Behavioral Health Is Essential To Health • Prevention Works • Treatment Is Effective • People Recover

ADVISORY

Winter 2016 • Volume 15 • Issue 1

Sublingual and Transmucosal 

Buprenorphine for Opioid Use Disorder: 

Review and Update

This Advisory reviews current information on the 

use of sublingual and transmucosal buprenorphine 

for the medication-assisted treatment of opioid use 

disorder. The intended audiences are prescribing 

physicians, other healthcare professionals, and 

healthcare policymakers. Topics include new 

formulations of buprenorphine, the effectiveness and 

safety of buprenorphine treatment, contraindications 

and cautions (including medication interactions), 

informed consent and treatment agreements, treatment 

monitoring, and indications of diversion and misuse.

Opioid misuse remains a significant problem in 

the United States. According to the 2014 National 

Survey on Drug Use and Health (NSDUH), 914,000 

people ages 12 or older used heroin in the past year; 

586,000 had heroin use disorder.1 Nonmedical use 

of prescription pain relievers continues to be more 

widespread than heroin use—the NSDUH estimates 

that 4.3 million people currently engage in nonmedical 

use of pain relievers and that 1.9 million people have 

a pain reliever use disorder.1

Mortality and morbidity are significant concerns. 

Hospitalizations involving opioid overuse among 

adults increased more than 150 percent between 1993 

and 2012.2

 The National Center for Health Statistics 

reports that although deaths from opioid analgesics 

have leveled off in recent years, 16,235 people died 

of an opioid analgesic-related overdose in 2013. 

Heroin deaths nearly tripled between 2010 and 2013, 

increasing to 8,257 deaths in 2013.3

Medication-assisted treatment (MAT) is an important 

part of an effective response to opioid use disorder.4

MAT, “including opioid treatment programs, combines 

behavioral therapy and medications to treat substance 

use disorders.”5

 Products approved by the Food and 

Drug Administration (FDA) for use in treating opioid 

use disorder include methadone, buprenorphine (or 

buprenorphine with naloxone), and naltrexone.* These 

medications have been shown to be effective, safe, and 

cost-effective treatments when used and monitored 

properly.7

* More specifically, methadone and buprenorphine (or buprenorphine/

naloxone) are approved to treat opioid dependence; extended-release 

injectable naltrexone is approved for prevention of relapse to opioid use.

Is MAT “Recovery?”

Recovery status is best defined 

by factors other than medication 

status. Neither medication-assisted 

treatment of opioid addiction nor 

the cessation of such treatment 

by itself constitutes recovery. 

Recovery status instead hinges on 

broader achievements in health and 

social functioning—with or without 

medication support.

—Recovery experts A. Thomas McLellan and 

William White6

MAT, particularly with opioid agonist medications, has 

been found to reduce morbidity and mortality, decrease 

overdose deaths, reduce transmission of infectious 

disease, increase treatment retention, improve social 

functioning, and reduce criminal activity.7

 National 

and international health organizations, such as the 

American Society of Addiction Medicine (ASAM)8

and the World Health Organization,9 consider MAT an 

evidence-based best practice for treating opioid use 

disorder. A study10 involving needle exchange program 

participants suggests that those who misuse opioids are 

both aware of and interested in buprenorphine therapy. 

However, despite governmental and professional 

endorsement of MAT, and potential patients’ apparent 

interest in it, there remains a significant gap between 

the need for and the availability of this treatment.10,11
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ADVISORY

Behavioral Health Is Essential To Health • Prevention Works • Treatment Is Effective • People Recover 

Online DATA 2000 Waiver-Qualifying 

Training Resource

www.samhsa.gov/medication-assisted-treatment

/training-resources/buprenorphine-physician-training

The Drug Addiction Treatment Act of 2000 (DATA 2000) 

enables qualifying physicians to receive a waiver from 

the special registration requirements in the Controlled 

Substances Act in order to prescribe an opioid agonist for 

the medication-assisted treatment of opioid use disorder. 

The waiver applies to Schedule III, IV, or V medications 

specifically approved by FDA for the treatment of opioid 

use disorder. Buprenorphine-containing products are 

currently the only pharmacotherapy covered by DATA 

2000. To obtain a waiver, a physician must submit 

to the Substance Abuse and Mental Health Services 

Administration (SAMHSA) a notice of intent to prescribe 

buprenorphine. Detailed information on physician 

waiver qualifications can be found through SAMHSA’s 

Buprenorphine Waiver Management Web page (www

.samhsa.gov/medication-assisted-treatment/buprenorphine

-waiver-management). To qualify, a physician must hold 

a valid medical license, be registered with the Drug 

Enforcement Administration, be capable of referring 

patients to counseling and other services, and meet at least 

one of the following criteria:12

● Hold a subspecialty board certification in addiction 

medicine or addiction psychiatry

● Have completed not less than 8 hours of approved 

training

● Have participated as an investigator in one or more 

clinical trials leading to the approval of a narcotic drug in 

Schedules III, IV, or V for maintenance or detoxification 

treatment

● Have experience or training deemed by his or her state 

medical licensing board or the U.S. Department of Health 

and Human Services to demonstrate the ability to treat 

and manage opioid dependence

Buprenorphine Products

Buprenorphine is available either alone (the mono-product) 

or in combination with naloxone (the combination product). 

Naloxone is an opioid antagonist with low bioavailability 

when taken orally or sublingually; when the combination 

product is taken as directed, naloxone has little effect on 

the action and efficacy of buprenorphine.13 However, if the 

combination product is injected, the naloxone produces 

significant attenuation of buprenorphine’s effects and 

may precipitate acute withdrawal.14 The combination 

product is designed to be less subject to diversion and 

injection misuse than the mono-product. For this reason, 

the combination product is the preferred formulation for all 

patients, with the exception of pregnant women15 and those 

with a demonstrated allergy to naloxone.

Buprenorphine, both as a mono- and as a combination 

product, has long been available in sublingual tablet form. 

Newer formulations include a soluble buprenorphine/

naloxone film for sublingual or buccal use. The films 

dissolve more quickly than tablets, an advantage when 

monitored dose ingestion is indicated.16

Two new formulations (Zubsolv sublingual tablets and 

Bunavail buccal film) provide higher bioavailability 

of buprenorphine than other formulations. Higher 

bioavailability means that more buprenorphine enters the 

bloodstream, allowing for lower doses. For example, one 

Bunavail 4.2 mg/0.7 mg buccal film provides buprenorphine 

exposure equivalent to one Suboxone 8 mg/2 mg sublingual 

tablet;17 one Zubsolv 5.7 mg/1.4 mg sublingual tablet 

provides buprenorphine exposure equivalent to one 

Suboxone 8 mg/2 mg sublingual tablet.18

Exhibit 1 provides a list of available buprenorphine 

products. As the safety and efficacy of each of these 

products are considered equivalent, practitioners should 

use the most cost-effective formulation that is most 

appropriate for the patient. Medicare Part D and many 

state Medicaid programs cover buprenorphine products.

Review: Effectiveness and Safety 

of Buprenorphine

Research has shown buprenorphine to be an effective 

pharmacotherapy for treating opioid use disorder. Clinical 

trials have demonstrated the efficacy of buprenorphine 

through patient retention and reductions in opioidpositive drug test results. For example, a Cochrane 

review19 evaluated the effectiveness of buprenorphine 

maintenance with various formulations of buprenorphine 

and buprenorphine/naloxone compared with placebo 

and with methadone maintenance treatment. The authors 

examined 31 randomized clinical trials (involving 5,430 

participants). They found that, compared with placebo, 

buprenorphine was effective at retaining patients in 

treatment at any dose above 2 mg, and was effective at 
Sublingual and Transmucosal Buprenorphine for Opioid Use Disorder: Review and Update

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suppressing illicit opioid use at doses equivalent to 16 mg 

or greater. However, buprenorphine was not as effective as 

methadone at retaining patients in treatment.

Maintenance treatment with buprenorphine is more 

effective than short-term buprenorphine treatment followed 

by medication tapering. A recent study24 examined use of 

buprenorphine to treat patients dependent on prescription 

opioids. The study compared use of a buprenorphine taper 

(6 weeks stabilization plus a 3-week taper) with ongoing 

buprenorphine maintenance and found that maintenance 

was superior to tapering in both patient retention and rate 

of relapse to opioid use. Earlier, Weiss et al.25 found that 

patients being treated for prescription opioid dependence 

were most successful at reducing opioid use while 

receiving buprenorphine (with naloxone) treatment. Even 

after 12 weeks of medication treatment with concurrent 

counseling, tapering was associated with very high relapse 

rates (higher than 90 percent, 8 weeks post-taper).

Studies have also assessed the efficacy of treatment with 

buprenorphine products in primary care settings and have 

found that buprenorphine can be safely and effectively 

used in these settings.26,27

One characteristic of buprenorphine, a partial mu 

opioid agonist, is that it is safer than full agonists (e.g., 

methadone) because of its relatively poor bioavailability 

and its ceiling effect.15,28 The ceiling effect means that as 

the buprenorphine dose increases, its effects (including 

respiratory depression) increase but only to a point. A 

plateau is reached at moderate doses, meaning the effects 

no longer increase even as the dose is increased. This 

ceiling effect also means that buprenorphine carries a 

lower risk of misuse, dependence, and side effects than full 

agonists.15,28 However, there is still some risk of overdose, 

particularly if the patient concurrently uses another 

opioid, benzodiazepines, alcohol, sedatives, or certain 

medications that interact with buprenorphine (see Exhibits 

2–4). Overdose prevention education and a prescription 

for naloxone (in case of overdose) should be considered for 

all patients considering or receiving buprenorphine; these 

should be provided again prior to discontinuation of MAT. 

Exhibit 1. Buprenorphine Products for Treatment of Opioid Use Disorder

Product Name/Active 

Ingredient(s)

Route of 

Administration/

Form

Available 

Strengths

Recommended Once-Daily 

Maintenance Dose

Bunavail®17,20

• Buprenorphine hydrochloride

• Naloxone hydrochloride

Buccal film 2.1 mg/0.3 mg

4.2 mg/0.7 mg

6.3 mg/1 mg

Target: 8.4 mg/1.4 mg

Range: 2.1 mg/0.3 mg to 

12.6 mg/2.1 mg

Generic combination product20,21

• Buprenorphine hydrochloride

• Naloxone hydrochloride

Sublingual tablet 2 mg/0.5 mg

8 mg/2 mg

Target: 16 mg/4 mg

Range: 4 mg/1 mg to 

24 mg/6 mg*

Generic mono-product20,22 

• Buprenorphine hydrochloride

Sublingual tablet 2 mg

8 mg

Target: 16 mg

Range: 4 mg to 24 mg*

Suboxone®20,23

• Buprenorphine hydrochloride

• Naloxone hydrochloride

Sublingual film 2 mg/0.5 mg

4 mg/1 mg

8 mg/2 mg

12 mg/3 mg

Target: 16 mg/4 mg

Range: 4 mg/1 mg to 

24 mg/6 mg*

Zubsolv®18,20

• Buprenorphine hydrochloride

• Naloxone hydrochloride

Sublingual tablet 1.4 mg/0.36 mg

2.9 mg/0.71 mg

5.7 mg/1.4 mg

8.6 mg/2.1 mg

11.4 mg/2.9 mg 

Target: 11.4 mg/2.9 mg

Range: 2.9 mg/0.71 mg to 

17.2 mg/4.2 mg

* Dosages higher than 24 mg buprenorphine per day and 24 mg/6 mg buprenorphine/naloxone per day have not been demonstrated to provide a 

clinical advantage.22,23
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Behavioral Health Is Essential To Health • Prevention Works • Treatment Is Effective • People Recover 

Exhibit 2 provides contraindications and cautions for use 

of buprenorphine.

Patients dependent on opioids frequently have cooccurring medical conditions. Rates of HIV infection 

and hepatitis C virus (HCV) infection are particularly 

high in people who inject drugs. There appear to be 

fewer potential interactions between buprenorphine and 

antiretrovirals (ARVs) than between methadone and 

ARVs. One explanation is that because buprenorphine is 

absorbed sublingually (or buccally in newer formulations), 

it is less competitive with ARVs for absorption in the 

gastrointestinal tract.31

There appear to be no significant interactions between 

buprenorphine and most HCV medications. In particular, 

most direct-acting antivirals approved for the treatment 

of HCV do not have clinically significant interactions 

with buprenorphine.32 Exhibit 3 lists potential interactions 

between buprenorphine and HIV medications, specifically 

ARVs. Exhibit 4 lists potential interactions between 

buprenorphine and medications in several drug classes.

Exhibit 2. Buprenorphine and Buprenorphine/Naloxone Contraindications and Cautions

Contraindication/Caution Management

Demonstrated allergy/hypersensitivity 

to buprenorphine (or naloxone)

Do not prescribe.22

Compromised respiratory function

(e.g., chronic obstructive pulmonary 

disease, decreased respiratory reserve, 

hypoxia, hypercapnia [abnormally 

elevated carbon dioxide levels in the 

blood], preexisting respiratory 

depression)

Prescribe with caution; monitor closely.

Warn patients about the risk of using benzodiazepines or other 

depressants while taking buprenorphine.22

Hepatic impairment

Both buprenorphine and naloxone are 

extensively metabolized by the liver. 

Moderate to severe liver impairment 

results in decreased clearance, increasing 

overall exposure to both medications, and 

resulting in higher risk of buprenorphine 

toxicity and precipitated withdrawal from 

naloxone. These effects have not been 

observed in patients with mild hepatic 

impairment.22,29

Mild impairment (Child-Pugh score of 5–6):30 No dose adjustment 

needed.

Moderate impairment (Child-Pugh score of 7–9):30 Combination 

products are not recommended for induction with patients with 

moderate hepatic impairment as they may precipitate withdrawal.* 

However, combination products may be used with caution for 

maintenance treatment in patients with moderate hepatic impairment 

who have been inducted with a mono-product;23,29 patients should be 

carefully monitored for signs and symptoms of buprenorphine toxicity 

or overdose.22 Also consider the possibility of naloxone interfering 

with buprenorphine’s efficacy.23,29

Severe impairment (Child-Pugh score of 10–15):30 Do not use the 

combination product.29 With a mono-product, consider reducing 

the starting and titration doses by half compared with patients with 

normal liver function; monitor for signs and symptoms of toxicity or 

overdose caused by increased levels of buprenorphine.22

* Moderate to severe hepatic impairment results in reduced clearance of naloxone much greater than clearance of buprenorphine. Nasser et al.29

found that moderate hepatic impairment led to 2 to 3 times the exposure (compared with subjects with no or mild impairment) for both naloxone 

and buprenorphine. In subjects with severe hepatic impairment, buprenorphine exposure was also 2 to 3 times higher; however, naloxone 

exposure increased more than tenfold.

Patients should be closely monitored for cognitive effects and sedation when therapies are initiated or 

discontinued or dosage is changed. For the most current product-specific information, review the product 

label (Section 7, Drug Interactions) through Drugs@FDA—www.accessdata.fda.gov/scripts/cder/drugsatfda.
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Bruce et al.34 note some caveats to relying on the current 

research regarding interactions between buprenorphine 

and other medications:

● Many studies have small numbers of patients and may 

not be generalizable to all populations.

● Studies typically exclude patients with many of the 

disorders that people with HIV, HCV, or both commonly 

experience (e.g., hepatic and renal impairments).

● Most studies focus on single drug–drug interactions;

however, a patient is frequently taking several 

medications concurrently, the combination of which may

not have been studied.

● The need for and level of dose adjustments may vary 

widely between patients.

● The practitioner must remain alert to the possibility of a 

medication interaction even when existing data do not 

support such an interaction.

● When an interaction is likely (e.g., with atazanavir, 

central nervous system depressants, CYP3A4 inhibitors), 

the patient should be clinically monitored daily;

practitioners should keep in mind that the timing of 

symptom development is variable and depends on a 

variety of factors.

Exhibit 3. Potential Interactions Between Buprenorphine and HIV Medications

Medication Type Potential Interaction 

Atazanavir Protease inhibitor (PI) Increased buprenorphine concentrations. Some patients may 

experience cognitive impairment22,33 or oversedation.33,34 Slower 

titration or dose reduction of buprenorphine may be warranted.22,34

DarunavirritonavirPI Some pharmacokinetic (PK) effect; dose adjustments unlikely to be 

needed but clinical monitoring is recommended.35

Delavirdine Nonnucleoside 

reverse transcriptase 

inhibitor (NNRTI)

Increased buprenorphine concentrations, but no clinically significant 

effect. Dose adjustments unlikely to be needed. However, use with 

caution, as long-term effects (more than 7 days) are unknown.34,36

Efavirenz NNRTI Some PK effect; dose adjustments unlikely to be needed.36

Elvitegravir 

(with cobicistat)

Integrase inhibitor Some PK effect; no dose adjustments needed.37

Nevirapine NNRTI Some PK effect; no dose adjustments needed.38

Ritonavir PI Some PK effect; no dose adjustments needed.39

Tipranavir PI Some PK effect; no dose adjustments needed.40

Buprenorphine Induction and 

Stabilization/Maintenance

“The goal of induction and stabilization is to find the 

lowest dose of buprenorphine at which the patient 

discontinues or markedly reduces the use of other opioids 

without experiencing withdrawal symptoms, significant 

side effects, or uncontrollable craving for the [opioid] of 

abuse.”41

Induction strategies vary somewhat depending on 

individual patient variables and the type of opioid a 

patient is using. A discussion of models of buprenorphine 

induction is at www.pcssmat.org/wp-content/uploads

/2015/02/Buprenorphine-Induction-Online-Module.pdf.

Following treatment induction and stabilization is 

the maintenance phase. The maintenance dose of 

Suboxone sublingual film is generally in the range of 

4 mg/1 mg buprenorphine/naloxone to 24 mg/6 mg 

buprenorphine/naloxone per day, with a target of 

16 mg/4 mg as a single daily dose23 (see Exhibit 1 for the 

recommended maintenance target dosages and ranges for 

other formulations). The optimal maintenance dose of 
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Behavioral Health Is Essential To Health • Prevention Works • Treatment Is Effective • People Recover 

buprenorphine products will vary from patient to patient. 

Doses should be incrementally adjusted to a level that 

holds the patient in treatment and suppresses opioid 

withdrawal effects. Dosages higher than 24 mg/6 mg daily 

of buprenorphine/naloxone have not been demonstrated to 

provide a clinical advantage.23

Exhibit 4. Potential Interactions Between Buprenorphine and Other Drug Classes

Drug Class Potential Interaction 

Benzodiazepines Some reports of coma and death associated with misuse of the 

combination of buprenorphine (particularly via injection) and 

benzodiazepines.22,42 Decreased ceiling effects on buprenorphineinduced respiratory depression, making the respiratory effects 

similar to those of full mu opioid agonists.42,43 Dose reduction of the 

benzodiazepine, of buprenorphine, or both may be necessary. Patients 

should be warned to use these medications only as directed.22

Other central nervous system 

depressants (e.g., sedatives, hypnotics, 

general anesthetics, tranquilizers, other 

opioids, alcohol)

Increased risk of respiratory depression, profound sedation, 

hypotension, coma, and death.42

CYP3A4 inducers (e.g., phenobarbital, 

carbamazepine, phenytoin, rifampicin)

May cause increased clearance of buprenorphine, which could lead 

to decreased plasma concentrations, lack of efficacy, or possibly 

abstinence syndrome.22,42

CYP3A4 inhibitors (e.g., azole 

antifungals such as ketoconazole; 

macrolide antibiotics such as 

erythromycin; HIV protease inhibitors; 

antidepressants such as fluoxetine, 

fluvoxamine, amitriptyline)

May cause decreased clearance of buprenorphine, leading to 

increased buprenorphine plasma concentrations and resulting in 

increased or prolonged opioid effects. Patients should be monitored 

for respiratory depression and sedation.42 Dose reduction of either 

medication may be necessary.22

Nonbenzodiazepine muscle relaxants

(e.g., carisoprodol, cyclobenzaprine)

May cause an increased degree of respiratory depression.42

Anticholinergics (e.g., inhaler 

medications such as ipratropium 

bromide, oxitropium bromide, tiotropium; 

medications used to treat gastrointestinal 

and urinary tract disorders) 

Increased risk of urinary retention and/or severe constipation, which 

may lead to paralytic ileus.42

Psychostimulants: cocaine May increase metabolism and diminish plasma concentrations of 

buprenorphine.44

Informed Consent and Treatment 

Agreements

Informed consent and treatment agreements can clarify 

expectations of both practitioner and patient and provide a 

structure for effective monitoring.

Informed Consent

Practitioners need to discuss the risks and benefits of the 

treatments available (including other MAT and non-MAT 

options) for opioid use disorder and should also explain:41

● The difference between addiction and physical 

dependence and why MAT is not simply “switching one 

addiction for another.”

● The patient’s risk of relapse with and without MAT.

● The estimated duration of treatment with buprenorphine.

● Reasonable expectations for treatment results.

● The importance of counseling and peer support.

A written informed consent should be reviewed and signed 

by both the practitioner and the patient.
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Treatment Agreements

Treatment agreements should also be written and signed, 

and updated periodically as treatment progresses. Typical 

provisions of treatment agreements include:41

● Acknowledgment by the patient of the potential benefits 

and risks of treatment and the goals of treatment.

● Identification of one physician and one pharmacy to 

provide the patient’s opioid prescriptions (for MAT or for

other conditions).

● Authorization for the physician and staff to communicate 

with other named providers of care and, as needed, with 

significant others.†

†

 Communication authorizations must comply with federal law and regulations 

(Confidentiality of Alcohol and Drug Abuse Patient Records, 42 CFR Part 2).

● Agreement to participate in other treatments or 

consultations, including counseling, as directed.

● Acknowledgment that the physician will be using the 

state’s prescription drug monitoring program (PDMP; 

see Monitoring Strategies section, below).

● Agreement to avoid all illicit use of substances.

● Agreement to undergo toxicology screens and pill/film

counts upon request.

● Procedures to obtain prescriptions and refills, including

exclusion of early refills.

● Expected frequency of office visits.

Patients should be warned of the significant risk all 

forms of buprenorphine pose to children. Even very 

brief exposure to buprenorphine formulations can lead 

to sedation, respiratory depression, cerebral anoxia, and 

death.45 Because buprenorphine is absorbed through the 

lining of the mouth, a child does not need to swallow or 

chew the medication to have significant exposure, even if 

the medication is quickly taken out of the child’s mouth. A 

child exposed to buprenorphine in any way, even for a few 

seconds, requires immediate medical attention and hospital 

observation for 24 hours.45 Practitioners should include 

child-safety recommendations in treatment agreements, 

such as:45

● Keep medications in a location inaccessible to children 

(e.g., a locked or otherwise secure cabinet).

● Never store buprenorphine in anything other than a childresistant container.

● If a child is exposed, or is thought to have been exposed, 

to buprenorphine, call 911 immediately.

● Remember that sharing your medication with others

could put someone else’s household members at risk.

Behavioral Treatment

Concurrent behavioral treatment is a critical element 

of MAT. The ASAM National Practice Guideline 

recommends that prescribers offer patients behavioral 

treatment early in their buprenorphine treatment.8

 The 

guideline recommends that behavioral treatment should 

include, at minimum:8

● Assessment of psychosocial needs.

● Supportive individual or group counseling (or both).

● Linkages to existing family support systems.

● Referrals to community-based services.

ASAM notes that models of behavioral treatment that 

appear to be effective with patients being treated with 

buprenorphine are:8

● Cognitive–behavioral therapies.

● Contingency management.

● Relapse prevention.

● Motivational interviewing.

Mutual-help programs may also benefit patients but are 

not a substitute for behavioral therapy.

Research shows that when treating 

SUDs [substance use disorders], 

a combination of medication and 

behavioral therapies is the most 

effective. Behavioral therapies help 

patients engage in the treatment 

process, modify their attitudes and 

behaviors related to drug and alcohol 

abuse, and increase healthy life skills. 

These treatments can also enhance 

the effectiveness of medications and 

help people stay in treatment longer.46
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Behavioral Health Is Essential To Health • Prevention Works • Treatment Is Effective • People Recover 

Information about incorporating behavioral 

treatment can be found at:

www.pcssmat.org/new-pcss-mat-module-posted

-developing-a-behavioral-treatment-protocol-in

-conjunction-with-mat 

www.pcssmat.org/new-online-module-counseling

-mat-better-outcomes-with-integraded-care

Monitoring of Adherence and 

Response to Treatment

Effective monitoring of adherence and response to 

treatment can increase the likelihood of positive clinical 

outcomes and reduce the possibility of diversion.

Monitoring Strategies

Monitoring medication adherence in office-based settings 

should include unannounced urine toxicology screening, 

pill/film counts, and observed ingestion.47 State PDMPs 

should also be used.

Urine toxicology

Urine testing can be used to determine whether the patient 

is taking the prescribed buprenorphine and to test for 

illicit substance use. Point-of-service dipstick tests and 

laboratory testing may both be useful. The Providers’ 

Clinical Support System for Medication Assisted 

Treatment suggests these strategies to minimize patients’ 

ability to tamper with urine samples:47

● Don’t allow patients to take purses, backpacks, and so on 

into the bathroom.

● Turn off running water and color the toilet water to 

eliminate possible dilution.

● Monitor the bathroom door so that only the patient 

can go in.

● Test the temperature, specific gravity, and creatinine 

of the urine immediately after it has been voided.

It is important to remember that urine toxicology is only a 

tool and should not be relied upon exclusively for clinical 

decision making.

Pill/film counts

The practitioner should have the patient bring his or her 

medication container to each appointment to show that 

the medication is being taken as directed. Unannounced 

inventories can help ensure that medication is not being 

diverted.

Observed ingestion

Observed ingestion (having the patient take the medication 

in front of the practitioner or a trained monitor) at 

the beginning of buprenorphine therapy can help the 

practitioner ensure that the patient knows how to take 

the medication. Later in therapy, observing ingestion 

periodically can help patients adhere to therapy.

See SAMHSA’s Technical Assistance Publication 

(TAP) 32, Clinical Drug Testing in Primary Care, 

for additional information about drug testing.

Prescription drug monitoring programs

PDMPs are state-operated electronic databases that collect 

data on controlled substances (and, in some cases, overthe-counter medications) dispensed in the state. PDMPs 

help physicians monitor whether patients are obtaining 

the prescribed medication, obtaining prescriptions for 

controlled substances from other prescribers, or refilling 

prescriptions early. Where available, prescribers should 

register with and check the PDMP for each patient before 

buprenorphine induction and prior to writing prescriptions. 

So that there is clear communication and transparency, 

patients should be informed up front that the PDMP will 

be accessed to monitor their controlled prescription drug 

use. PDMP information can also help practitioners educate 

patients about the risk of overdose and potential drug–drug 

interactions, particularly related to benzodiazepines and 

other sedative-hypnotics.

The PDMP Training and Technical Assistance 

Center Web site provides current information 

about PDMPs at www.pdmpassist.org.
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Responding to Patient Behaviors

Practitioners should verbally acknowledge and 

reinforce a patient’s adherence to treatment, 

reduction of illicit drug use, and positive life changes. 

Practitioners may also concretely reinforce progress 

by reducing the frequency of office visits and/or 

increasing the patient’s responsibility for his or her 

medication.41 Some patients will continue to illicitly 

use opioids and/or other substances or relapse to 

opioid use after a period of abstinence. Other patients 

may have trouble adhering to the treatment plan 

(e.g., not taking buprenorphine as directed, missing 

appointments). Diversion or misuse of buprenorphine 

may also occur. Signs and behaviors suggestive of 

diversion and misuse of buprenorphine products 

include:47

● Unsupported claims of intolerance or allergy to 

naloxone to obtain the mono-product, which is more 

subject to misuse.

● Early requests for refills for unsubstantiated reasons 

(e.g., prescription was “lost” or “stolen”).

● Difficulty keeping appointments or providing 

payment.

● A sudden request for a dose increase by a previously 

stabilized patient.

● Positive toxicology screens for illicit substance use 

or negative toxicology screens for buprenorphine.

● Ongoing close ties to individuals (e.g., spouse, 

partner, significant others, friends) who sell opioids

or have opioid use disorder but are not in treatment.

Relapse or continued substance use are not reasons 

for automatically discontinuing MAT.41 Instead, either 

situation should prompt discussion with the patient 

and evaluation of the treatment plan. If the situation 

is handled well, a stronger patient–physician alliance 

can be formed. Changes to treatment should be 

made on an individual basis and could include any 

combination of the following: adjusting the patient’s 

buprenorphine dosage, increasing the frequency of 

office visits, requiring supervised administration, 

intensifying counseling, or encouraging the patient to 

engage in more intensive peer support programs.41,47

Some patients may require more structured treatment, 

such as that offered in a residential program or an opioid 

treatment program.41,47 See the Resources section of 

this publication for treatment locators.

Duration and Discontinuation 

of Treatment

The optimal duration of office-based buprenorphine 

treatment remains unclear. A decision to discontinue 

buprenorphine therapy should be made based on 

clinical judgment and upon mutual agreement by 

the practitioner and patient. ASAM suggests that 

certain factors may be associated with successful 

discontinuation of buprenorphine treatment:8

● Employment, engagement in mutual-help programs, 

or involvement in other meaningful activities

● Sustained abstinence from opioids and other 

substances during treatment

● Positive changes in the psychosocial environment

● Evidence of additional psychosocial supports

● Persistent engagement in treatment for ongoing 

monitoring past the point of medication 

discontinuation

Discontinuation of buprenorphine therapy requires a 

tapering regimen. ASAM recommends a slow taper 

(usually over several months) with close monitoring. 

A patient who relapses to illicit use of opioids should 

resume MAT.8

Resources

Relevant Publications From SAMHSA

(see back page for electronic access and ordering information)

Technical Assistance Publication (TAP) 30: 

Buprenorphine: A Guide for Nurses

TAP 32: Clinical Drug Testing in Primary Care

Treatment Improvement Protocol (TIP) 40: Clinical 

Guidelines for the Use of Buprenorphine in the 

Treatment of Opioid Addiction

TIP 43: Medication-Assisted Treatment for Opioid 

Addiction in Opioid Treatment Programs

Other Resources

Behavioral Health Treatment Services Locator

http://findtreatment.samhsa.gov

Buprenorphine Treatment Physician Locator

www.samhsa.gov/medication-assisted-treatment

/physician-program-data/treatment-physician-locator
10

ADVISORY

Behavioral Health Is Essential To Health • Prevention Works • Treatment Is Effective • People Recover 

Medication-Assisted Treatment Web Site

www.samhsa.gov/medication-assisted-treatment

Opioid Treatment Program Directory

http://dpt2.samhsa.gov/treatment/directory.aspx

National Alliance for Model State Drug Laws

www.namsdl.org/prescription-monitoring-programs.cfm

Poison Help Line

1-800-222-1222 (24 hours a day, 7 days a week)

www.aapcc.org

Prescription Drug Monitoring Program Center of 

Excellence

www.pdmpexcellence.org

Prescription Drug Monitoring Program Training and 

Technical Assistance Center 

www.pdmpassist.org

Providers’ Clinical Support System for Medication 

Assisted Treatment

www.pcssmat.org

Notes

1 Substance Abuse and Mental Health Services Administration. (2015). 

Behavioral health trends in the United States: Results from the 2014 

National Survey on Drug Use and Health. NSDUH Series H-50, HHS 

Publication No. (SMA) 15-4927. Rockville, MD: Substance Abuse and 

Mental Health Services Administration.

2 Owens, P. L., Barrett, M. L., Weiss, A. J., Washington, R. E., & Kronick, 

R. (2014). Hospital inpatient utilization related to opioid overuse 

among adults, 1993-2012. HCUP Statistical Brief #177. Rockville, MD: 

Agency for Healthcare Research and Quality.

3 Hedegaard, H., Chen, L.-H., & Warner, M. (2015, March). Drugpoisoning deaths involving heroin: United States, 2000–2013. NCHS 

Data Brief, No. 190. Hyattsville, MD: National Center for Health 

Statistics, Centers for Disease Control and Prevention. Retrieved 

January 20, 2016, from www.cdc.gov/nchs/data/databriefs/db190.pdf

4 National Institute on Drug Abuse. (2012). Principles of drug addiction 

treatment: A research-based guide (3rd ed.). NIH Publication No. 

12-4180. Bethesda, MD: Author.

5 Substance Abuse and Mental Health Services Administration. (n.d.). 

Medication-assisted treatment [Web page]. Retrieved January 22, 2016, 

from www.samhsa.gov/medication-assisted-treatment

6 McLellan, A. T., & White, W. (2012). Opioid maintenance and 

recovery-oriented systems of care: It is time to integrate (p. 2). London, 

England: National Treatment Agency for Substance Misuse. 

7 Volkow, N. D., Frieden, T. R., Hyde, P. S., & Cha, S. S. (2014). 

Medication-assisted therapies—Tackling the opioid-overdose epidemic. 

New England Journal of Medicine, 370(22), 2063–2066.

8 American Society of Addiction Medicine. (2015). National practice 

guideline for the use of medications in the treatment of addiction 

involving opioid use. Retrieved January 20, 2016, from www.asam.org

/docs/default-source/practice-support/guidelines-and-consensus-docs

/national-practice-guideline.pdf?sfvrsn=22

9 World Health Organization. (2009). Guidelines for the psychosocially 

assisted pharmacological treatment of opioid dependence. Geneva, 

Switzerland: Author.

10 Fox, A. D., Shah, P. A., Sohler, N. L., Lopez, C. M., Starrels, J. L., & 

Cunningham, C. O. (2014). I heard about it from a friend: Assessing 

interest in buprenorphine treatment. Substance Abuse, 35(1), 74–79.

11 Jones, C. M., Campopiano, M., Baldwin, G., & McCance-Katz, E. 

(2015). National and state treatment need and capacity for opioid 

agonist medication-assisted treatment. American Journal of Public 

Health. Advance online publication. doi:10.2105/AJPH.2015.302664

12 Substance Abuse and Mental Health Services Administration. (n.d.). 

Buprenorphine waiver management [Web page]. Retrieved January 20, 

2016, from www.samhsa.gov/medication-assisted-treatment

/buprenorphine-waiver-management

13 Chiang, C. N., & Hawks, R. L. (2003). Pharmacokinetics of the 

combination tablet of buprenorphine and naloxone. Drug and Alcohol 

Dependence, 70(Suppl. 2), S39–S47.

14 Yokell, M. A., Zaller, N. D., Green, T. C., & Rich, J. D. (2011). 

Buprenorphine and buprenorphine/naloxone diversion, misuse, and 

illicit use: An international review. Current Drug Abuse Review, 4(1), 

28–41.

15 Center for Substance Abuse Treatment. (2004). Clinical guidelines for 

the use of buprenorphine in the treatment of opioid addiction. Treatment 

Improvement Protocol (TIP) Series 40. HHS Publication No. (SMA) 

07-3939. Rockville, MD: Substance Abuse and Mental Health Services 

Administration.

16 Strain, E. C., Harrison, J. A., & Bigelow, G. E. (2011). Induction of 

opioid-dependent individuals onto buprenorphine and buprenorphine/

naloxone soluble-films. Clinical Pharmacology and Therapeutics, 

89(3), 443–449.

17 BioDelivery Sciences International. (2014). Bunavail (buprenorphine 

and naloxone) buccal film: Full prescribing information. Retrieved 

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18 Orexo US. (2015). Zubsolv (buprenorphine and naloxone) 

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22, 2016, from www.zubsolv.com/wp-content/uploads/2015/01

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19 Mattick, R. P., Breen, C., Kimber, J., & Davoli, M. (2014). 

Buprenorphine maintenance versus placebo or methadone maintenance 

for opioid dependence. Cochrane Database of Systematic Reviews, 

2014(2), i–84. doi:10.1002/14651858.CD002207.pub4
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Winter 2016, Volume 15, Issue 1

11

Behavioral Health Is Essential To Health • Prevention Works • Treatment Is Effective • People Recover

20 Food and Drug Administration. (n.d.). Drugs@FDA: FDA approved 

drug products. Retrieved January 22, 2016, through www.accessdata

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21 Roxane Laboratories. (2015). Buprenorphine and naloxone sublingual 

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22 Roxane Laboratories. (2015). Buprenorphine HCl sublingual tablets: 

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23 Indivior. (2015). Suboxone (buprenorphine and naloxone) sublingual 

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24 Fiellin, D. A., Schottenfeld, R. S., Cutter, C. J., Moore, B. A., Barry, 

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1954.

25 Weiss, R. D., Potter, J. S., Fiellin, D. A., Byrne, M., Connery, H. S., 

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26 Finch, J. W., Kamien, J. B., & Amass, L. (2007). Two-year experience 

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27 Mintzer, I. L., Eisenberg, M., Terra, M., MacVane, C., Himmelstein, 

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28 Substance Abuse and Mental Health Services Administration. (n.d.). 

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29 Nasser, A. F., Heidbreder, C., Liu, Y., & Fudala, P. J. (2015). 

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30 Durand, F., & Valla, D. (2008). Assessment of prognosis of cirrhosis. 

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31 Gruber, V. A., & McCance-Katz, E. F. (2010). Methadone, 

buprenorphine, and street drug interactions with antiretroviral 

medications. Current HIV/AIDS Reports, 7(3), 152–160.

32 Meemken, L., Hanhoff, N., Tseng, A., Christensen, S., & Gillessen, 

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33 McCance-Katz, E. F., Moody, D. E., Morse, G. D., Ma, Q., 

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34 Bruce, R. D., Moody, D. E., Altice, F. L., Gourevitch, M. N., & 

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36 McCance-Katz, E. F., Moody, D. E., Morse, G. D., Friedland, G., Pade, 

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ADVISORY

44 McCance-Katz, E. F., Sullivan, L. E., & Nallani, S. (2010). Drug 

interactions of clinical importance among the opioids, methadone and 

buprenorphine, and other frequently prescribed medications: A review. 

American Journal on Addictions, 19(1), 4–16.

45 Boyer, E. W., McCance-Katz, E. F., & Marcus, S. (2010). Methadone 

and buprenorphine toxicity in children. American Journal on 

Addictions, 19(1), 89–95.

46 Mann, C., Frieden, T., Hyde, P. S., Volkow, N. D., & Koob, G. F. (2014, 

July 11). Medication assisted treatment for substance use disorders

(p. 5). Informational Bulletin. Retrieved January 20, 2016, from www

.medicaid.gov/Federal-Policy-Guidance/downloads/CIB-07-11-2014

.pdf

47 Martin, J. (2014). PCSS Guidance: Adherence, diversion and 

misuse of sublingual buprenorphine. Retrieved January 20, 2016, 

from www.pcssmat.org/wp-content/uploads/2014/02/PCSS

-MATGuidanceAdherence-diversion-bup.Martin.pdf

SAMHSA Advisory

This Advisory was written and produced under contract numbers 270-09-0307 and 270-14-0445 by the Knowledge Application 

Program (KAP), a Joint Venture of JBS International, Inc., and The CDM Group, Inc., for the Substance Abuse and Mental 

Health Services Administration (SAMHSA), U.S. Department of Health and Human Services (HHS). Christina Currier and 

Suzanne Wise served as the Contracting Officer’s Representatives, and Candi Byrne served as KAP Project Coordinator.

Disclaimer: The views, opinions, and content of this publication are those of the authors and do not necessarily reflect the 

views, opinions, or policies of SAMHSA or HHS.

Public Domain Notice: All materials appearing in this document except those taken from copyrighted sources are in the 

public domain and may be reproduced or copied without permission from SAMHSA or the authors. Citation of the source is 

appreciated. However, this publication may not be reproduced or distributed for a fee without the specific, written authorization 

of the Office of Communications, SAMHSA, HHS.

Electronic Access and Copies of Publication: This publication may be ordered or downloaded from SAMHSA’s Publications 

Ordering Web page at http://store.samhsa.gov. Or, please call SAMHSA at 1-877-SAMHSA-7 (1-877-726-4727) (English and 

Español).

Recommended Citation: Substance Abuse and Mental Health Services Administration. (2016). Sublingual and Transmucosal 

Buprenorphine for Opioid Use Disorder: Review and Update. Advisory, Volume 15, Issue 1.

Originating Office: Quality Improvement and Workforce Development Branch, Division of Services Improvement, Center for 

Substance Abuse Treatment, Substance Abuse and Mental Health Services Administration, 5600 Fishers Lane, Rockville, MD 

20857.

SAMHSA Advisory

Sublingual and Transmucosal Buprenorphine 

for Opioid Use Disorder: Review and Update

HHS Publication No. (SMA) 16-4938 

Printed 2016