compared to methadone, buprenorphine has the following advantages:

• It is safer even at high doses.
• Optional therapeutic doses are achieved relatively quickly
• There is less risk of abuse and diversion
• The drug is easier to taper
• There is less stigma associated with buprenorphine than methadone.
• Patients can get the medication from any healthcare provider and do not have to go to specialized methadone clinics.

Buprenorphine, because of its partial opioid receptor agonist activity, is said to cause less euphoria compared to full agonists like methadone or morphine and, thus, is less likely to be abused or diverted.

The buprenorphine treatment typically lasts 3 to 6 months (or sometimes 1 to 2 years); conversely, methadone treatment is often lifelong.

Patient Education

The success of buprenorphine/naloxone is dependent on patient education. The patient should have counsel about the drug's addiction potential and avoidance of other CNS sedatives at each visit. Family members, or caregivers, should receive education about the signs and symptoms of buprenorphine toxicity. Patients should also understand what to do if the patient is lethargic and had depressed respiration.

To ensure that there is continuity in care, healthcare workers need to communicate all aspects of the treatment at a weekly meeting to ensure that there are no omissions or overlaps in the dosing of buprenorphine. These meetings are vital when a patient gets discharged from jail or a healthcare institution.

Pearls of Wisdom

• Buprenorphine acts as a partial agonist at the mu-opioid receptor and, overall, is safer than methadone. However, it should not be combined with other CNS depressants like alcohol or benzodiazepines; otherwise, this can lead to respiratory depression.
• If an overdose occurs with buprenorphine, much higher doses of naloxone plus other supportive measures are required.
• Because the drug is a partial opioid agonist, it has a much lower potential for dependence and misuse than pure agonists like heroin or morphine; however, misuse still occurs.
• The addition of naloxone to the formula is designed to lower the risk of abuse by injection further but does not always eliminate the risk.
• Unlike methadone, the therapeutic dose of buprenorphine is titratable to a stable dose within several days. In contrast, methadone often takes many weeks or even months to reach a therapeutic dose.
• There are some patients in whom, despite the maximal dose of buprenorphine, it may not be sufficient to treat the dependence; in such scenarios, one could consider switching the patient to methadone.
• Buprenorphine can induce withdrawal symptoms in patients dependent on opioids if it is administered quickly after the last dose of a pure agonist like fentanyl or oxycodone.

Enhancing Healthcare Team Outcomes

The success of buprenorphine/naloxone is dependent on patient education. Thus, the patient should be educated about the drug's addiction potential and avoidance of other CNS sedatives at each visit. Family members, or caregivers, should receive education about the signs and symptoms of buprenorphine toxicity. Patients and/or caregivers should also receive instruction regarding actions to take in the event of depressed respiration.

The pharmacists need to work in concert with the prescriber to ensure proper dosing, monitor drug interactions, and counsel the patient on appropriate administration. Nursing should be alert for signs of adverse effects or poor compliance. All professionals must be aware of the potential for diversion and keep the entire interprofessional team informed should any possible signs present. Given the nature of the therapy when using buprenorphine, interprofessional team coordination, and communication are essential to driving improved patient outcomes. 

To ensure that there is continuity in care, healthcare workers need to communicate all aspects of the treatment with each other at the weekly meeting to ensure that there are no omissions or overlaps in the dosing of buprenorphine. This approach is vital following a patient's discharge from jail or a healthcare institution. The outcomes depend on compliance with therapy. However, because many patients with substance misuse disorder have other significant comorbidities, the overall effectiveness is poor, marked by remissions and relapses.[17] As with any drug, but perhaps even more so with buprenorphine, the regimen needs to be part of an interprofessional team approach to ensure optimal patient outcomes with minimal harm. [Level 5]