Current Drug Therapy

A practical guide for buprenorphine initiation in the primary care setting

Roberto León-Barriera, MD, Samantha Jayne Zwiebel, MD, MA and Vania Modesto-Lowe, MD, MPH
Cleveland Clinic Journal of Medicine September 2023, 90 (9) 557-564; DOI: https://doi.org/10.3949/ccjm.90a.23022

ABSTRACT

Buprenorphine is a safe and effective treatment for opioid use disorder but remains underutilized because a major challenge of conventional buprenorphine initiation (termed induction) is that the patient must already be in opioid withdrawal. Previous legal barriers and clinician lack of familiarity with the unique pharmacology of buprenorphine have also limited its use. In this review, we outline changes regarding buprenorphine prescribing laws and physician perceptions of buprenorphine. We also review buprenorphine pharmacology and novel low-dose buprenorphine induction procedures that can be adopted in primary care settings to improve treatment acceptability, retention, and outcomes.

KEY POINTS

  • Buprenorphine can be prescribed in the primary care setting, which can help improve treatment access and retention.

  • Standard induction of buprenorphine requires that patients be in mild to moderate opioid withdrawal.

  • Low-dose buprenorphine induction permits safe initiation of buprenorphine regardless of whether the patient is in withdrawal or has recently used opioids.

Buprenorphine is a safe and effective treatment for opioid use disorder (OUD) but remains underutilized owing to previous prescribing limitations, lack of physician familiarity with the unique pharmacology of buprenorphine, and the need for the patient to be in opioid withdrawal before initiating treatment. Low-dose buprenorphine induction (LDBI) is a recent treatment protocol that can be adopted in primary care settings to improve treatment acceptability, retention, and outcomes.

OUD is characterized by compulsive opioid use regardless of negative consequences.1 Individuals with OUD suffer a 15 to 20 times greater risk of mortality than that of the general population and at an unprecedented epidemic level.2 As of 2020, the US Centers for Disease Control and Prevention reported that 2.4 million people in the United States suffer from OUD,3,4 with only 6% to 7% likely to receive pharmacotherapy.4

Until recently, prescribing buprenorphine was limited by the Drug Abuse Treatment Act of 2000 and required completion of an 8-hour training course or addiction board certification to apply for a designated license (X-waiver) to treat.1,5 In 2021, the 8-hour training requirement was removed, though an X-waiver was still required, and clinicians were still limited by monthly patient caps.6 In December 2022, the Consolidated Appropriations Act of 2023 was signed into law, entirely eliminating the X-waiver requirement and monthly treatment caps, allowing clinicians to treat as many patients as they can support with buprenorphine.5

As of June 27, 2023, all who prescribe controlled substances must fulfill at least 1 of the following requirements before applying for or renewing their Drug Enforcement Administration registration: 8 hours of training on opioid or substance use disorders; board certification in addiction medicine or addiction psychiatry from the American Board of Medical Specialties, American Board of Addiction Medicine, or American Osteopathic Association; or graduation within 5 years in good standing from a medical, advanced practice, or physician assistant school in the United States that included at least 8 hours of opioid or substance use disorder curriculum.5

This easing of prescribing limitations presents an opportunity to expand buprenorphine treatment in primary care, thus increasing access to treatment for OUD. In this article, we review existing evidence supporting the use of buprenorphine in the primary care setting, provide an accessible overview of buprenorphine pharmacology, and describe buprenorphine induction protocols that can be adopted in primary care settings.

SHOULD PRIMARY CARE CLINICIANS PRESCRIBE BUPRENORPHINE?

Prior studies have found that primary care physicians (PCPs) regularly encounter patients with OUD and believe buprenorphine is an effective treatment for OUD, but do not always feel prepared to prescribe buprenorphine.7,8 One investigation found that 82% of individuals newly diagnosed with OUD had visited a PCP in the preceding 12 months.7 Another study in rural New England found that more than 80% of family physicians regularly encountered patients with OUD in their practice.8 Most of these physicians (73%) believed that they had a professional responsibility to treat OUD.8 More recently, a survey of physicians’ perceptions of pharmacotherapy for OUD found that 53 and 52 of 127 respondents indicated that buprenorphine decreases opioid cravings and fatal overdoses, respectively.9 Despite the interest of PCPs in treating OUD with buprenorphine and having some knowledge of this medication, they may not yet feel comfortable prescribing buprenorphine.10 A cross-sectional survey of PCPs found that approximately 80% of respondents were very or somewhat comfortable identifying OUD.10 However, only 36.9% were very or somewhat comfortable treating OUD with pharmacotherapy.10 Physician respondents identified lack of access to behavioral treatments and lack of experience with pharmacotherapy for OUD as the main reasons for feeling uncomfortable.10 The authors concluded that identifying comprehensive models of care and improving physicians’ sense of self-efficacy (one’s belief that one can succeed at a certain task) could help expand access to buprenorphine treatment through PCPs.10

The treatment of OUD in primary care clinics typically involves medications such as buprenorphine in conjunction with services to address psychosocial needs.7 Data from rural and community primary care settings that prescribe buprenorphine demonstrate superior treatment retention relative to designated buprenorphine clinics.6,11–13 Though this model has been implemented in the United States to varying degrees, 91% to 99% of opioid agonist treatment is prescribed by PCPs in France.6 French primary care settings have improved OUD outcomes with decreased fatal opioid overdoses and overall mortality,8 suggesting that PCPs with proper buprenorphine training are well poised to have an enormous impact on the trajectory of patients with OUD.

BUPRENORPHINE: PHARMACOLOGY AND FORMULATIONS

Pharmacology

Successful buprenorphine induction requires familiarity with its unique pharmacologic properties. Buprenorphine is a semisynthetic opioid with partial agonism at the mu-opioid receptor (MOR), antagonism at the kappa-opioid receptor, and agonism at the opioid receptor-like 1 receptor.2 There is controversy about the action of buprenorphine on the delta-opioid receptor, with some sources describing it as an agonist and others as an antagonist.2,14 Kappa-opioid receptor antagonism is thought to play a role in the antidepressant and antiaddictive properties of buprenorphine.15 Human and animal models show that kappa-opioid receptor activation by stress neuropeptides produces dysphoria and drug-seeking behaviors.15 There is current interest in studying buprenorphine and other kappa-opioid receptor antagonists as adjuncts to treat depression and drug-seeking behaviors.15 Buprenorphine’s actions at the MOR and opioid receptor-like 1 likely account for its rewarding and analgesic properties, while its action at the MOR decreases opioid cravings and withdrawal2 and is therefore considered the most pharmacodynamically significant in the treatment of OUD.

When binding to the MOR, buprenorphine acts as a partial agonist with high receptor affinity and potency, which can pose both clinical advantages and challenges.2,16 Because of the partial agonism at the MOR, buprenorphine demonstrates beneficial ceiling effects for respiratory depression, euphoria, and physiologic dependence that offer high clinical safety with relatively infrequent overdoses reported.2,16–19 Buprenorphine’s affinity for the MOR is about 120 times higher than that of oxycodone and 6.2 times higher than that of fentanyl16,20,21 and can therefore quickly and easily displace these opioids from the MOR.20 As a result of the ability of buprenorphine to displace almost all other opioids, in conjunction with its partial opioid-agonist activity, patients starting buprenorphine are at high risk of experiencing precipitated withdrawal.16 Precipitated withdrawal is characterized by the rapid onset of opioid withdrawal and occurs when the partial MOR agonist buprenorphine displaces a full MOR agonist, such as heroin, leading to a relative withdrawal despite a high percentage of MORs still being occupied.2,16

Formulations

Buprenorphine is available in a wide variety of formulations (Table 1)22,23 and is often paired with naloxone (an opioid antagonist) as a deterrent for misuse.2,22 Though naloxone has very limited oral bio-availability, it becomes highly bioavailable through insufflation (“snorting”) or intravenous injection, thus precipitating opioid withdrawal and reversing opioid overdose.2,22 It was believed that naloxone would therefore precipitate withdrawal if consumed intranasally or intravenously in combination with buprenorphine, but it should be noted that buprenorphine still has a binding affinity that is 10 times higher than naloxone.24 Although selecting the ideal formulation of buprenorphine for induction can seem daunting for the novice prescriber, we describe below a practical guide for induction.

View this table:
TABLE 1

Buprenorphine formulations and indications

STANDARD BUPRENORPHINE INDUCTION: METHOD AND CHALLENGES

Clinicians face a peculiar challenge in initiating buprenorphine for OUD using a standard induction approach. If buprenorphine is started in the setting of recent opioid use, as is expected in patients with OUD, it will cause precipitated withdrawal as the partial MOR agonist buprenorphine displaces almost all other opioids, including full MOR agonists.16 Successful induction is therefore difficult, but can be accomplished when patients abstain from opioids before initiating buprenorphine or when LDBI guidelines are followed.

Method

Standard buprenorphine induction requires that patients abstain from opioids and present with moderate withdrawal to initiate buprenorphine.19 Withdrawal should be measured by the clinical opiate withdrawal scale, an 11-item scale that is readily available online and in many clinical calculator applications.25 The patient’s clinical opiate withdrawal scale score should be greater than 12 prior to giving the first buprenorphine dose.2,17,19,26 Another challenge of the standard induction approach is that a 2-day process is recommended, with a maximum total dose of 8 mg on the first day.19

Guidelines from the Substance Abuse and Mental Health Services Administration suggest giving a single starting dose of 2 mg to 4 mg buprenorphine sublingual if the patient is in adequate withdrawal,19 though we recommend starting with 2 mg. If the patient experiences precipitated withdrawal (marked by an abrupt worsening of withdrawal), symptoms should be treated, and induction reattempted 24 hours later.19 However, if withdrawal symptoms are instead partially relieved, another 2-mg or 4-mg dose is given after 2 to 4 hours.19 This process can be repeated until with drawal symptoms are controlled, up to a total of 8 mg daily on the first day.19 The total dose received on the first day should then be prescribed for the next day, and the patient should return to clinic for the second day of induction.19 If the patient reports adequate symptom relief, the induction is complete.19 If symptoms are not yet controlled, the patient will resume the induction process of taking repeated 2-mg or 4-mg doses, with assessment of withdrawal symptoms every 2 to 4 hours.19 This process can be repeated as needed until a total of 16 mg of buprenorphine has been given on the second day, or until symptoms are controlled.19

Challenges

At a dose of 16 mg buprenorphine, it is believed that approximately 80% to 90% of MORs are occupied, and withdrawal symptoms should theoretically be controlled.27 Yet there is evidence that 16 mg may not suppress opioid cravings in severely dependent patients.27 Patients with severe OUD may require doses up to 24 to 32 mg (maximum approved dose) or even higher for adequate control of withdrawal and cravings.27–29

It is important to note that when the standard induction protocol was developed, heroin (a short-acting opioid) dominated the illicit opioid supply.17,19 Patients only needed to abstain from heroin for 4 to 12 hours before experiencing adequate withdrawal to safely start buprenorphine.17,19 However, with the shift from heroin to fentanyl as the current prevalent illicit opioid, the abstinence time required has dramatically increased.2,16,17,21,26 The total abstinence time required depends on the type of opioid used, and ranges from 4 hours for heroin to 36 to 48 hours for methadone, and 3 days or more is often needed for fentanyl.2,16,17,21,26,30 Notably, fentanyl users may experience buprenorphine-precipitated withdrawal even after prolonged abstinence.16,21,31 Fentanyl is stored in adipose tissue with chronic high-dose use,2,16,21,26,31 and therefore demonstrates an unexpectedly long renal clearance time despite a half-life comparable to that of heroin.30 Fentanyl’s prolonged clearance time as the drug is slowly released from adipose tissue likely accounts for why patients using fentanyl are at higher risk of precipitated withdrawal compared with other opioids.32 The prolonged clearance time and requirement of multiple days of abstinence can prove difficult for patients and may lead to treatment dropout or relapse.2,16,17,21,31

LOW-DOSE BUPRENORPHINE INDUCTION

LDBI strategies are designed to avoid precipitated withdrawal and are feasible to implement in the primary care setting.6,11,16 LDBI was first described (in English) in 2016 by Hämmig et al.17 This method was based on previous research showing that doses of 0.2 mg of buprenorphine did not precipitate withdrawal in patients taking methadone for OUD.33 LDBI involves giving very small doses of buprenorphine, with gradual dose increases. When the patient continues using full-agonist opioids or illicit opioids concurrently with LDBI, this approach is called the Bernese method.2,16,17 Hämmig et al described 2 cases in which this approach was taken.17 In case 1, the patient received an initial buprenorphine dose of 0.2 mg, followed by slowly increasing incremental doses of buprenorphine while tapering heroin use.17 After multiple attempts with conventional induction, the patient was weaned with the Bernese method, and on day 9, the patient had been 4 days without heroin while taking 12 mg/day of buprenorphine, and tolerated this process much better.17 In case 2, the patient was titrated slowly to a dose of 24 mg of buprenorphine with ongoing full-opioid-agonist use over 29 days.17 On day 29, full agonists were stopped without any symptoms of withdrawal.17

Buprenorphine films or tablets are often cut to make these smaller doses.34,35 Off-label use of the buprenorphine transdermal patch (dosed in micrograms) has also been reported.18 LDBI takes advantage of buprenorphine’s higher affinity for and slower dissociation from the MOR with commonly used full agonists (eg, heroin, fentanyl, oxycodone).2,16,17 In this manner, small doses of buprenorphine slowly displace full agonists at the MOR, without precipitating withdrawal.2,16,17

There are multiple LDBI protocols but no current standard protocols, with some more suitable protocols used in the supervised inpatient setting.2,16–18,26,34,36 Ahmed et al16 noted an excellent review of studied techniques. A 2022 case report of a patient with a 3-year history of treatment with a 72-mg daily dose of methadone who needed to switch treatments owing to age, excessive sedation, and inability to come into clinic regularly detailed LDBI over 3 days in the outpatient setting.34 A 2-mg/0.5-mg buprenorphine/naloxone sublingual film was cut into 4 parts (approximately 0.5 mg of buprenorphine each), and each piece was given in intervals of 30 minutes to 1 hour on the first day.34 On the second day, buprenorphine was increased to 4 mg, and on the third day, buprenorphine was increased to 8 mg.34 A methadone dose of 72 mg was administered after every successful induction of buprenorphine for the day for 3 days. Mild withdrawal was treated symptomatically. Methadone was fully discontinued on day 4 once stabilization was confirmed.34

Recommended protocols

For patients using fentanyl in the outpatient setting, we recommend one of the 3 induction protocols that are available online from Penn Medicine’s Center for Addiction Medicine and Policy and summarized in Table 2.36 The first protocol is more complex and occurs over the course of 4 days.36 For patients who may benefit from simpler dosing, patients can also complete a 2-day induction.36 Because cutting films or tablets can be cumbersome and may lead to less-precise dosing,37 some institutions have endorsed off-label use of buprenorphine buccal films (dosed in micrograms and approved for pain).36 Penn Medicine’s Center for Addiction Medicine and Policy also describes this approach.36 There is no current consensus on optimal time to fully discontinue MOR agonists,2 though a cross-titration from the full MOR agonist to buprenorphine is most desirable. Once the patient is on 16 mg of buprenorphine or higher and 90% of MORs are occupied, abrupt cessation of full agonists should theoretically not cause clinically significant withdrawal.25,35

View this table:
TABLE 2

Options for home buprenorphine induction

Though LDBI can seem complicated, it offers many clinical advantages. It decreases the risk of precipitated withdrawal, does not require that the patient already be in withdrawal to start buprenorphine, and may thus provide better treatment outcomes for patients, especially those using fentanyl.16 Additionally, the Bernese method of treating with LDBI while reducing full-agonist opioids is gaining popularity among patients.38

TIPS FOR MANAGING PRECIPITATED WITHDRAWAL

Even with appropriate precautions, precipitated withdrawal may occur during buprenorphine initiation. One theory of the mechanism of precipitated withdrawal proposes that an abrupt reduction in opioid tone in certain brain areas, including the locus coeruleus and mesolimbic areas, occurs and causes withdrawal.2 More specifically, neuroadaptations in MOR signaling caused by chronic exposure to high-dose opioids, followed by a sudden reduction of MOR occupancy by full MOR agonists, likely causes precipitated opioid withdrawal.2 Precipitated withdrawal—much dreaded and called “precip” by patients—constitutes a major risk to overcome during early induction.2,17

Withdrawal symptoms can include diarrhea, abdominal cramps, anxiety, yawning, rhinorrhea, lacrimation, myalgias, arthralgias, diaphoresis, and mydriasis,31,39 and can be quantified using the Clinical Opiate Withdrawal Scale.25 The medications noted in Table 3 can be used to alleviate symptoms of precipitated withdrawal and can also be used to facilitate induction.36,39,40 One current recommendation for managing precipitated withdrawal is to give 2 mg of buprenorphine every 1 to 2 hours, a strategy that may have limited utility in patients using fentanyl.26,31

View this table:
TABLE 3

Symptomatic management of opioid withdrawal

Another approach involves using high-dose buprenorphine, often referred to as macroinduction.21,31,39 This method relies on using repeated doses of 4 to 8 mg of buprenorphine to saturate MORs and reverse withdrawal symptoms.31,39 A recent case report from an emergency department setting detailed using a total dose of 20 mg of buprenorphine on the day of induction as a rescue strategy for precipitated withdrawal.31 Alternatively, macroinduction itself has also been described as an induction strategy, with a relatively low risk of precipitated withdrawal when given in various dose increments up to 32 mg in a single day.41 Macroinduction is typically used in emergency medicine settings and merits further study as it may not be suitable for the outpatient primary care setting given the intense monitoring that is required.39

TAKE-HOME MESSAGES

The increasing prevalence of OUD in the United States has led to mortality rates increasing to epidemic proportions. Buprenorphine is a MOR partial agonist approved for treatment of OUD. Advantages of induction with buprenorphine include its partial agonist properties that provide a ceiling effect and decrease the risk of overdose. Historically, buprenorphine treatment has been underutilized owing to prescribing restrictions and legal and pharmacologic barriers. While restrictions have been removed, thus positioning PCPs to be key prescribers of buprenorphine, pharmacologic challenges such as the risk of precipitated withdrawal still exist. Hence, standard induction guidelines suggest that patients take their first buprenorphine dose only after the onset of opioid withdrawal, which can be challenging with many patients now using fentanyl and experiencing complex, prolonged withdrawal.

LDBI is an alternate strategy that involves starting at and repeating small doses of buprenorphine and slowly titrating to therapeutic doses. These protocols can be implemented in primary care settings, with patients being able to complete most of the induction at home. Initiation in the primary care setting can help patients continue treatment and improves access to much needed OUD treatment.

DISCLOSURES

The authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.

Acknowledgments

The authors would like to thank Dr. Roberto León-Pérez and Dr. Agnes León-Barriera for their helpful comments and revision of the manuscript.

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