Buprenorphine is a partial opioid agonist, and while it is associated with respiratory depression and euphoria, these effects are considerably weaker than full opioid agonists. It is associated with a lower level of misuse, reduces cravings and withdrawal, and is safer in overdose.
Buprenorphine is a schedule III-controlled substance and can be dispensed in a licensed opioid treatment program or an office-based practice. Advanced Practice Registered Nurses (APRN) are being called on to participate in patient care with addiction disorders. In Kentucky, according to KAR 20:065, "Buprenorphine" means the controlled substances Buprenorphine-Mono-Product and Buprenorphine-Combined-with-Naloxone (Kentucky Administrative Regulations, 2021).
To prescribe buprenorphine in Kentucky, the APRN should (Kentucky Administrative Regulations, 2021):
- Be Drug Enforcement Agency (DEA) registered to prescribe the medication
- Present a copy of the DEA Controlled Substance Registration Certificate to the Board of Nursing
- Have completed medication-assisted treatment (MAT) education through a course sponsored by the Substance Abuse and Mental Health Services Administration (SAMHSA)
- Follow all federal statutes and regulations relating to the prescribing of buprenorphine.
- The maximum number of patients allowed to be seen by the APRN annually
- Placing the special DEA identification number and the regular DEA registration number on all prescriptions written for opioid dependence
- Obtain a DATA 2000 waiver as an APRN; without a DATA 2000 waiver, the APRN cannot perform a focused examination necessary to prescribe buprenorphine for those with substance use disorders
- Comply with all federal statutes and regulations relating to the prescription of controlled substances via telehealth for MAT for opioid use disorder
- APRNs in the United States who practice telemedicine (in accordance with 21 U.S.C. § 802(54)) do not have to perform an in-person evaluation before prescribing/dispensing controlled substances via the internet
Buprenorphine is a partial mu-opioid agonist and has fewer restrictions when compared to methadone. It comes in multiple formulations, including an injection, implant, and transmucosal form. The transmucosal form is often combined with naloxone (even though naloxone has poor bioavailability, sublingually). The addition of naltrexone reduces the risk of abusing the buprenorphine. By adding naloxone to buprenorphine, it causes withdrawal symptoms if the medication is dissolved and injected. In addition, naloxone prevents other opioids from causing euphoric effects.
Side effects of buprenorphine include insomnia, dry mouth, dizziness, tremors, palpitations, constipation, nausea, vomiting, headache, fatigue, myalgia, fever, sweating, blurry vision, and dilated pupils. More severe side effects include overdose, respiratory depression, dependence, withdrawal, and adrenal insufficiency. Buprenorphine-naloxone should not be used in severe liver impairment. It has a lower risk for lethal overdose when compared to methadone. Overdose risk is highest in individuals who use buprenorphine with alcohol or benzodiazepines. Buprenorphine has proven to be effective in the management of opioid use disorder. Mortality rates are reduced in OUD when patients are treated with buprenorphine-naloxone compared to being off the medication. In addition to overall death rates, mortality was reduced due to reduced drug use and accidental poisoning. The same study showed that mortality rates were lower on buprenorphine-naloxone when compared to methadone (Pearce et al., 2020).
When starting buprenorphine, the buprenorphine-naloxone combination is generally recommended (Strain, 2019). The patient should be abstinent from opioids for a period to be in a state of mild/moderate withdrawal. During withdrawal, buprenorphine will alleviate the symptoms of withdrawal.
Before starting buprenorphine, the patient must refrain from opioids for at minimum 12-24 hours and be in the initial stages of opioid withdrawal. If a patient is given buprenorphine when there are opioids in the system or the patient is not in the early stages of withdrawal, an acute withdrawal state may ensue.
Before buprenorphine is prescribed for OUD or supervised withdrawal, the APRN must thoroughly evaluate the patient and the patient’s record. The evaluation should include the patient’s history of present illness (HPI), history of drug use, social and family history, medical/psychiatric history, a physical exam, and laboratory testing. Part of the evaluation should be obtaining prior medical records for evaluation and discussing and documenting prior treatments.
Appropriate laboratory tests include a drug screen, liver function tests (LFTs), metabolic panel, complete blood count (CBC), HIV screening, and hepatitis serology. In addition, an evaluation by a mental health care provider with expertise in addiction should ensue.
The APRN should review the prescription drug monitoring program (PDMP) and obtain a report if the patient has been prescribed a controlled substance in the last 12 months.
Buprenorphine should not be used with other opioids, stimulants, benzodiazepines, or other sedative-hypnotics unless there is consultation with a certified physician in psychiatry or addiction medicine; an APRN certified in addiction therapy or a psychiatric-mental health nurse practitioner. For no more than 30 days, an APRN may prescribe buprenorphine, without consultation, to an individual who is also on another opioid, stimulant, benzodiazepine, or other sedative-hypnotics when the provider is addressing a “documented extraordinary and acute medical need” (Kentucky Administrative Regulations, 2021).
The APRN should have a conversation with the patient and discuss alternative treatment options. In addition, the APRN should discuss the risks and benefits of treatment with buprenorphine. Before treatment, informed consent should be obtained. The treatment plan should include an evaluation by a mental health professional with addiction expertise and should also include a twelve-step program or mental health counseling during treatment. Compliance with the mental health professional recommendations should be documented within 90 days of starting treatment (Kentucky Administrative Regulations, 2021).
The starting dose for buprenorphine-naloxone is typically 4mg/1mg. Two hours after the dose was given, if the patient is still having withdrawal, 2 to 4 mg of buprenorphine-naloxone can be taken. The next day the patient gets one dose with the exact total dosing he/she took the day before. If any withdrawal symptoms are noted, the dose may be increased to a maximum of 16 mg of buprenorphine in 4 mg steps. Eight to 16 mg will stabilize most patients, but responses are variable, and a few may need up to 32 mg/day (Strain, 2021).
If the APRN prescribes the medication and is not certified in addiction therapy and the dose of buprenorphine exceeds 16 milligrams per day, then the patient should be referred. The referral should go to a psychiatrist, addiction medicine specialist, an APRN certified in addiction therapy, or a psychiatric-mental health nurse practitioner. The consult should determine if the current dose is appropriate and continued treatment (Kentucky Administrative Regulations, 2021).
Some suggest the use of buprenorphine over methadone in moderate to severe OUD as it is less lethal. However, methadone should be considered in those with misused buprenorphine, who had an inadequate response with buprenorphine, those with high levels of opioid dependence, and those who prefer methadone due to previous success (Strain, 2021).
It is difficult to get through the opioid withdrawal, and therefore opioid agonists (instead of antagonists) can manage symptoms of opioid withdrawal (Lee et al., 2018). If a complete withdrawal can be accomplished, then the effectiveness of a long-acting agent such as naltrexone has similar outcomes to buprenorphine (Lee et al., 2018). Research has shown little difference in abstinence rates between daily transmucosal buprenorphine and long-acting injectable naltrexone, but stabilization was easier on the buprenorphine (Tanum et al., 2017).
In a study, 570 people with OUD were given an injection of long-acting naltrexone or daily transmucosal buprenorphine for 24 weeks. The study concluded that buprenorphine was 94 percent successful in inducing (moving the user from an abused opioid to a dose of buprenorphine which will offer relief from withdrawal), and the naltrexone induced only 72 percent. In addition, those assigned to naltrexone were more likely to relapse when compared to those on buprenorphine. However, there was no significant difference in relapse when comparing naltrexone and buprenorphine in those who were successfully induced onto their respective medications, with rates for both groups being slightly above 50 percent (Lee et al., 2018).
Buprenorphine is preferred over methadone as it is safer, although some evidence suggests that methadone is slightly more effective (Saxon & Strain, 2019). A meta-analysis of 11 studies concluded that methadone and buprenorphine effectively manage OUD, but methadone is more effective in keeping patients in treatment (Strain, 2019).
The risk of overdose is much more significant with methadone when compared to buprenorphine. Methadone is much more challenging to use as it requires daily clinic monitoring, and it may lead to an increased risk of respiratory depression and lethal overdose. As a partial opioid agonist, buprenorphine is much less likely to cause respiratory depression. Methadone is associated with a fourfold greater mortality rate from overdose than buprenorphine. All patients who are prescribed either methadone or buprenorphine must be educated regarding overdose.
Less research is available regarding treatment efficacy on mild OUD than moderate to severe OUD. Naltrexone is often recommended for mild OUD. It blocks the mu-opioid receptor, so if a patient takes another opioid, there will be no euphoria. It is also not associated with withdrawal if stopped. Unlike methadone and buprenorphine, it does not lead to physiological dependence. It is easier to switch from naltrexone to methadone or buprenorphine but switching from buprenorphine or methadone to naltrexone requires up to 10 days to withdraw from the medication.
Specific interventions may be helpful in certain situations. For example, those who continue to use opioids or do not participate in treatment may benefit from motivational interviewing. In addition, nonadherence can be remedied by the supervised taking of the medication or using long-acting injections of naltrexone or buprenorphine. Long-acting formulations of naltrexone are more effective than oral agents in reducing heroin use and reducing heroin relapse (Saxon & Strain, 2019).
Certain situations do not allow the use of controlled substances. For example, individuals who transport hazardous material, health care workers, and commercially licensed drivers are sometimes not allowed to use methadone or buprenorphine. In addition, incarcerated individuals are generally not allowed to utilize these agents.
Pregnancy increases the risk of certain medications. Research suggests that buprenorphine and methadone are not teratogenic (Zedler et al., 2016). The use of buprenorphine is less likely to cause a fatal overdose when compared to methadone. The use of naltrexone in pregnancy is not considered a first-line treatment as it lacks good clinical data that shows its safety and effectiveness. In addition, there are concerns about the stresses of withdrawal on the mother and fetus (Rodriguez & Klie, 2019). Observational studies show that outcomes are not significantly different between buprenorphine or methadone versus naltrexone in managing pregnant women (Saxon & Strain, 2019). While methadone has been the treatment of choice in pregnant women with OUD, mainly due to years of experience, buprenorphine is adequate and safe. Compared to methadone, it has a lower rate of neonatal abstinence syndrome (Strain, 2019).
Females of childbearing age should have a pregnancy test. If the test is positive, then the patient should be counseled regarding the risk of neonatal abstinence syndrome. In addition, before buprenorphine is prescribed to a pregnant or breastfeeding patient, the APRN should consult with a maternal-fetal medical specialist or obstetrician who has a DATA 2000 waiver to determine if benefits outweigh the risks (Kentucky Administrative Regulations, 2021).
When a patient is hospitalized and is currently being treated with methadone or buprenorphine, treatment should continue. Ideally, the hospital should contact the prescriber or check the state prescription monitoring program to determine the appropriate dose. Thirty milligrams of methadone may be prescribed for those in whom the dose cannot be verified. That dose is enough to prevent an acute withdrawal. When using buprenorphine, the buprenorphine dose the patient states they take should be used; respiratory depression is uncommon with buprenorphine.
Patients on MAT should be involved in some sort of psychosocial treatment. Common interventions include group or individual counseling, a mutual-help group such as a 12-step program, cognitive behavioral therapy, emotional interviewing, behavioral drug counseling, and acceptance and commitment therapy.
Psychosocial treatment alone is inferior to MAT therapy and is not recommended in OUD as first-line treatment (Saxon & Strain, 2019). In addition, it is unclear which psychosocial interventions are most effective in managing OUD. One approach involves using weekly addiction counseling, help groups several times per week, and another method that has proven efficacy, such as CBT, motivational interviewing reinforcement approach, contingency management, or community reinforcement programs (Saxon & Strain, 2019).
Appropriate interventions can be implemented by determining the patient’s readiness to change. Those who are in the pre-contemplation or contemplation stages should be managed with motivational interviewing to encourage change. Those in the action stage may be better suited to CBT, which provides steps to move them toward their goals.
How long can one remain on MAT? No guidelines definitively define this question. Patients who have a good response may remain on MAT indefinitely. It is reasonable to taper the medication for those who are doing well for 6-12 months, as evidence by not using, is productive, not engaged in criminal activity, and has stable interpersonal relationships. If the patient becomes unstable during the taper, the taper should be halted. For patients on naltrexone, the medication can be abruptly stopped. The patient should be monitored closely for any indications of relapse and started back on treatment if they occur. (Saxon & Strain, 2019).
Limited data is available to help clinicians whose patients had an inadequate response to opioid use disorder treatment. For patients who had an unsuccessful response to an opioid agonist, utilization of the other opioid agonist could be considered. For example, if a patient has an unsuccessful response to transmucosal buprenorphine, switching to a long-acting injection of buprenorphine can be considered. When taking buprenorphine and an inadequate response is obtained, one could consider a switch to methadone. When methadone is used as the first agent and the patient has an inadequate response, it is a little more complicated to switch to buprenorphine. The patient may need to be off methadone for a few days, so there is no precipitated withdrawal when starting the buprenorphine.
Patients who continue to use opioids despite treatment with opioid agonists could be considered for naltrexone injection if they can tolerate a supervised withdrawal from the opioid. For patients who do not respond to oral naltrexone, the use of a long-acting injection of naltrexone could be considered. Intensifying psychosocial therapies should also be considered.
Here is a list of buprenorphine products used for OUD that the FDA approved.
- Generic Buprenorphine/naloxone sublingual tablets
- Buprenorphine/naloxone sublingual films (Suboxone®)
- Buprenorphine/naloxone sublingual tablets (Zubsolv®)
- Buprenorphine sublingual tablets (Subutex®)
- Buprenorphine extended-release injection (Sublocade®)
- Buprenorphine/naloxone buccal film (Bunavail®)
- Buprenorphine implants (Probuphine®)
Key points of patient education with buprenorphine include:
- Tell your prescriber if you are planning to become pregnant
- Discuss other medications taken with your prescriber; there are a lot of potential interactions
- Avoid using alcohol, sedatives, other opioids, tranquilizers, or illegal drugs with buprenorphine
- Keep medication stored safely
- Do not share medication
Buprenorphine has misuse potential, and the addition of naloxone to buprenorphine reduces its chance of being abused. For patients who have issues with misuse, diversion, or adherence issues, the use of implanted or injected buprenorphine has benefits over the transmucosal formulations. The implanted version of buprenorphine was approved in 2016 and provided six months of medication. Those stabilized on a buccal or sublingual formulation of 8 mg or less are candidates for implanted buprenorphine (Strain, 2019). A surgical procedure is needed to insert and remove the device. The implanted device may be used two times for 12 months (Strain, 2019). The implant is associated with reduced rates of positive urine drug tests compared to placebo.
Injectable buprenorphine came to market in 2018. Buprenorphine XR is approved for use after at least one week of clinical stabilization with transmucosal buprenorphine and is dosed monthly. It is dosed 300 mg in the first two months and then 100 mg monthly after that. Some patients may receive 300 mg monthly maintenance doses (e.g., patients not adequately managed on 100 mg per month). A longer duration of treatment (12 months) is associated with a better chance of abstinence, a better mood, quality of life scores, pain, and improved employment rates (Ling et al., 2020). In addition, the injection formulation is known to be more effective than placebo in those with severe opioid use disorder (Haight et al., 2019).
The most severe side effect is death by overdose, but overdose rates are less than methadone (Strain, 2019). All-cause mortality rates for those on buprenorphine is 4.3 per 1000 person-years when patients are in treatment and 9.5 per 1000 person-years when patients are out of treatment (Sordo et al., 2017).
Many people are maintained on buprenorphine indefinitely, but some are weaned. If weaning is to occur, it should be tapered gradually. Reducing the dose by 2 mg every 7 to 14 days is one strategy(Strain, 2019). More rapid tapers may be done but are not as effective. Some individuals who need to be rapidly weaned can have the dose reduced by 2 mg every one to three days (Strain, 2019).
Patients who are placed on buprenorphine after being on methadone may have withdrawal symptoms (Strain, 2019). Therefore, methadone should be reduced to less than 30 mg before starting buprenorphine to reduce the risk of withdrawal.