Chapter 21. Buprenorphine Maintenance

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Chapter 21. Buprenorphine Maintenance

BUPRENORPHINE MAINTENANCE: INTRODUCTION

Buprenorphine is a partial opioid agonist and antagonist that was synthesized in 1973 and initially

used for the treatment of pain. In the 1990s there developed growing evidence that buprenorphine was

also efficacious for the treatment of opioid dependence; individuals addicted to heroin submitted fewer

opioid-positive urine tests and reported less participation in illegal activities while receiving sublingual

buprenorphine maintenance treatment (Bickel et al. 1988b; Johnson et al. 1992, 1995b; Ling et al.

1996, 1998; Schottenfeld et al. 1997; Strain et al. 1994). Outside of the United States, several

countries, such as France, made buprenorphine available to general practitioners to prescribe in

office-based settings for the treatment of opioid addiction and results also were positive (Strain et al.

2003). However, in the United States during the 1990s, the Harrison Narcotic Act of 1914 continued to

make it illegal for physicians to prescribe opioids in an office-based setting for opioid addiction.

Methadone remained the primary opioid maintenance medication treatment, but its availability was

limited and many individuals who were addicted to opioids remained out of treatment despite having

sought treatment.

In 2000, Congress passed the Drug Abuse Treatment Act (DATA), and in 2002, the U.S. Food and Drug

Administration (FDA) approved buprenorphine for the treatment of opioid dependence. The DATA

allows Schedule III, IV, and V medications approved by the FDA for the treatment of opioid

dependence to be prescribed by qualified physicians in office-based practice. Buprenorphine is a

Schedule III controlled substance. Thus, buprenorphine is the first and currently only opioid available

to U.S. physicians for prescription in office-based opioid treatment (OBOT). The hope is that more

physicians will begin treating opioid-dependent adults, thereby increasing the availability of treatment

for opioid addiction. Opioid addiction is often a chronic relapsing disorder (McLellan et al. 2000), and

the movement of opioid addiction treatment into a physician office–based setting is consistent with the

treatment of other chronic medical illnesses. Increased access to physicians also may aid in the

prevention, diagnosis, and treatment of common medical and psychiatric comorbidities (Brooner et al.

1997; Fingerhood et al. 1993).

The purpose of this chapter is to provide an overview to buprenorphine treatment beginning with a

discussion of buprenorphine’s pharmacology. Evidence for buprenorphine’s clinical efficacy and

recommendations for use in OBOT within the United States and within special populations (e.g.,

pregnant women) is discussed. While the focus here is on buprenorphine OBOT in the United States, it

should be acknowledged that buprenorphine can be prescribed within methadone maintenance clinics

in the United States and that other countries outside the United States utilize buprenorphine in OBOT

but have different regulations governing its usage and employ different practice models that are

beyond the scope of this chapter (Fiellin and Strain 2006).

Preparation of this chapter was supported in part by National Institute of Health grants K12 DA14040, K02

DA00332, and R01 DA08045.

PHARMACOLOGY OF BUPRENORPHINE

Buprenorphine Doses and Formulations

Buprenorphine is available in sublingual tablets in two doses, 2 mg and 8 mg, both with and without

naloxone. Buprenorphine alone is marketed as Subutex, and combined with naloxone it is marketed as

Suboxone. Combination tablets are available in two doses: one with 2 mg of buprenorphine and 0.5 mg

of naloxone and one with 8 mg of buprenorphine and 2 mg of naloxone. The combination tablets are

recommended for OBOT, therefore mention of buprenorphine in clinical contexts will refer to the

combination product unless otherwise specified. Sublingual buprenorphine solution was used in many

of the initial clinical trials before the tablet formulation was available, but the solution is not currentlyPrint: Chapter 21. Buprenorphine Maintenance http://www.psychiatryonline.com/popup.aspx?aID=352366&print=yes…

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available for opioid dependence treatment. There is a parenteral form of buprenorphine, but this is

approved for pain treatment and it is not approved for opioid addiction treatment. A depot form of

buprenorphine is under investigation for use in opioid addiction treatment (Sigmon et al. 2004, 2006).

Receptor Profile

Buprenorphine is a partial opioid agonist and antagonist that is often referred to as a partial

agonist/antagonist or mixed agonist/antagonist. Buprenorphine’s activity at the opioid receptor is

primarily responsible for its efficacy in treating opioid addiction. Figure 21–1 illustrates the difference

between a partial and full opioid agonist. A partial agonist is defined as a drug that will bind to a

receptor and activate that receptor, but as the dose of the partial agonist increases, it will not produce

the same degree or intensity of maximal drug effects as can be produced by a full agonist. That is,

there is a ceiling to maximal opioid agonist effects (e.g., respiratory depression) that a partial opioid

agonist like buprenorphine can produce that is lower than the effects produced by a full opioid agonist

such as methadone (Walsh et al. 1994). The partial opioid agonist activity of buprenorphine enhances

its safety profile as compared with full opioid agonists.

FIGURE 21–1. Hypothetical dose response curve for a partial and full opioid agonist.

Bioavailability, Metabolism, and Half-Life

Buprenorphine has poor bioavailability when swallowed but fair bioavailability when taken

sublingually. Naloxone has poor sublingual bioavailability, therefore the combination tablet results

primarily in a buprenorphine effect when taken as prescribed (Strain et al. 2004). However, if the

combination tablet is crushed and injected intravenously in an attempt to get high, both drugs will be

bioavailable. If the person is physically dependent on opioids, naloxone will precipitate opioid

withdrawal, deterring future misuse by this route. Thus, the combination formulation was meant to

decrease buprenorphine diversion (e.g., selling on the street) and parenteral misuse/abuse that has

been reported by other countries that have only buprenorphine monotablets available (Lavelle et al.

1991; Robinson et al. 1993); San et al. 1989; Vidal-Trecan et al. 2003).

Buprenorphine is highly lipid soluble, crosses the blood brain barrier, circulates within the blood highly

plasma protein bound (96%), and undergoes metabolism by the liver primarily by the cytochrome P450

3A4 enzyme system (Marquet 2002; Zhang et al. 2003). Physicians should be aware of medications

that may interact with the P450 3A4 enzyme system and consequently alter the metabolism ofPrint: Chapter 21. Buprenorphine Maintenance http://www.psychiatryonline.com/popup.aspx?aID=352366&print=yes…

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buprenorphine. A table of P450 3A4 inducers, substrates, and inhibitors is available and periodically

updated online at http://medicine.iupui.edu/flockhart/table.htm (see also Cozza et al. 2003).

The primary metabolite of buprenorphine is norbuprenorphine, which is also a partial opioid agonist

(Huang et al. 2001), although it differs from buprenorphine in several ways. Norbuprenorphine has

only a fraction (2%–25%) of buprenorphine’s analgesic activity and it remains predominantly outside

the central nervous system (Marquet 2002; Ohtani et al. 1995). Both drugs are eliminated through the

feces and urine (Cone et al. 1984). Buprenorphine has a slow onset and offset of drug effects and a

mean terminal half-life of 37 hours (U.S. Food and Drug Administration 2002). This long half-life has

made less-than-daily opioid maintenance dosing possible (Johnson et al. 1995a, 2000).

Opioid Blockade

One of the important pharmacological features of any opioid agonist medication used to treat opioid

dependence is that, when taken as prescribed, the medication should block the effects of other opioids.

That is, if the person lapses and ingests another opioid while taking buprenorphine, buprenorphine

should, if dosed adequately, block the feeling high and good effects from that ingested opioid.

Laboratory studies with human volunteers who were addicted to opioids (primarily heroin) and

receiving buprenorphine maintenance treatment have demonstrated buprenorphine’s opioid blockade

effects (Bickel et al. 1988a; Correia et al. 2006; Jasinski et al. 1978; Rosen et al. 1994; Schuh et al.

1999; Strain et al. 1997, 2002). In addition, individuals self-administer less heroin when receiving

buprenorphine mainentance doses that suppress typical opioid agonist effects (Comer et al. 2001;

Mello and Mendelson 1980; Mello et al. 1982), indicating that opioid blockade decreases the drive

and/or desire to use opioids. Thus, if a patient lapses while taking buprenorphine and reports

significant opioid agonist effects, a buprenorphine dose increase should be strongly considered (Strain

2006b).

Withdrawal Suppression

A pharmacological advantage of opioid agonist medications over non-opioid agonist medications in

treating opioid dependence is that they will suppress opioid withdrawal symptoms among those who

are physically dependent, which in turn increases patient compliance and treatment retention, and

decreases illicit opioid use. Opioid withdrawal can be a contributing component to continued illicit

opioid use.

Buprenorphine decreases withdrawal signs and symptoms more than placebo among heroin addicts in

opioid withdrawal (Mendelson et al. 1996), and buprenorphine prevents the emergence of opioid

withdrawal when substituted for morphine in adults who are physically dependent on morphine

(Jasinski et al. 1984). Compared with individuals receiving clonidine, patients treated with

buprenorphine were more likely to complete a 5-day detoxification protocol (Fingerhood et al. 2001)

and report more early opioid withdrawal symptom relief (Cheskin et al. 1994).

Precipitated Withdrawal

Buprenorphine has a high affinity for the opioid receptor and because it is a partial opioid agonist, it

is possible that under certain conditions it could displace a full opioid agonist from the opioid receptor

resulting in less receptor stimulation. This decrease in receptor stimulation could precipitate opioid

withdrawal, although notably the withdrawal syndrome is not as severe as that produced by an opioid

antagonist (e.g., naloxone). There are three factors that appear to play a role in the occurrence of

buprenorphine-precipitated opioid withdrawal.

The current level of opioid physical dependence. The higher the level of current opioid physical dependence,

the more likely that buprenorphine will induce opioid withdrawal. For example, among opioid-dependent

research volunteers receiving 30 mg/day of oral methadone, acute doses of buprenorphine (administered 40

hours after the last methadone dose) produced no observable signs of opioid withdrawal, but there was

evidence of opioid withdrawal among volunteers receiving 60 mg/day of methadone who were administered

the same acute doses of buprenorphine (Walsh et al. 1995).

1.  

Time since the last opioid dose was taken. The shorter the duration of time since last opioid use, the greater

the likelihood that buprenorphine will induce opioid withdrawal. For example, buprenorphine produced signs

of opioid withdrawal 2 hours after the last methadone dose among volunteers receiving 30 mg/day of

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methadone, but did not produce opioid withdrawal signs when given 20 hours after the last methadone dose

(Strain et al. 1992, 1995).

The dose of buprenorphine administered. The higher the dose of buprenorphine administered, the more

likely that buprenorphine will precipitate opioid withdrawal (Strain et al. 1995; Walsh et al. 1995).

3.  

Thus, in order to avoid buprenorphine-related precipitated withdrawal, it is recommended that patients

present in mild, observable, spontaneous opioid withdrawal on the day of buprenorphine induction.

Patients physically dependent on methadone and requesting transfer to buprenorphine maintenance

treatment should decrease their methadone dosage to approximately 40 mg/day prior to

buprenorphine induction. Buprenorphine induction doses should be given at least 20 hours after the

last methadone dose and with observable signs of opioid withdrawal present in order to minimize the

risk of precipitated withdrawal.

BUPRENORPHINE VERSUS PLACEBO AND METHADONE

Compared with placebo, buprenorphine has superior outcomes on measures of treatment retention,

illicit opioid use, and opioid craving (Fudala et al. 2003; Johnson et al. 1995b; Kakko et al. 2003; Ling

et al. 1998). Daily buprenorphine (approximately 12 mg sublingually) appears to be as effective as

50–60 mg/day of methadone (Johnson et al. 1992; Strain et al. 1996) in reducing rates of

opioid-positive urine samples and maintaining subjects in treatment. One study reported that thrice

weekly dosing of buprenorphine (each dose was 16–32 mg of buprenorphine solution, which is

approximately equal to 24–48 mg of the tablet formulation) may be as effective as 60–100 mg/day of

methadone (Johnson et al. 2000). Several published reviews further detailing the clinical trials

conducted with buprenorphine are available (Ling and Wesson 2003; Mattick et al. 2003; Strain

2006a).

CLINICAL USE OF BUPRENORPHINE IN AN OFFICE-BASED SETTING

The clinical use of buprenorphine is relatively straightforward and physicians with limited substance

abuse treatment experience have reported success treating this population (Galanter et al. 2003). The

Substance Abuse and Mental Health Services Administration Center for Substance Abuse Treatment

(SAMHSA/CSAT) has published a comprehensive Treatment Improvement Protocol titled Clinical

Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction that outlines

best-practice guidelines for buprenorphine use in OBOT (McNicholas 2004). The SAMHSA book is

recommended for any physician or health care provider considering providing OBOT. (A free copy can

be ordered online at http://www.kap.samhsa.gov/products/manuals/index.htm.) The following

discussion highlights the major elements of OBOT.

Physician Requirements

The DATA states that only qualified physicians can prescribe an opioid through OBOT. Table 21–1 lists

the criteria necessary in order to be considered qualified. Once a physician has met these criteria he or

she can apply to SAMHSA for a waiver, which allows the physician to prescribe a Schedule III, IV, or V

opioid medication approved for the indication of opioid dependence treatment under the DATA. Most

buprenorphine training courses will assist with this process, and more information about this process

is online at http://www.fda.gov/cder/drug/infopage/subutex_suboxone/default.htm. Once the

waiver is granted, the physician will receive a new U.S. Drug Enforcement Administration (DEA)

number that begins with the letter X, which then allows the physician to begin prescribing

buprenorphine. Legislation in 2007 allows a physician to treat up to 30 patients concurrently in the

first year of practice, and after the first year, a physician can apply for an allowance to increase the

number of patients concurrently in treatment up to 100.

TABLE 21–1. Physician qualifications for buprenorphine office-based treatment

Valid state medical license and DEA certificate

Ability to refer patients for counseling or other nonpharmacological therapies when needed

Have one of the following:

1. Subspecialty board certification in addiction psychiatry from the American Board of Medical Specialties
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3. Subspecialty board certification in addiction medicine from the American Osteopathic Association
4. Completed an 8-hour training course on opioid dependence and its treatment a
5. Participated as an investigator in a clinical trial evaluating buprenorphine or another opioid medication for the

treatment of opioid addiction

aCourses must be sponsored by one of five specified medical societies.

Setting Up an Office-Based Practice

Prior to starting OBOT, physicians are encouraged to determine the specifics of how their practice will

function considering the anticipated patient population. Several important areas of consideration

include developing patient selection criteria and referral resources for psychosocial services and

common comorbid illnesses that the physician cannot treat on-site; making plans for dispensing

medication and urine toxicology testing; educating staff; assuring reimbursement for treatment

services; and developing a patient contract that outlines behavioral requirements and treatment

expectations (Fiellin and Strain 2006).

When considering patient selection criteria, the physician must determine whether he or she can safely

and effectively provide OBOT to a patient who is also concurrently physically dependent on alcohol,

benzodiazepines, and/or other sedative-hypnotics. If the answer is no, then the physician will need to

refer the patient for treatment elsewhere, at least until the patient is no longer physically dependent

on these other substances. While most clinical trials excluded volunteers with physical dependence on

drugs requiring medical detoxification, many studies did safely and successfully treat opioid addiction

among volunteers that frequently used benzodiazepines and cocaine.

Another consideration is whether the treating psychiatrist will be able and willing to treat

opioid-dependent patients with other major mental illnesses, such as bipolar disorder. If treatment

services are available on-site for these common comorbid psychiatric illnesses, the dually diagnosed

patient ideally should receive all psychiatric treatment services at the same location and with the same

physician. One of the major hopes of OBOT, in addition to increasing access to treatment for patients

with opioid addiction, is that more patients will have direct access to physicians so that comorbid

illnesses that are within that physician’s area of practice can be treated simultaneously. Off-site

referrals for patients with addictions commonly result in lack of follow-up, which in turn leads to

comorbid illnesses being untreated (Umbricht-Schneiter et al. 1994).

It is important to offer accessible, affordable, and good quality counseling services either on-site or

off-site; on-site is preferable to improve compliance. Counseling does not necessarily have to be

individual counseling and can include group and/or family therapy. Psychosocial counseling services

are integral to the treatment of patients with addiction and are associated with improved treatment

outcomes (Galanter et al. 2004; McLellan et al. 1993).

Physicians can dispense buprenorphine provided that they comply with the appropriate state law and

DEA requirements for storage, receipt, and dispensing of controlled substances. Advantages of

dispensing medication from the office include increased opportunities for therapeutic patient contact

and decreased risk that the patient will fill a prescription for buprenorphine induction and take the

medication before his or her scheduled induction date. Providing a prescription, however, certainly is

acceptable.

Urine drug testing is an integral feature of OBOT because it is one of the primary methods used to

guide treatment and determine patients’ progress in treatment. Arrangements for urine drug testing

should be made prior to starting OBOT because urine toxicology testing can vary widely in the methods

used, drugs tested, expense, and availability. For the purposes of OBOT, testing for the type of opioid

abused as well as other commonly abused drugs in the patient population and geographic area is

recommended. It is important to remember that if a patient is using prescription opioids, such as

Oxycontin or Lortab, that the standard opiate toxicology screen, which is for morphine, may not be

sensitive to these drugs and could result in a false negative test result. Testing specifically for

oxycodone and hydrocodone may be necessary. Methadone and buprenorphine also will not be detected

on an opiate-only urine drug screen. Qualitative urine drug testing is often sufficient (drug is presentPrint: Chapter 21. Buprenorphine Maintenance http://www.psychiatryonline.com/popup.aspx?aID=352366&print=yes…

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or absent); however, many commercial laboratories offer only quantitative testing that can be

prohibitively expensive. There are many inexpensive and easy-to-use qualitative urine tests available

for purchase so that urine testing can occur on-site if desired or needed (McNicholas 2004). Schedules

for urine toxicology testing should also be considered. Ideally, random urine drug testing should occur,

making it more difficult for patients to use illicit opioids on a schedule that allows their drug use to go

undetected. Patients can either be called by office staff on the day that their random drug test is due or

they can be instructed to call a phone number that gives a message with patient identification numbers

(without personal information) scheduled for urine testing that day.

Office staff and other medical professionals that will be in contact with potential patients should be

educated about OBOT to the extent that they will be interacting with patients. Payment for services

also should be determined because insurance coverage for substance abuse treatment varies widely,

and it would be unfortunate for patients and the physician to start treatment only to discover that

treatment services cannot be reimbursed.

A treatment contract is an important element of addiction treatment and a sample contract is provided

as Figure 21–2. A treatment contract typically outlines the expectations of patient behavior with the

consequences of noncompliance (e.g., missed office visits) along with treatment requirements (e.g.,

urine toxicology testing and random pill counts). This contract should be available to the patient so

that it can be explicitly reviewed and signed by patients before starting treatment. Modifications can be

made to the standard contract throughout a patient’s course of treatment so that it becomes tailored to

the patient’s progress and ongoing needs.

FIGURE 21–2. Sample treatment contract.Print: Chapter 21. Buprenorphine Maintenance http://www.psychiatryonline.com/popup.aspx?aID=352366&print=yes…

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Initial Patient Evaluation

Only opioid-dependent patients can receive buprenorphine treatment. Criteria used to diagnose opioid

dependence are listed in Table 21–2. In addition to establishing the diagnosis of opioid dependence, a

thorough evaluation should be completed that involves the same components as any otherPrint: Chapter 21. Buprenorphine Maintenance http://www.psychiatryonline.com/popup.aspx?aID=352366&print=yes…

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comprehensive medical evaluation (e.g., complete psychiatric and detailed substance abuse history,

personal and family history, review of systems, physical exam, mental status exam, and screening

laboratories). There are several purposes of this initial evaluation, including establishing diagnoses,

appropriateness for treatment, initial treatment recommendations, and possible problems outside of

opioid addiction that may need follow-up and continued assessment early in treatment.

TABLE 21–2. DSM-IV-TR criteria for substance dependence

A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by

three (or more) of the following, occurring at any time in the same 12-month period:

(1) tolerance, as defined by either of the following:

(a) a need for markedly increased amounts of the substance to achieve intoxication or desired effect

(b) markedly diminished effect with continued use of the same amount of the substance

(2) withdrawal, as manifested by either of the following:

(a) the characteristic withdrawal syndrome for the substance (refer to Criteria A and B of the criteria sets for

Withdrawal from the specific substances)

(b) the same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms

(3) the substance is often taken in larger amounts or over a longer period than was intended

(4) there is a persistent desire or unsuccessful efforts to cut down or control substance use

(5) a great deal of time is spent in activities necessary to obtain the substance (e.g., visiting multiple doctors or

driving long distances), use the substance (e.g., chain-smoking), or recover from its effects

(6) important social, occupational, or recreational activities are given up or reduced because of substance use

(7) the substance use is continued despite knowledge of having a persistent or recurrent physical or

psychological problem that is likely to have been caused or exacerbated by the substance (e.g., current cocaine

use despite recognition of cocaine-induced depression, or continued drinking despite recognition that an ulcer

was made worse by alcohol consumption)

Specify if:

With Physiological Dependence: evidence of tolerance or withdrawal (i.e., either Item 1 or 2 is present)

Without Physiological Dependence: no evidence of tolerance or withdrawal (i.e., neither Item 1 nor 2 is

present)

Course specifiers (see text for definitions):

Early Full Remission

Early Partial Remission

Sustained Full Remission

Sustained Partial Remission

On Agonist Therapy

In a Controlled Environment

Baseline laboratories should be completed before treatment is initiated. Recommended tests include

serum electrolytes, liver function tests (LFTs), hemogram, urine toxicology tests for opioids as well as

other common drugs of abuse in the patient population, and a pregnancy test for females. Hepatitis B

and C, rapid plasma reagin, and HIV testing as well as purified protein derivative placement should

also be considered based on each patient’s risk factors for these infectious diseases.

For patients desiring OBOT that the clinician is not already familiar with, it can be helpful to contact an

outside treatment provider or close family member or friend that can help gauge the suitability of the

patient for OBOT, confirm the diagnosis of opioid dependence, and help ensure a successful induction

on buprenorphine. For example, if a patient presents from a methadone maintenance clinic, it is

important to contact the clinic and confirm the reason for transferring care and to find out if there were

significant problems with clinic attendance, behavior, or nonadherence to treatment. If it is decided toPrint: Chapter 21. Buprenorphine Maintenance http://www.psychiatryonline.com/popup.aspx?aID=352366&print=yes…

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accept a patient in OBOT from a methadone clinic, it is important that the methadone clinic arrange for

a methadone dose taper to approximately 40 mg/day and know when the last dose of methadone

should be given based on the scheduled buprenorphine induction date.

Dose Induction

Induction is the initial phase of treatment with buprenorphine. The goals of induction are to engage the

patient in treatment, begin buprenorphine dosing, alleviate opioid withdrawal, and initiate a process

that will lead to abstinence from illicit opioid use. While abstinence from illicit opioid use is the

ultimate goal of OBOT, it may not be achieved in the induction phase; however, abstinence is discussed

with the patient with regard to the long-term treatment plan, and opioid use often begins to decrease

during this phase.

The initial evaluation and buprenorphine induction are typically completed on separate days. This

allows baseline laboratories to be completed and any outside information to be gathered. If patients

will be filling a prescription for buprenorphine and bringing it with them to use for induction, it is

recommended that the physician write for a medication pick-up date no more than 1 day prior to

scheduled induction. This decreases the likelihood the patient will start the medication on their own.

Patients should be instructed to come for their induction appointment in mild opioid withdrawal. This

will decrease the risk of buprenorphine-precipitated withdrawal and increase the likelihood of

withdrawal suppression. Patients should also be told to expect to spend approximately 2 hours in the

office during the induction day. This observation period allows for an initial dose of 4 mg to be given

along with an additional 4-mg dose approximately 1–2 hours later if there is continued evidence of

opioid withdrawal. The maximum dose recommended for the first day is 8 mg.

Dose increases on subsequent days can occur at the doctor’s office or patients can increase their dose

on their own, provided they are given clear instructions on how to do so and are given ready access to

the physician or nursing staff if they have questions. Over subsequent days, the dose may be increased

with generally no more than an 8-mg/day increase (McNicholas 2004). Dose increases during the

induction phase should be based on the presence of opioid withdrawal and craving.

Maintenance

The maintenance phase of OBOT begins when there is evidence of significantly reduced illicit opioid use

and when the patient no longer has evidence of significant signs of opioid withdrawal. The patient

should progress steadily toward sustained opioid abstinence during this phase. Further dosage

increases may occur during this phase based primarily on evidence of continued opioid use, particularly

if the patient reports inadequate opioid blockade and is compliant with buprenorphine ingestion. The

frequency of dosage increases may be decreased during the maintenance phase in order to determine if

an increase produces a change in urine toxicology results. The final stabilization dosage may vary

greatly among individuals but likely will range between 8 mg/day and 32 mg/day (Strain 2006a), with

the majority of patients stabilizing in the range of 8–24 mg/day (McNicholas 2004). Continued opioid

use in the context of repeated dosage increases and counseling may require referral to a more

intensive treatment setting, such as a methadone maintenance clinic.

Due to the long half-life of buprenorphine, less-than-daily dosing is possible during the maintenance

phase (Johnson et al. 1995a, 2000). For example, buprenorphine dosing three times a week (e.g.,

Monday, Wednesday, and Friday) can be accomplished by multiplying the daily maintenance dose by

two for Monday and Wednesday doses and by three for Friday doses to allow for the additional day

over the weekend. Thus, if a patient is receiving 12 mg/day and conversion to dosing three times a

week is desired, 24 mg would be taken on Monday and Wednesday, and 36 mg would be taken on

Friday.

Treatment Monitoring

The frequency of urine testing and office visits for counseling and medication prescription and

dispensation has not been well established. Most clinical trials involved daily visits for medication

dispensation and thrice-weekly urine testing, which is not feasible or expected for OBOT. One study of

patients receiving buprenorphine maintenance treatment (dose range 16–24 mg/day) in a primary

care clinic demonstrated that frequent medication dispensation and counseling visits by a trained nursePrint: Chapter 21. Buprenorphine Maintenance http://www.psychiatryonline.com/popup.aspx?aID=352366&print=yes…

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(3 days/week with counseling sessions lasting 20–45 minutes) was not superior to once-weekly

medication dispensation and counseling visits (20 minutes duration) for outcomes of decreased opioid

use, increased opioid abstinence periods, or retention in treatment (Fiellin et al. 2006). In addition,

patient satisfaction was higher for weekly visits than for thrice-weekly visits.

The current recommendation is for patients to initially be seen weekly (McNicholas 2004). Less

frequent visits may be possible and appropriate once the patient has progressed to the maintenance

phase, has shown evidence of drug abstinence, and is deemed appropriate for less frequent monitoring

based on treatment needs. However, physicians will need to determine on a case-by-case basis the

appropriate frequency of visits when significant barriers to weekly visits arise, such as long driving

distances (e.g., patients in rural areas) and child care and work responsibilities. Less-than-monthly

visits or more than a 30-day prescription is not currently recommended.

It is important to remember that the purpose of office visits is not only to assess drug use and deliver

psychosocial and counseling services aimed at helping the patient achieve and maintain drug

abstinence but also to help in the overall rehabilitation of the person. For example, it may become clear

that the patient has an independent psychiatric disorder, such as a mood or anxiety disorder; has a

newly diagnosed HIV or hepatitis C infection; lacks jobs skills or drug abstinence supports; or requires

further physician and/or counselor assistance for these problems. In these cases, more frequent doctor

and/or counselor visits may be appropriate.

Although opioid agonist treatment is effective for the treatment of opioid addiction, continued opioid

use can be a problem for some patients. For example, opioid-dependent patients in methadone

maintenance treatment typically attend fewer than half of their prescribed counseling sessions (Kidorf

and Stitzer 1999) and treatment retention was less than 50% in the OBOT study mentioned earlier by

Fiellin et al. (2006). Addressing poor attendance and progress in treatment can be difficult; a

comprehensive evaluation of the patient should determine the barriers to a patient’s success. Even if

barriers can be identified, it can be difficult to address them if the patient fails to attend appointments.

One strategy that has had considerable success in motivating patients with illicit drug use disorders to

decrease drug use and comply with treatment is contingency management (Higgins and Silverman

1999). Contingency management uses rewards to motivate patients to change their behavior. It may

be possible to structure a treatment plan in OBOT using the number of medication doses (through a

prescription or dispensing through the office) or frequency of office visits as a reward for treatment

progress. For example, once the patient has remained on a stable maintenance dosage of

buprenorphine for 2 weeks or more and has demonstrated urine tests that tested negative for illicit

drug use consecutively for 2 weeks or more, the patient could earn 2 weeks of buprenorphine

prescription (versus 1 week). When there is a lapse or noncompliance with treatment, the patient

would be required to go back to weekly visits and weekly prescriptions with the opportunity of earning

the reward again after documented drug abstinence. Evaluation of other treatment goals (e.g., having

at least one outside drug-abstinent friend or family member supportive of the patient’s treatment,

obtaining work, or engaging in some other structured activity) may also be used as a reward to

determine the frequency of visits or number of days of buprenorphine medication dispensed. The use of

rewards and steps up and down in terms of treatment intensity has been successfully implemented in

methadone maintenance clinics and is worthy of consideration for use in OBOT (Brooner et al. 2004).

Drug Safety and Side Effect Profile

Respiratory depression

Buprenorphine has an enhanced safety profile in contrast to full agonist opioids because of its ceiling

effects on respiratory depression. However, when buprenorphine is misused and injected, especially if

combined with other central nervous system depressants, such as a parenteral benzodiazepine,

clinically significant respiratory depression can occur and result in death (Kintz 2001; Reynaud et al.

1998).

Liver function

Moderate to severe hepatic pathology (i.e., jaundice, panlobular necrosis, and steatosis) has been

reported among hepatitis C–positive patients who misused and injected high doses of buprenorphinePrint: Chapter 21. Buprenorphine Maintenance http://www.psychiatryonline.com/popup.aspx?aID=352366&print=yes…

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and also reported use of other potentially hepatotoxic substances (e.g., alcohol and acetominophen)

(Berson et al. 2001). However, when taken as prescribed, buprenorphine is generally well tolerated by

the liver. A clinical trial of methadone- and buprenorphine-maintained volunteers found no significant

differences between the two medications in the rate of development of abnormal LFTs or further

elevation of LFTs among those volunteers with abnormal LFTs prior to treatment (Lofwall et al. 2005).

One study reported small increases in aspartate transaminase (median increase of 9.5 U/L) and

alanine transaminase (median increase of 8.5 U/L) among patients with hepatitis C infection receiving

buprenorphine maintenance treatment, although there was no clear clinical significance associated

with these increases (Petry et al. 2000). It is prudent to obtain baseline LFTs prior to buprenorphine

induction and periodically during maintenance treatment with consideration of more frequent

monitoring for patients with hepatitis C or pre-existing liver pathology. Elevated LFTs at baseline do

not necessarily exclude a patient from buprenorphine maintenance treatment.

Other side effects

Chronic dosing with buprenorphine is not associated with significant cognitive or psychomotor

impairment (Mintzer et al. 2004) or electrocardiogram (ECG) QTc prolongation (Wedam et al. 2004).

Buprenorphine produces a similar side effect profile as methadone. Commonly reported side effects

include constipation, nausea, decreased interest in sex, headache, upset stomach, feeling

groggy/sleepy after medication, and diarrhea; most side effects are mild in severity and decrease as

time in treatment continues (Lange et al. 1990; Lofwall et al. 2005).

Duration of Treatment and Withdrawal From Buprenorphine

There is no time requirement or restriction to the length of time patients can receive buprenorphine

maintenance treatment. In general, relapse to illicit opioid use and treatment dropout is high during

opioid detoxification (Resnick et al. 1992), such that opioid addiction is considered a chronic, relapsing

disorder deserving of ongoing treatment and monitoring much like other chronic medical illnesses

(e.g., diabetes mellitus) (McLellan et al. 2000). Patients receiving methadone maintenance treatment

for up to 18 years have not suffered adverse medical consequences as a result (Novick et al. 1993).

While patients may express worry about becoming addicted to buprenorphine and want to stop taking

buprenorphine once they achieve opioid abstinence, it is important to remind the patient of the

ultimate goal, which is to continue to not use illicit drugs and to achieve and maintain other life goals

(e.g., employment, meaningful relationships, successful management of comorbid disorders).

If it is decided that the patient should stop receiving buprenorphine, a gradual detoxification is

recommended, based on data from methadone detoxifications showing that longer and more gradual

dose reductions are associated with less opioid drug use and a less intense opioid withdrawal

syndrome (Gossop et al. 1989; Senay et al. 1977). Buprenorphine withdrawal may be less severe and

better tolerated by patients than methadone withdrawal because of its partial agonist activity (Kosten

and Kleber 1988; Kosten et al. 1992). Urine drug testing should continue through the detoxification

period and if illicit drug use resumes, there should be strong consideration for stopping the

detoxification and resuming maintenance treatment.

Once detoxification is complete, the patient’s progress should be followed, urine test results should be

monitored, and naltrexone treatment should be considered. This continuation of treatment, albeit

without buprenorphine, allows for continued assessment, rehabilitation, and management of the

patient’s drug use disorder and related conditions. Recognition that opioid addiction as a chronic illness

may require multiple courses of opioid maintenance treatment or chronic maintenance treatment will

greatly improve the continuity and overall quality of care for these patients.

SPECIAL POPULATIONS

Pregnant Opioid-Dependent Females

Methadone is the standard of care for the treatment of opioid addiction during pregnancy. Given the

limited availability of methadone treatment, having another effective pharmacotherapy for the

treatment of pregnant opioid-dependent women would be useful, and buprenorphine is currently under

investigation in a large, multisite, randomized clinical trial as a potential treatment for opioid addiction

in this population. When buprenorphine is prescribed to pregnant women for off-label use, it isPrint: Chapter 21. Buprenorphine Maintenance http://www.psychiatryonline.com/popup.aspx?aID=352366&print=yes…

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prescribed without naloxone.

Several case reports and open-label studies of buprenorphine maintenance treatment during pregnancy

have reported decreases in illicit opioid use among pregnant women with similar incidence of and

possibly decreased severity of the neonatal abstinence syndrome among their newborns (Johnson et

1. 2003). Neonatal abstinence syndrome is an important outcome in determining whether

buprenorphine is safe and effective for use in this vulnerable population. It is characterized by

multisystem dysfunction including autonomic, respiratory, and gastrointestinal distress, and it can be

fatal to the newborn if left untreated. Two small randomized and controlled studies compared

methadone and buprenorphine maintenance treatment in pregnant women and results supported

earlier findings that buprenorphine appeared safe and effective. There were similar incidences of

neonatal abstinence syndrome among newborns of buprenorphine-treated pregnant women compared

with those receiving methadone maintenance treatment (Fischer et al. 2006; Jones et al. 2005). In

addition, the study by Jones et al. (2006) reported that neonates born to pregnant women receiving

buprenorphine maintenance treatment had shorter hospital stays compared with neonates born to

pregnant women receiving methadone maintenance treatment, which resulted in significant cost

savings.

Patients With HIV

Integration of buprenorphine OBOT into HIV clinical care models can be an effective way to deliver

both addiction and HIV treatment simultaneously, resulting in significant decreases in illicit drug use

along with reductions in HIV viral load (Sullivan et al. 2006). There have been concerns about possible

buprenorphine-HIV medication interactions, as many HIV medications interact with the cytochrome

P450 3A4 system. However, studies to date have demonstrated an overall lack of clinically significant

interactions (e.g., signs and symptoms of opioid excess or withdrawal, ECG QTc prolongation) that

would require alteration of buprenorphine doses (Bruce et al. 2006). These studies have investigated

buprenorphine in combination with the protease inhibitors nelfinavir, lopinavir/ritonavir, and ritonavir;

the non-nucleoside reverse-transcriptase inhibitors efavirenz and delavirdine; and the nucleoside

reverse-transcriptase inhibitor zidovudine (QTc prolongation not evaluated for zidovudine) (Baker et

1. 2006; McCance-Katz et al. 2001, 2006a, 2006b).

There is a report of a possible medication interaction between buprenorphine and atazanavir/ritonavir.

A case report describes three HIV-positive patients developing clinically significant signs of opioid

excess with buprenorphine and atazanavir/ritonavir, including sedation, feeling “doped up” and high,

dizziness, and exhibiting “decreased mental functioning” (Bruce and Altice 2006). One patient had

been maintained on 14 mg/day of buprenorphine when atazanavir/ritonavir was added to the existing

HIV drug regimen, while the other two patients had been maintained on atazanavir/ritonavir and were

then inducted on buprenorphine (8 mg/day). Buprenorphine dose reductions subsequently ameliorated

the symptoms in all three patients. This potential drug interaction may be minimized during

buprenorphine induction by using 4 mg as an initial dose, observing patients closely for signs of opioid

excess, and by providing small dosage increases (2 mg) during the induction and maintenance phase.

Providers should be aware of potential drug interactions with buprenorphine and monitor patients

accordingly.

Patients Experiencing Pain

The treatment of pain among opioid-addicted patients, particularly for those with chronic pain, with

opioid analgesics is a controversial topic and the guidelines for the treatment for acute and chronic

pain in subjects receiving buprenorphine maintenance treatment are limited (Alford et al. 2006;

McNicholas 2004). For all buprenorphine-maintained patients with complaints of pain, it is preferable

to continue buprenorphine maintenance treatment and attempt to manage the pain with non-opioid

medications (e.g., acetaminophen and nonsteroidal anti-inflammatory drugs [NSAIDs]) and

nonpharmacological interventions when possible. When these methods are not successful, it is helpful

to distinguish between patients with acute pain and those with chronic pain.

Acute pain

The possible treatment options for acute pain management include the following:Print: Chapter 21. Buprenorphine Maintenance http://www.psychiatryonline.com/popup.aspx?aID=352366&print=yes…

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Provide the patient with buprenorphine maintenance treatment, but divide the daily dose into four doses in

attempt to maximize the analgesia from each individual dose. Buprenorphine was initially approved as an

analgesic; however, when prescribed for analgesic purposes it is dosed multiple times per day. Add

non-opioid analgesics if the divided doses are not adequate to determine if the combination can provide

adequate pain relief.

Provide the patient with buprenorphine maintenance treatment, but titrate a short-acting full opioid

agonist to achieve adequate analgesia. Although the pharmacology of buprenorphine would make this seem

like an ineffective analgesic plan because of its tight binding to the opioid receptor and its opioid blockade

effects, a recent case report suggests otherwise. Two pregnant women participating in a randomized,

controlled clinical trial of buprenorphine compared with methadone for opioid-dependent pregnant women

underwent cesarean section while continuing their blinded opioid maintenance medication. After the

cesarean sections, both women were given access to a morphine patient-controlled analgesia (PCA) pump

for 24 hours (maximum dosage of 180 mg in 24 hours) with subsequent oral oxycodone/acetaminophen on

hospital discharge (maximum daily dose of oxycodone was 60 mg). The woman receiving buprenorphine

(18 mg/day) reported a pain score of 0 (range 0–10) with the PCA pump and pain scores between 0–5 with

the oxycodone/acetaminophen doses. The woman receiving methadone (80 mg/day) also reported a pain

score of 0 with the PCA pump, but reported a pain score of 7 with oxycodone/acetaminophen and required

the addition of an NSAID to assist with pain management (Jones et al. 2006).

Discontinue buprenorphine maintenance treatment and start the patient on a short-acting full opioid

agonist, which should be dosed adequately to avoid opioid withdrawal and titrated to desired analgesic

effect. After the acute pain episode passes, the patient can be inducted back on buprenorphine (McNicholas

2004).

Consider regional anesthesia, conscious sedation using a benzodiazepine, or general anesthesia for

unanticipated acute severe pain that may require further medical or surgical intervention (e.g., trauma)

when patients are in an appropriate medical setting for such care (e.g., emergency room).

Chronic pain

It is important to thoroughly evaluate the chronic pain syndrome taking into account etiologies and

possible psychiatric comorbidities that may exacerbate the pain. Strong consideration should be given

to nonpharmacological treatments, and pain reduction and elimination should not be the sole treatment

focus for patients experiencing chronic pain (Cohen and Jasser 2006). Methadone dosed multiple times

per day can be helpful for chronic severe pain. If the person is receiving buprenorphine maintenance

treatment but is not receiving adequate pain relief and is not able to achieve illicit opioid abstinence, a

transfer to methadone maintenance treatment is recommended (McNicholas 2004).

Adolescents

With the continued use of heroin and rapid rise in prescription opioid misuse within the United States,

particularly among adolescents (Sung et al. 2005), there is a growing need to determine the best

treatment practices and the appropriate role of opioid maintenance treatment for opioid addiction in

this population. Buprenorphine is approved for use in adolescents age 16 years or older in OBOT, and

there are no requirements of prior failed treatment in order to be eligible for buprenorphine OBOT, in

contrast to methadone (U.S. Food and Drug Administration 2002). Studies of buprenorphine for pain in

children and adolescents have shown it to be safe and effective (Girotra et al. 1993; Harcus et al.

1980); however, there is little research on the use of buprenorphine in this population for the

treatment of opioid addiction.

There has been one randomized, double-blind clinical trial of buprenorphine for opioid-dependent

adolescents, although this was a detoxification study completed in an outpatient opioid treatment clinic

(not an office-based setting) (Marsch et al. 2005). Thirty-six adolescents (average age 17 years; 13- to

18-year-olds were eligible) were randomly assigned to a 28-day detoxification regimen with either

buprenorphine or clonidine. There were thrice-weekly individual counseling sessions and urine drug

toxicology testing, daily medication dispensation, and monetary rewards for providing opioid-negative

urine test results. Treatment retention (buprenorphine: 72%; clonidine: 39%), percentage of opioid

urine test results that were negative (buprenorphine: 64%; clonidine: 32%), and medication liking

were significantly higher for those adolescents taking buprenorphine compared with those taking

clonidine. In addition, after completion of the 28-day detoxification, naltrexone maintenance treatmentPrint: Chapter 21. Buprenorphine Maintenance http://www.psychiatryonline.com/popup.aspx?aID=352366&print=yes…

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was accepted by a significantly higher proportion of adolescents in the buprenorphine (61%) versus

clonidine condition (5%). There were no significant adverse effects reported or evidence of opioid

intoxication associated with buprenorphine, and buprenorphine was well tolerated by all subjects. This

study provides important information about the safety, tolerability, and short-term treatment outcomes

among adolescents receiving buprenorphine detoxification in an outpatient opioid maintenance

treatment setting with intensive nonpharmacological services. Future work will need to determine the

effectiveness and role of buprenorphine maintenance for adolescents in less intensive treatment

settings, such as OBOT.

CONCLUSION

Buprenorphine is a partial opioid agonist used in the treatment of opioid addiction. It has been shown

to effectively increase treatment retention and decrease opioid use, craving, and participation in illegal

activities. Buprenorphine maintenance treatment is safe, relatively straightforward to prescribe, and

generally well tolerated by patients. Treatment involves not only the prescription of buprenorphine and

monitoring of urine drug test results but also the assessment, diagnosis, and treatment of comorbid

illnesses and provision of nonpharmacological services aimed at the total rehabilitation of each patient.

With the passage of the DATA in 2000 and the subsequent FDA approval of buprenorphine for the

treatment of opioid dependence, buprenorphine currently is the only opioid agonist treatment available

in the United States that can be prescribed in an office-based setting by qualified physicians. As such,

buprenorphine maintenance treatment holds the promise of increasing the availability of opioid

addiction treatment and increasing patient access to physicians. However, the ultimate success of

buprenorphine treatment will depend largely on the number of physicians willing to provide

buprenorphine maintenance treatment in an office-based setting.

KEY POINTS

Buprenorphine is currently a Schedule III medication that is approved for opioid maintenance treatment and

that can be used in an office-based setting.

Buprenorphine can be prescribed by a qualified physician that obtains a waiver and X number from the U.S.

Drug Enforcement Administration.

Buprenorphine is a partial opioid agonist, which means that it stimulates the opioid receptor, but that there is

a limit (ceiling) to the degree of opioid effects (e.g., respiratory depression) that it can produce, thereby

enhancing its safety profile.

Naloxone is included in sublingual buprenorphine tablets to decrease the misuse and abuse of the drug; if

tablets are tampered with and injected, the naloxone will precipitate opioid withdrawal among persons with opioid

physical dependence. If tablets are taken as prescribed by the sublingual route there is little absorption of

naloxone.

Buprenorphine is metabolized by the liver cytochrome P450 3A4 enzyme system so inducers or inhibitors of

P450 3A4 could interact with buprenorphine’s metabolism.

A comprehensive initial evaluation is required before beginning buprenorphine treatment, and treatment

requirements (e.g., random urine toxicology screens and/or random pill counts) and expectations should be

explicitly communicated between physician and patient prior to commencing treatment.

Effective treatment includes addressing medical and psychiatric comorbidities and rehabilitation of the patient.

Buprenorphine is not currently approved for the treatment of opioid dependence in pregnancy, but early

research findings are promising for its use in this population.

Office-based buprenorphine maintenance treatment has the potential to substantially increase the availability of

treatment for opioid addiction, but buprenorphine’s actual impact will be determined largely by the number of

physicians willing to treat these patients.

REFERENCES

Alford DP, Compton P, Samet JH: Acute pain management for patients receiving maintenance methadone or

buprenorphine therapy. Ann Intern Med 144:127–134, 2006; erratum in Ann Intern Med 144:460, 2006

Baker JR, Best AM, Pade PA, et al: Effect of buprenorphine and antiretroviral agents on the QT interval inPrint: Chapter 21. Buprenorphine Maintenance http://www.psychiatryonline.com/popup.aspx?aID=352366&print=yes…

15 of 19

18/10/2008 10:21

opioid-dependent patients. Ann Pharmacother 40:392–396, 2006 [PubMed]

Berson A, Gervais A, Cazals D, et al: Hepatitis after intravenous buprenorphine misuse in heroin addicts. J Hepatol

34:346–350, 2001 [PubMed]

Bickel WK, Stitzer ML, Bigelow GE, et al: Buprenorphine: dose-related blockade of opioid challenge effects in opioid

dependent humans. J Pharmacol Exp Ther 247:47–53, 1988a

Bickel WK, Stitzer ML, Bigelow GE, et al: A clinical trial of buprenorphine: comparison with methadone in the

detoxification of heroin addicts. Clin Pharmacol Ther 43:72–78, 1988b

Brooner RK, King VL, Kidorf M, et al: Psychiatric and substance use comorbidity among treatment-seeking opioid

abusers. Arch Gen Psychiatry 54:71–80, 1997 [PubMed]

Brooner RK, Kidorf M, King VL, et al: Behavioral contingencies improve counseling attendance in an adaptive

treatment model. J Subst Abuse Treat 27:223–232, 2004 [PubMed]

Bruce RD, Altice FL: Three case reports of a clinical pharmacokinetic interaction with buprenorphine and atazanavir

plus ritonavir. AIDS 20:783–784, 2006 [PubMed]

Bruce RD, McCance-Katz E, Kharasch ED, et al: Pharmacokinetic interactions between buprenorphine and

antiretroviral medications. Clin Infect Dis 43 (suppl 4):S216–S223, 2006

Cheskin LJ, Fudala PJ, Johnson RE: A controlled comparison of buprenorphine and clonidine for acute detoxification

from opioids. Drug Alcohol Depend 36:115–121, 1994 [PubMed]

Cohen MJM, Jasser SA: Pain management in addicted patients, in The Treatment of Opioid Dependence. Edited by

Strain EC, Stitzer ML. Baltimore, MD, The Johns Hopkins University Press, 2006, pp 527–546

Comer SD, Collins ED, Fischman MW: Buprenorphine sublingual tablets: effects on IV heroin self-administration by

humans. Psychopharmacology (Berl) 154:28–37, 2001 [PubMed]

Cone EJ, Gorodetzky CW, Yousefnejad D, et al: The metabolism and excretion of buprenorphine in humans. Drug

Metab Dispos 12:577–581, 1984 [PubMed]

Correia CJ, Walsh SL, Bigelow GE, et al: Effects associated with double-blind omission of buprenorphine/naloxone

over a 98-h period. Psychopharmacology (Berl) 189:297–306, 2006 [PubMed]

Cozza KL, Armstrong SC, Oesterheld JR: Concise Guide to Drug Interaction Principles for Medical Practice:

Cytochrome P450s, UGTs, P-Glycoproteins, 2nd Edition. Washington, DC, American Psychiatric Publishing, 2003

Fiellin DA, Strain EC: Office-based treatment with buprenorphine and other medications, in The Treatment of

Opioid Dependence. Edited by Strain EC, Stitzer ML. Baltimore, MD, The Johns Hopkins University Press, 2006, pp

253–276

Fiellin DA, Pantalon MV, Charwaski MC, et al: Counseling plus buprenorphine-naloxone maintenance therapy for

opioid dependence. N Engl J Med 355:365–374, 2006 [PubMed]

Fingerhood MI, Jasinski DR, Sullivan JT: Prevalence of hepatitis C in a chemically dependent population. Arch

Intern Med 153:2025–2030, 1993 [PubMed]

Fingerhood MI, Thompson MR, Jasinski DR: A comparison of clonidine and buprenorphine in the outpatient

treatment of opiate withdrawal. Subst Abus 22:193–199, 2001 [PubMed]

Fischer G, Ortner R, Rohrmeister K, et al: Methadone versus buprenorphine in pregnant addicts: a double-blind,

double-dummy comparison study. Addiction 101:275–281, 2006 [PubMed]

Fudala PJ, Bridge TP, Herbert S, et al: Office-based treatment of opiate addiction with a sublingual-tablet

formulation of buprenorphine and naloxone. N Engl J Med 349:949–958, 2003 [PubMed]

Galanter M, Dermatis H, Resnick R, et al: Short-term buprenorphine maintenance: treatment outcome. J Addict Dis

22:39–49, 2003 [PubMed]

Galanter M, Dermatis H, Glickman L, et al: Network therapy: decreased secondary opioid use during

buprenorphine maintenance. J Subst Abuse Treat 26:313–318, 2004 [PubMed]

Girotra S, Kumar S, Rajendran KM, et al: Comparison of caudal morphine and buprenorphine for post-operativePrint: Chapter 21. Buprenorphine Maintenance http://www.psychiatryonline.com/popup.aspx?aID=352366&print=yes…

16 of 19

18/10/2008 10:21

analgesia in children. Eur J Anaesthesiol 10:309–312, 1993 [PubMed]

Gossop M, Griffiths P, Bradley B, et al: Opiate withdrawal symptoms in response to 10-day and 21-day methadone

withdrawal programmes. Br J Psychiatry 154:360–363, 1989 [PubMed]

Harcus AW, Ward AE, Smith DW, et al: The monitored release of buprenorphine: results in the young. J Int Med

Res 8:153–155, 1980 [PubMed]

Higgins ST, Silverman K (eds): Motivating Behavior Change Among Illicit-Drug Abusers. Washington, DC, American

Psychological Association, 1999

Huang P, Kehner GB, Cowan A, et al: Comparison of pharmacological activities of buprenorphine and

norbuprenorphine: norbuprenorphine is a potent opioid agonist. J Pharmacol Exp Ther 297:688–695, 2001

[PubMed]

Jasinski DR, Pevnick JS, Griffith JD: Human pharmacology and abuse potential of the analgesic buprenorphine: a

potential agent for treating narcotic addiction. Arch Gen Psychiatry 35:501–516, 1978 [PubMed]

Jasinski DR, Boren JJ, Henningfield JE, et al: Progress report from the NIDA Addiction Research Center. Baltimore,

Maryland. NIDA Res Monogr 49:69–76, 1984 [PubMed]

Johnson RE, Jaffe JH, Fudala PJ: A controlled trial of buprenorphine treatment for opioid dependence. JAMA

267:2750–2755, 1992 [PubMed]

Johnson RE, Eissenberg T, Stitzer ML, et al: Buprenorphine treatment of opioid dependence: clinical trial of daily

versus alternate-day dosing. Drug Alcohol Depend 40:27–35, 1995a

Johnson RE, Eissenberg T, Stitzer ML, et al: A placebo controlled clinical trial of buprenorphine as a treatment for

opioid dependence. Drug Alcohol Depend 40:17–25, 1995b

Johnson RE, Chutuape MA, Strain EC, et al: A comparison of levomethadyl acetate, buprenorphine, and methadone

for opioid dependence. N Engl J Med 343:1290–1297, 2000 [PubMed]

Johnson RE, Jones HE, Fischer G: Use of buprenorphine in pregnancy: patient management and effects on the

neonate. Drug Alcohol Depend 70 (suppl 2):S87–S101, 2003

Jones HE, Johnson RE, Jasinski DR, et al: Buprenorphine versus methadone in the treatment of pregnant

opioid-dependent patients: effects on the neonatal abstinence syndrome. Drug Alcohol Depend 79:1–10, 2005

[PubMed]

Jones HE, Johnson RE, Milio L, et al: Post-cesarean pain management of patients maintained on methadone or

buprenorphine. Am J Addict 15:258–259, 2006 [PubMed]

Kakko J, Svanborg KD, Kreek MJ, et al: 1-year retention and social function after buprenorphine-assisted relapse

prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial. Lancet

361:662–668, 2003 [PubMed]

Kidorf M, Stitzer ML: Contingent access to clinic privileges reduces drug abuse in methadone maintenance

patients, in Motivating Behavior Change Among Illicit-Drug Abusers. Edited by Higgins ST, Silverman K.

Washington, DC, American Psychological Association, 1999

Kintz P: Deaths involving buprenorphine: a compendium of French cases. Forensic Sci Int 121:65–69, 2001

[PubMed]

Kosten TR, Kleber HD: Buprenorphine detoxification from opioid dependence: a pilot study. Life Sci 42:635–641,

1988

Kosten TR, Morgan C, Kleber HD: Phase II clinical trials of buprenorphine: detoxification and induction onto

naltrexone. NIDA Res Monogr 121:101–119, 1992 [PubMed]

Lange WR, Fudala PJ, Dax EM, et al: Safety and side-effects of buprenorphine in the clinical management of heroin

addiction. Drug Alcohol Depend 26:19–28, 1990 [PubMed]

Lavelle TL, Hammersley R, Forsyth A: The use of buprenorphine and temazepam by drug injectors. J Addict Dis

10:5–14, 1991 [PubMed]

Ling W, Charuvastra C, Collins JF, et al: Buprenorphine maintenance treatment of opiate dependence: aPrint: Chapter 21. Buprenorphine Maintenance http://www.psychiatryonline.com/popup.aspx?aID=352366&print=yes…

17 of 19

18/10/2008 10:21

multicenter, randomized clinical trial. Addiction 93: 475–486, 1998 [PubMed]

Ling W, Wesson DR: Clinical efficacy of buprenorphine: comparisons to methadone and placebo. Drug Alcohol

Depend 70 (Suppl 2):S49–S57, 2003

Ling W, Wesson DR, Charuvastra C, et al: A controlled trial comparing buprenorphine and methadone maintenance

in opioid dependence. Arch Gen Psychiatry 53:401–407, 1996 [PubMed]

Lofwall MR, Stitzer ML, Bigelow GE, et al: Comparative safety and side effect profiles of buprenorphine and

methadone in the outpatient treatment of opioid dependence. Addictive Disorders and Their Treatment 4:49–64,

2005

Marquet P: Pharmacology of high-dose buprenorphine, in Buprenorphine Therapy of Opiate Addiction. Edited by

Kintz P, Marquet P. Totowa, NJ, Humana Press, 2002, pp 1–11

Marsch LA, Bickel WK, Badger GJ, et al: Comparison of pharmacological treatments for opioid-dependent

adolescents: a randomized controlled trial. Arch Gen Psychiatry 62:1157–1164, 2005 [PubMed]

Mattick RP, Kimber J, Breen C, et al: Buprenorphine maintenance versus placebo or methadone maintenance for

opioid dependence. Cochrane Database of Systematic Reviews, Issue 2, Article No: CD002207, 2003

McCance-Katz EF, Rainey PM, Friedland G, et al: Effect of opioid dependence pharmacotherapies on zidovudine

disposition. Am J Addict 10:296–307, 2001 [PubMed]

McCance-Katz EF, Moody DE, Morse GD, et al: Interactions between buprenorphine and antiretrovirals, I: the

nonnucleoside reverse-transcriptase inhibitors efavirenz and delavirdine. Clin Infect Dis 43 (suppl 4):S224–S234,

2006a

McCance-Katz EF, Moody DE, Smith PF, et al: Interactions between buprenorphine and antiretrovirals, II: the

protease inhibitors nelfinavir, lopinavir/ritonavir, and ritonavir. Clin Infect Dis 43 (suppl 4):S235–S246, 2006b

McLellan AT, Arndt IO, Metzger DS, et al: The effects of psychosocial services in substance abuse treatment. JAMA

269:1953–1959, 1993 [PubMed]

McLellan AT, Lewis DC, O’Brien CP, et al: Drug dependence, a chronic medical illness: implications for treatment,

insurance, and outcomes evaluation. JAMA 284:1689–1695, 2000 [PubMed]

McNicholas L (ed): Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction. TIP Series

#40 (DHHS Publ No SMA-04-3939). Rockville, MD, U.S. Department of Health and Human Services, 2004

Mello NK, Mendelson JH: Buprenorphine suppresses heroin use by heroin addicts. Science 207:657–659, 1980

[PubMed]

Mello NK, Mendelson JH, Kuehnle JC, et al: Buprenorphine effects on human heroin self-administration: an operant

analysis. J Pharmacol Exp Ther 223:30–39, 1982 [PubMed]

Mendelson J, Jones RT, Fernandez I, et al: Buprenorphine and naloxone interactions in opiate-dependent

volunteers. Clin Pharmacol Ther 60:105–114, 1996 [PubMed]

Mintzer MZ, Correia CJ, Strain EC: A dose-effect study of repeated administration of buprenorphine/naloxone on

performance in opioid-dependent volunteers. Drug Alcohol Depend 74:205–209, 2004 [PubMed]

Novick DM, Richman BL, Friedman JM, et al: The medical status of methadone maintenance patients in treatment

for 11–18 years. Drug Alcohol Depend 33:235–245, 1993 [PubMed]

Ohtani M, Kotaki H, Sawada Y, et al: Comparative analysis of buprenorphine- and norbuprenorphine-induced

analgesic effects based on pharmacokinetic-pharmacodynamic modeling. J Pharmacol Exp Ther 272:505–510,

1995 [PubMed]

Petry NM, Bickel WK, Piasecki D, et al: Elevated liver enzyme levels in opioid-dependent patients with hepatitis

treated with buprenorphine. Am J Addict 9:265–269, 2000 [PubMed]

Resnick RB, Galanter M, Psycha C, et al: Buprenorphine: an alternative to methadone for heroin dependence

treatment. Psychopharmacol Bull 28:109–113, 1992 [PubMed]

Reynaud M, Petit G, Potard D, et al: Six deaths linked to concomitant use of buprenorphine and benzodiazepines.

Addiction 93:1385–1392, 1998 [PubMed]Print: Chapter 21. Buprenorphine Maintenance http://www.psychiatryonline.com/popup.aspx?aID=352366&print=yes…

18 of 19

18/10/2008 10:21

Robinson GM, Dukes PD, Robinson BJ, et al: The misuse of buprenorphine and a buprenorphine-naloxone

combination in Wellington, New Zealand. Drug Alcohol Depend 33:81–86, 1993 [PubMed]

Rosen MI, Wallace EA, McMahon TJ, et al: Buprenorphine: duration of blockade of effects of intramuscular

hydromorphone. Drug Alcohol Depend 35:141–149, 1994 [PubMed]

San L, Tremoleda J, Ollé JM, et al: Prevalence of buprenorphine use by heroin addicts undergoing treatment. Med

Clin (Barc) 93:645–648, 1989 [PubMed]

Schottenfeld RS, Pakes JR, Oliveto A, et al: Buprenorphine vs methadone maintenance treatment for concurrent

opioid dependence and cocaine abuse. Arch Gen Psychiatry 54:713–720, 1997 [PubMed]

Schuh KJ, Walsh SL, Stitzer ML: Onset, magnitude and duration of opioid blockade produced by buprenorphine and

naltrexone in humans. Psychopharmacology (Berl) 145:162–174, 1999 [PubMed]

Senay EC, Dorus W, Goldberg F, et al: Withdrawal from methadone maintenance. Rate of withdrawal and

expectation. Arch Gen Psychiatry 34:361–367, 1977 [PubMed]

Sigmon SC, Wong CJ, Chausmer AL, et al: Evaluation of an injection depot formulation of buprenorphine: placebo

comparison. Addiction 99:1439–1449, 2004 [PubMed]

Sigmon SC, Moody DE, Nuwayser ES, et al: An injection depot formulation of buprenorphine: extended

bio-delivery and effects. Addiction 101:420–432, 2006 [PubMed]

Strain EC: Clinical use of buprenorphine, in The Treatment of Opioid Dependence. Edited by Strain EC, Stitzer ML.

Baltimore, MD, The Johns Hopkins University Press, 2006a, pp 230–252

Strain EC: Pharmacology of buprenorphine, in The Treatment of Opioid Dependence. Edited by Strain EC, Stitzer

1. Baltimore, MD, The Johns Hopkins University Press, 2006b, pp 213–229

Strain EC, Preston KL, Liebson IA, et al: Acute effects of buprenorphine, hydromorphone and naloxone in

methadone-maintained volunteers. J Pharmacol Exp Ther 261:985–993, 1992 [PubMed]

Strain EC, Stitzer ML, Liebson IA, et al: Comparison of buprenorphine and methadone in the treatment of opioid

dependence. Am J Psychiatry 151:1025–1030, 1994 [Full Text] [PubMed]

Strain EC, Preston KL, Liebson IA, et al: Buprenorphine effects in methadone-maintained volunteers: effects at two

hours after methadone. J Pharmacol Exp Ther 272:628–638, 1995 [PubMed]

Strain EC, Stitzer ML, Liebson IA, et al: Buprenorphine versus methadone in the treatment of opioid dependence:

self-reports, urinalysis, and addiction severity index. J Clin Psychopharmacol 16:58–67, 1996 [PubMed]

Strain EC, Walsh SL, Preston KL, et al: The effects of buprenorphine in buprenorphine-maintained volunteers.

Psychopharmacology (Berl) 129:329–338, 1997 [PubMed]

Strain EC, Walsh SL, Bigelow GE, et al: Blockade of hydromorphone effects by buprenorphine/naloxone and

buprenorphine. Psychopharmacology (Berl) 159:161–166, 2002 [PubMed]

Strain EC, Clark HW, Auriacombe M, et al: Symposium XV French experience with buprenorphine. NIDA Res

Monograph 183:134–141, 2003

Strain EC, Moody DE, Stoller KB, et al: Relative bioavailability of different buprenorphine formulations under

chronic dosing conditions. Drug Alcohol Depend 74:37–43, 2004 [PubMed]

Sullivan LE, Barry D, Moore BA, et al: A trial of integrated buprenorphine/naloxone and HIV clinical care. Clin

Infect Dis 43 (suppl 4):S184–S190, 2006

Sung HE, Richter L, Vaughan R, et al: Nonmedical use of prescription opioids among teenagers in the United

States: trends and correlates. J Adolesc Health 37:44–51, 2005 [PubMed]

Umbricht-Schneiter A, Ginn DH, Pabst KM, et al: Providing medical care to methadone clinic patients: referral vs

on-site care. Am J Public Health 84:207–210, 1994 [PubMed]

U.S. Food and Drug Administration: Drug label. 2002. Available online at:

http://www.fda.gov/cder/foi/label/2002/20732lbl.pdf. Accessed December 3, 2007.

Vidal-Trecan G, Varescon I, Nabet N, et al: Intravenous use of prescribed sublingual buprenorphine tablets by drugPrint: Chapter 21. Buprenorphine Maintenance http://www.psychiatryonline.com/popup.aspx?aID=352366&print=yes…

19 of 19

18/10/2008 10:21

users receiving maintenance therapy in France. Drug Alcohol Depend 69:175–181, 2003 [PubMed]

Walsh SL, Preston KL, Stitzer ML, et al: Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin

Pharmacol Ther 55:569–580, 1994 [PubMed]

Walsh SL, June HL, Schuh KJ, et al: Effects of buprenorphine and methadone in methadone-maintained subjects.

Psychopharmacology (Berl) 119:268–276, 1995 [PubMed]

Wedam EF, Haigney MCP, et al: EKG QT-prolongation effects of methadone, LAAM, and buprenorphine in a

randomized trial. Paper presented at conference of the College on Problems of Drug Dependencem San Juan,

Puerto Rico, 2004

Zhang W, Ramamoorthy Y, Tyndale RF, et al: Interaction of buprenorphine and its metabolite norbuprenorphine

with cytochromes p450 in vitro. Drug Metab Dispos 31:768–772, 2003 [PubMed]

SUGGESTED READING

Johnson RE, Strain EC, Amass L: Buprenorphine: how to use it right. Drug Alcohol Depend 70 (suppl 2):

S59–S77, 2003

McNicholas L (ed): Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction.

TIP Series #40 (DHHS Publ No SMA-04-3939). Rockville, MD, U.S. Department of Health and Human

Services, 2004. Available for free by calling the National Clearing House for Alcohol and Drug

Information at (800) 487–4889 or on-line at

http://www.kap.samhsa.gov/products/manuals/index.htm.

Strain EC, Stitzer ML (eds): The Treatment of Opioid Dependence. Baltimore, MD, Johns Hopkins

University Press, 2006, pp 213–276

U.S. Food and Drug Administration: Center for Drug Evaluation and Research: Drug information. 2002.

Available at: http://www.fda.gov/cder/drug/infopage/subutex_suboxone/default.htm.

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