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Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 2004. (Treatment Improvement Protocol (TIP) Series, No. 40.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction

Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction.

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1 Introduction

Practical Guidelines for Physicians

Physicians are invited to use the Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction to make practical and informed decisions about the treatment of opioid addiction with buprenorphine. This document provides step‐by‐step guidance through the opioid addiction treatment decisionmaking process. Using the materials provided in these guidelines, physicians should be able to (1) perform initial screening and assessment of patients with opioid addiction, (2) determine the appropriateness of buprenorphine treatment for patients with opioid addiction, (3) provide treatment of opioid addiction with buprenorphine according to established protocols, (4) assess for the presence of and arrange appropriate treatment services for comorbid medical and psychosocial conditions, and (5) determine when to seek specialty addiction treatment referral or consultation.

The history of opioid addiction treatment forms an important backdrop for the decisions that physicians will make regarding their use of buprenorphine. Developing informed decisions about care should take into account the state of the art of opioid addiction treatment and ancillary services that exist to support both the patient and physician.

Historical Context

A significant breakthrough in the treatment of opioid addiction occurred with the introduction of methadone in the 1960s. Methadone maintenance proved safe and effective and enabled patients to lead functional lives—something that was often not possible using only drug‐free approaches. Within a few years of its introduction, however, new laws and regulations in the United States, including the Methadone Regulations in 1972 and the Narcotic Addict Treatment Act of 1974, effectively limited methadone maintenance treatment to the context of the Opioid Treatment Program (OTP) (i.e., methadone clinic) setting. These laws and regulations established a closed distribution system for methadone that required special licensing by both Federal and State authorities. The new system made it very difficult for physicians to use methadone to treat opioid addiction in an office setting or even in a general drug rehabilitation program. To receive methadone maintenance, patients were required to attend an OTP, usually on a daily basis. The stigma and inconvenience associated with receiving methadone maintenance in the OTP setting led, in part, to the current situation in the United States in which it is estimated that fewer than 25 percent of the individuals with opioid addiction receive any form of treatment for it (National Institutes of Health 1997). Another result of the closed distribution system was that most U.S. physicians were prevented from gaining experience and expertise in the treatment of opioid addiction. The Food and Drug Administration (FDA) approval of the longer acting opioid agonist levo‐alpha‐acetyl‐methadol (LAAM) in the 1990s did little to change the situation.* (Additional information about substance abuse statistics and treatment availability in the United States can be found on the Substance Abuse and Mental Health Services Administration [SAMHSA] Office of Applied Studies [OAS] Web site at http://www.oas.samhsa.gov/).

Efforts to return opioid addiction treatment to the mainstream of medical care began to take shape and gain momentum in the 1990s. In October 2000, the Children’s Health Act of 2000 (P.L. 106‐310) was enacted into law. Title XXXV of the Act provides a “Waiver Authority for Physicians Who Dispense or Prescribe Certain Narcotic Drugs for Maintenance Treatment or Detoxification Treatment of Opioid‐Dependent Patients.” This part of the law is known as the Drug Addiction Treatment Act of 2000 (DATA 2000; Clark 2003).

Under the provisions of DATA 2000, qualifying physicians may now obtain a waiver from the special registration requirements in the Narcotic Addict Treatment Act of 1974, and its enabling regulations, to treat opioid addiction with Schedule III, IV, and V opioid medications that have been specifically approved by FDA for that indication, and to prescribe and/or dispense these medications in treatment settings other than licensed OTPs, including in office‐based settings. On October 8, 2002, two new sublingual formulations of the opioid partial agonist buprenorphine, Subutex® (buprenorphine) and Suboxone® (buprenorphine/naloxone), became the first and, as of this writing, the only Schedule III, IV, or V medications to have received this FDA approval.

To qualify for a DATA 2000 waiver, physicians must have completed at least 8 hours of approved training in the treatment of opioid addiction or have certain other qualifications defined in the legislation (e.g., clinical research experience with the treatment medication, certification in addiction medicine) and must attest that they can provide or refer patients to necessary, concurrent psychosocial services. (Chapter 6 provides a detailed discussion of the qualifying criteria defined in DATA 2000 and of the procedure for obtaining a waiver.)

Physicians who obtain DATA 2000 waivers may treat opioid addiction with Subutex® or Suboxone® in any appropriate clinical settings in which they are credentialed to practice medicine. The promise of DATA 2000 is to help destigmatize opioid addiction treatment and to enable qualified physicians to manage opioid addiction in their own practices, thus greatly expanding currently available treatment options and increasing the overall availability of treatment.

New Guidelines

The new guidelines provide information about the medical use of buprenorphine, based on (1) the evidence available from buprenorphine studies and (2) clinical experience using buprenorphine in the treatment of opioid addiction. The guidelines are as complete as the expert members of the Consensus Panel on Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction could make them and should provide a reasonable basis for current best practices in the area. Physicians should note that the guidelines are not intended to fully address all possible issues that can arise in the treatment of patients who are addicted to opioids. Some issues cannot be substantively addressed in the guidelines because of the lack of controlled studies and the limited U.S. experience using buprenorphine in office‐based settings. Physicians are urged to seek the advice of knowledgeable addiction specialists if their questions are not answered fully by the guidelines, and should keep themselves aware of training and information on the use of buprenorphine that becomes available after the publication of this document. Such information will be posted regularly on the SAMHSA Buprenorphine Web site at http://www.buprenorphine.samhsa.gov.

Opioid Addiction Today in the United States

Opioid Addiction

Opioid addiction is a neurobehavioral syndrome characterized by the repeated, compulsive seeking or use of an opioid despite adverse social, psychological, and/or physical consequences.

Addiction is often (but not always) accompanied by physical dependence, a withdrawal syndrome, and tolerance. Physical dependence is defined as a physiological state of adaptation to a substance, the absence of which produces symptoms and signs of withdrawal. Withdrawal syndrome consists of a predictable group of signs and symptoms resulting from abrupt removal of, or a rapid decrease in the regular dosage of, a psychoactive substance. The syndrome is often characterized by overactivity of the physiological functions that were suppressed by the drug and/or depression of the functions that were stimulated by the drug. Tolerance is a state in which a drug produces a diminishing biological or behavioral response; in other words, higher doses are needed to produce the same effect that the user experienced initially.

It is possible to be physically dependent on a drug without being addicted to it, and conversely, it is possible to be addicted without being physically dependent (Nelson et al. 1982). An example of physical dependence on opioids without addiction is a patient with cancer who becomes tolerant of and physically dependent on opioids prescribed to control pain. Such a patient may experience withdrawal symptoms with discontinuation of the usual dose but will not experience social, psychological, or physical harm from using the drug and would not seek out the drug if it were no longer needed for analgesia (Jacox et al. 1994). An example of addiction to opioids without physical dependence is a patient addicted to oxycodone who has been recently detoxified from the drug. In this situation, the patient may no longer be suffering from withdrawal symptoms or tolerance but may continue to crave an opioid high and will invariably relapse to active opioid abuse without further treatment.

Factors contributing to the development of opioid addiction include the reinforcing properties and availability of opioids, family and peer influences, sociocultural environment, personality, and existing psychiatric disorders. Genetic heritage appears to influence susceptibility to alcohol addiction and, possibly, addiction to tobacco and other drugs as well (Goldstein 1994).

Addiction Rates

According to the January 2003 Drug Abuse Warning Network (DAWN) Report published by SAMHSA’s OAS, the incidence of abuse of prescription opioid pain medications (also known as narcotic analgesics), such as hydrocodone, oxycodone, meperidine, and propoxyphene, has risen markedly in recent years (Crane 2003). The incidence of emergency department (ED) visits related to these medications has been increasing since the 1990s and has more than doubled between 1994 and 2001 (Crane 2003). In 2001, there were an estimated 90,232 ED visits related to opioid analgesic abuse, a 117 percent increase since 1994. Nationally, opioid analgesics were involved in 14 percent of all drug‐abuse‐related ED visits in 2001 (SAMHSA 2002b). According to the DAWN Mortality Data Report for 2002 (SAMHSA 2002c ), hydrocodone ranked among the 10 most common drugs related to deaths in 18 cities, including Detroit (63), Las Vegas (46), Dallas (36), New Orleans (33), and Oklahoma City (31). Oxycodone ranked among the 10 most common drugs related to deaths in 19 cities, including Philadelphia (88), Baltimore (34), Boston (34), Phoenix (34), and Miami (28).

According to the Office of National Drug Control Policy (ONDCP), there were an estimated 810,000 to 1,000,000 individuals addicted to heroin in the United States in the year 2000—which is the highest number since the mid‐to‐late 1970s (ONDCP 2003). Several factors have contributed to this increase. Historically, heroin purity has been less than 10 percent. By the late 1990s, however, purity was between 50 and 80 percent. The increase in purity has made heroin easier to use by noninjection routes, such as snorting and smoking. Because individuals can become addicted to or overdose from heroin taken via any route, the increase in the type and number of routes used has led to a rise in new cases of heroin addiction across all sociodemographic categories.

Many addicted individuals may switch to the injection route as their heroin use continues to increase, or if heroin purity should decrease again. An increase in rates of injection drug use would have a significant effect on the incidence of human immunodeficiency virus (HIV) infection, hepatitis B and C, and other infectious diseases.

The rise of heroin use appears to be a nationwide phenomenon in the United States. Heroin overdose deaths have risen sharply, as have ED admissions involving heroin. The most recent data on such ED admissions come from SAMHSA’s DAWN reports, which can be accessed via the Web at the following sites: http://dawninfo.samhsa.gov/ or http://www.nida.nih.gov/CEWG/DAWN.html.

Current State of Opioid Addiction Treatment

There are two main modalities for the treatment of opioid addiction: pharmacotherapy and psychosocial therapy. Pharmacotherapies now available for opioid addiction include (1) agonist maintenance with methadone; (2) partial‐agonist maintenance with buprenorphine or buprenorphine plus naloxone; (3) antagonist maintenance using naltrexone; and (4) the use of antiwithdrawal (“detoxification”) agents (e.g., methadone, buprenorphine, and/or clonidine) for brief periods, and in tapering doses, to facilitate entry into drug‐free or antagonist treatment.

Psychosocial approaches (e.g., residential therapeutic communities), mutual‐help programs (e.g., Narcotics Anonymous), and 12‐Step‐ or abstinence‐based treatment programs are important modalities in the treatment of addiction to heroin and other opioids, either as stand‐alone interventions or in combination with pharmacotherapy.

In 2003, more than 200,000 individuals in the United States were maintained on methadone or LAAM (SAMHSA 2002a ). Although precise data are difficult to obtain, it is estimated that fewer than 5,000 individuals are maintained on naltrexone for opioid addiction. The number of individuals in 12‐Step programs is unknown because of the undisclosed nature of the programs and their assurance of anonymity. The number of patients in residential therapeutic community treatment who identify opioids as their primary drugs of abuse is conservatively estimated at 3,000–4,000. (This estimate is derived from various sources, both published, such as Drug Abuse Treatment Outcome Studies [DATOS], and unpublished, such as Therapeutic Communities of America reports, found at http://www.drugabuse.gov/about/organization/despr/DATOS.html and http://www.therapeuticcommunitiesofamerica.org.)

Current Pharmacotherapy Treatment Options for Opioid Addiction

Three traditional types of pharmacotherapy for opioid addiction are described briefly in this section: (1) agonist treatment (e.g., methadone pharmacotherapy), (2) antagonist treatment (e.g., naltrexone), and (3) the use of these and other agents (e.g., clonidine) to help withdrawal from opioid drugs as a means of entry into treatment. A discussion of the new treatment option using buprenorphine follows.

Agonist Pharmacotherapy

Methadone is the most commonly used medication for opioid addiction treatment in the United States. Well‐run OTPs—with appropriate drug monitoring, counseling services (individual, group, family), and vocational resources and referrals—have been demonstrated to decrease heroin use and related crime, increase employment, improve physical and mental health (McLellan et al. 1993), and markedly reduce mortality (see the forthcoming TIP Medication‐Assisted Treatment for Opioid Addiction [CSAT in development ]), as well as the incidence of needle sharing (Metzger et al. 1991) and HIV transmission (Metzger et al. 1993). Methadone suppresses opioid withdrawal, blocks the effects of other opioids, and decreases craving for opioids.

Antagonist Pharmacotherapy

Naltrexone is an opioid antagonist that blocks the effects of heroin and most other opioids. It does not have addictive properties or produce physical dependence, and tolerance does not develop. It has a long half‐life, and its therapeutic effects can last up to 3 days. Naltrexone is not a stigmatized treatment. It also decreases the likelihood of alcohol relapse when used to treat alcohol dependence.

From a purely pharmacological point of view, naltrexone would appear to have the properties of a useful medication for the treatment of opioid addiction. Its usefulness in the treatment of opioid addiction, however, has been limited because of certain disadvantages. First, many addicted patients are not interested in taking naltrexone because, unlike methadone and LAAM, it has no opioid agonist effects; patients continue to experience cravings and are thereby not motivated to maintain adherence to the medication regimen. Second, a patient addicted to opioids must be fully withdrawn for up to 2 weeks from all opioids before beginning naltrexone treatment. Unfortunately, during this withdrawal period, many patients relapse to use of opioids and are unable to start on naltrexone. Furthermore, once patients have started on naltrexone, it may increase the risk for overdose death if relapse does occur.

Naltrexone has demonstrated some utility among subgroups of addicted patients with strong motivation and psychosocial support for treatment and medication adherence (e.g., healthcare professionals, business executives, younger patients, patients involved in the criminal justice system). Because most addicted patients will not voluntarily take naltrexone, however, the number of individuals maintained on it continues to be low. Research is under way on a number of sustained‐release, injectable forms of naltrexone in an effort to increase adherence, particularly in the early stages of treatment.

Agents Used To Assist With Withdrawal From Opioid Drugs

Medically supervised withdrawal (detoxification) from opioids is an initial component of certain treatment programs but, by itself, does not constitute treatment of addiction. A variety of agents and methods are available for medically supervised withdrawal from opioids. These include methadone dose‐reduction, the use of clonidine and other alpha‐adrenergic agonists to suppress withdrawal signs and symptoms, and rapid detoxification procedures (e.g., with a combination of naltrexone or naloxone and clonidine and, more recently, buprenorphine). Each of these methods has strengths and weaknesses. When used properly, various pharmacological agents can produce safe and less uncomfortable opioid withdrawal. As a result of the increasing purity of street heroin, however, physicians are reporting more difficulty managing patients with the use of clonidine and other alpha‐adrenergic agonists during withdrawal.

Unfortunately, the majority of individuals addicted to opioids relapse to opioid use after withdrawal, regardless of the withdrawal method used. Too often, physicians and facilities use dose‐reduction and withdrawal in isolation without adequate arrangements for the appropriate treatment and support services that decrease the likelihood of relapse and that are usually necessary for long‐term recovery. (For more information about agents used to assist with withdrawal, see the forthcoming TIP Medication‐Assisted Treatment for Opioid Addiction [CSAT in development].)

Buprenorphine: A New Treatment Option for Opioid Addiction

Buprenorphine’s pharmacological and safety profile (see chapter 2) makes it an attractive treatment for patients addicted to opioids as well as for the medical professionals treating them. Buprenorphine is a partial agonist at the mu opioid receptor and an antagonist at the kappa receptor. It has very high affinity and low intrinsic activity at the mu receptor and will displace morphine, methadone, and other opioid full agonists from the receptor. Its partial agonist effects imbue buprenorphine with several clinically desirable pharmacological properties: lower abuse potential, lower level of physical dependence (less withdrawal discomfort), a ceiling effect at higher doses, and greater safety in overdose compared with opioid full agonists.

At analgesic doses, buprenorphine is 20–50 times more potent than morphine. Because of its low intrinsic activity at the mu receptor, however, at increasing doses, unlike a full opioid agonist, the agonist effects of buprenorphine reach a maximum and do not continue to increase linearly with increasing doses of the drug—the ceiling effect. One consequence of the ceiling effect is that an overdose of buprenorphine is less likely to cause fatal respiratory depression than is an overdose of a full mu opioid agonist.

In the pharmacotherapy of opioid addiction, buprenorphine, as a partial opioid agonist, can be thought of as occupying a midpoint between opioid full agonists (e.g., methadone, LAAM) and opioid antagonists (e.g., naltrexone, nalmefene). It has sufficient agonist properties such that individuals addicted to opioids perceive a reinforcing subjective effect from the medication, often described in terms of “feeling normal.” In higher doses, and under certain circumstances, its antagonist properties can cause the precipitation of acute withdrawal if administered to an individual who is physically dependent on opioids and maintained on a sufficient dose of a full agonist. In this scenario, buprenorphine can displace the full agonist from the mu receptors, yet not provide the equivalent degree of receptor activation, thereby leading to a net decrease in agonist effect and the onset of withdrawal. (See chapter 2 for more details on such effects.) Furthermore, because of the high affinity of buprenorphine for the opioid receptor, this precipitated abstinence syndrome may be difficult to reverse. Buprenorphine produces a blockade to subsequently administered opioid agonists in a dose‐responsive manner. This effect makes the drug particularly appealing to well‐motivated patients, as it provides an additional disincentive to continued opioid use.

Buprenorphine can produce euphoria, especially if it is injected. Buprenorphine does produce physical dependence, although it appears to do so to a lesser degree than do full opioid agonists, and it appears to be easier to discontinue at the end of medication treatment.

Buprenorphine has several pharmaceutical uses. It is a potent analgesic, available in many countries as a 0.3–0.4 mg sublingual tablet (Temgesic®). Until 2002, the only form of buprenorphine approved and marketed in the United States was the parenteral form for treatment of pain (Buprenex®). In 2002, two sublingual tablet formulations of buprenorphine were approved by FDA as opioid addiction treatment medications: buprenorphine alone (Subutex®) and a combination tablet containing buprenorphine plus naloxone in a 4:1 ratio (Suboxone®). Both of these tablets are Schedule III opioids and therefore eligible for use in the treatment of opioid addiction under DATA 2000. Figure 1-1 shows the dosage forms of buprenorphine currently available in the United States. Note that, as of the date of this publication, Subutex® and Suboxone® are the only forms of buprenorphine that are indicated and can be legally used for the treatment of opioid addiction in the United States—neither Buprenex® nor its generic equivalent can be used legally to treat opioid addiction.

Dosage Forms of Buprenorphine Available in the United States (as of July 2004)

MedicationTrade NameDosage Form(s)IndicationCompanyFDA‐Approved for Opioid Addiction Treatment
BuprenorphineSubutex®2‐ or 8‐mg sublingual tabletsOpioid addictionReckitt BenckiserYes
Buprenorphine/ naloxone combinationSuboxone®2‐ or 8‐mg sublingual tablets with buprenorphine/ naloxone in 4:1 ratioOpioid addictionReckitt BenckiserYes
BuprenorphineBuprenex®Injectable ampulesModerate‐ to‐severe painReckitt BenckiserNo
BuprenorphineBuprenorphine injectable (generic)Injectable ampulesModerate‐ to‐severe painAbbott LaboratoriesNo

Many of the large clinical studies of buprenorphine in the treatment of opioid addiction in the United States have been conducted under the joint sponsorship of the National Institute on Drug Abuse (NIDA) and Reckitt Benckiser, the company holding the buprenorphine patent. The most extensive clinical experience with buprenorphine used for treatment of opioid addiction is in France, where the medication has been available for office‐based treatment of opioid addiction since February 1996. In France, buprenorphine can be prescribed for maintenance treatment by both addiction specialists and general practitioners. It is estimated that close to 70,000 patients are currently receiving maintenance treatment with buprenorphine in France.

Buprenorphine doses studied for opioid addiction treatment have ranged from 1–2 mg to 16–32 mg, depending upon the formulation (solution versus tablet), with duration of treatment lasting from a few weeks to years. Using the outcome measures of illicit opioid use, retention in treatment, and assessment for adverse events, studies have shown that buprenorphine treatment reduces opioid use, retains patients in treatment, has few side effects, and is acceptable to most patients (Johnson et al. 1992, 2000; Ling et al. 1996, 1998; O'Connor and Fiellin 2000).

Although buprenorphine has been abused and injected by individuals addicted to opioids in countries where the sublingual tablet is available as an analgesic, its abuse potential appears substantially less than that of full opioid agonists. To reduce the potential for abuse even further, the sublingual tablet dosage form combining buprenorphine with naloxone was developed by NIDA and Reckitt Benckiser.

The buprenorphine/naloxone combination tablet appears to have reduced abuse potential compared with buprenorphine alone when studied in opioid‐dependent populations. It works on the principle that naloxone is approximately 10–20 times more potent by injection than by the sublingual route. Therefore, if the combination is taken sublingually, as directed, the small amount of naloxone available should not interfere with the desired effects of buprenorphine. If the combination form is dissolved and injected by an individual physically dependent on opioids, however, the increased bioavailability of naloxone via the parenteral route should precipitate an opioid withdrawal syndrome.

Summary and Overview of the Guidelines

Buprenorphine as a medication, and the circumstances under which it can be used, together provide a new means to treat opioid addiction in the United States. Buprenorphine’s usefulness stems from its unique pharmacological and safety profile, which encourages treatment adherence and reduces the possibilities for both abuse and overdose. Because buprenorphine has unusual pharmacological properties, physicians may want to consult with addiction specialists to understand more fully the partial opioid agonist effects of buprenorphine and how these properties are useful in opioid addiction treatment. Although buprenorphine offers special advantages to many patients, it is not for everyone. Care must be taken to assess each patient fully and to develop a realistic treatment plan for each patient accepted for buprenorphine treatment.

Chapter 2 provides additional information on the pharmacological properties of opioids in general and of buprenorphine in particular, along with safety considerations (especially drug interactions). Chapter 3 provides important screening guidelines and specific tools for initially assessing patients. Chapter 4 provides a step‐by‐step guide for initiating and maintaining treatment and developing a treatment plan. Chapter 5 provides guidelines on the use of buprenorphine with special populations, including, for example, pregnant women, adolescents, individuals leaving controlled environments (e.g., prison), and healthcare professionals who are addicted. Chapter 6 provides important information on policies and procedures relevant to opioid addiction treatment under the DATA 2000 paradigm. References (see appendix A) are provided so that physicians can consult them to develop the best fit for each patient’s treatment plan.

As of the date of this publication, Subutex® (buprenorphine) and Suboxone® (buprenorphine/naloxone) are the only forms of buprenorphine that have received FDA approval for use in opioid addiction treatment. Throughout the remainder of this document, use of the term buprenorphine will apply to both sublingual formulations of buprenorphine and to any similarly formulated generic products that may receive FDA approval in the future. When information is presented that is specific to either the buprenorphine monotherapy formulation or to the buprenorphine/naloxone combination, the specific designation will be employed, either by the trade name of the currently approved products (which will be meant to include any similar generic equivalents that may be approved in the future) or by the full formula designation.

The consensus panel notes that these guidelines represent one approach, but not necessarily the only approach, to the treatment of opioid addiction with buprenorphine. The panel considers these guidelines not as inflexible rules that must be applied in every instance, but rather as guidance to be considered in the evaluation and treatment of individual patients. Because each patient is unique, and because scientific knowledge and clinical best practices change over time, the application of these guidelines to the treatment of an individual patient must be informed by the needs of the patient, the changing body of scientific and clinical knowledge, and the clinical judgment of the physician.

Footnotes

Due to a number of factors, including the association of LAAM with cardiac arrhythmias in some patients, as of January 1, 2004, the sole manufacturer has ceased production of the drug.

Some TIPs are available online at http://www​.kap.samhsa​.gov/products/manuals/index.htm. Others can be ordered from the National Clearinghouse for Alcohol and Drug Information (NCADI) by accessing its electronic catalog http://store​.health.org/catalog/ or by calling 1‐800‐729‐6686. Up to five free hard copies may be ordered using the NCADI order number.

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