ReviewBuprenorphine: how to use it right
Introduction
It is estimated there are at least 898 000 chronic users of illicit opioids in the US (Office of National Drug Control Policy, 2002). For the past several decades, there have been only two types of medications approved for the treatment of opioid dependence in the US (although in some European countries the alpha-adrenergic agonist lofexidine is approved for medical withdrawal from opioids). The first type of approved medication, agonist substitution therapies, consists of methadone and LAAM. It is estimated that 179 000 patients receive this type of treatment in the US (American Methadone Treatment Association, 1999). These medications produce morphine-like agonist effects and cross substitute for heroin. Both have proven to be extremely effective in reducing illicit opioid use and maintaining patients in treatment. However, some people view these medications as less than adequate treatments since they “merely substitute one addiction for another.” The second type of medication for the treatment of opioid dependence is antagonist therapy, and the one medication approved for this use is naltrexone. Unlike agonist therapies, naltrexone does not produce morphine-like subjective effects. Naltrexone, a full opioid antagonist, is an excellent medication pharmacologically (i.e. it blocks the effects normally observed following the administration of an opioid); however, it is difficult to retain patients in treatment due to a lack of desired positive subjective effects. While rates of naltrexone use for the treatment of opioid dependence are not known, general clinical impression is that antagonist therapy is used relatively infrequently compared with agonist therapy.
The pharmacology and clinical use of these therapies is straightforward given that these medications are either full agonists or antagonists. In general, the dose of methadone or LAAM is increased until opioid craving, illicit opioid use, and withdrawal symptoms have abated or until excessive side-effects (i.e. sedation, constipation, etc.) require a reduction in dose. Likewise, naltrexone is used on a daily or thrice-weekly schedule to produce blockade of illicit opioids.
With the discovery of multiple opioid receptors, newer opioid analgesics (mixed agonist/antagonists and partial agonists) have been developed to take advantage of the pharmacologic effects mediated by these receptors. This development effort has been aimed primarily at reducing the abuse potential and physical dependence properties of these medications, while maintaining analgesic efficacy. These medications have varying degrees of affinity and intrinsic activity at different opioid receptors, and thereby can produce a more complex array of pharmacological effects than observed with full agonists or antagonists. The array of pharmacologic effects elicited by these medications has clinical implications. In the case of buprenorphine, it has high affinity and low intrinsic activity at the mu receptor (i.e. partial agonist). Buprenorphine has high affinity for and produces antagonist properties at the kappa receptor. This unique pharmacologic profile at the mu and kappa receptors gives buprenorphine certain advantages over the other mixed agonist–antagonist medications as it relates to the treatment of opioid dependence. These advantages include a greater safety index relative to respiratory depression, less autonomic signs of opioid withdrawal, and less psychomimetic or dysphoric effects.
Although labeled as a mixed agonist/antagonist for its activity at the mu and kappa receptors, respectively, it is the partial agonist properties buprenorphine exhibits at the mu receptor that are thought to be primarily responsible for its effectiveness in treating opioid dependence. Under appropriate conditions, buprenorphine may interact with opioid receptors to act as an agonist (morphine-like) or as an antagonist (naltrexone-like). As such, buprenorphine combines several of the strengths of methadone, naltrexone, and LAAM (cf. Bickel and Amass, 1995). Like methadone and LAAM, buprenorphine is an opioid agonist that is reinforcing (and hence can maintain compliance with regular ingestion). Like methadone, naltrexone and LAAM, it blocks the effects of illicit opioids, and like naltrexone and LAAM, it can be dosed on a less-than-daily basis. Like naltrexone, under the appropriate conditions buprenorphine can cause a withdrawal syndrome when administered to a person dependent on opioids.
Thus, buprenorphine can be visualized on a continuum between a full agonist (i.e. morphine, methadone, and LAAM) and an antagonist (i.e. naloxone, nalmefene and naltrexone) (Fig. 1). In individuals not tolerant to opioids, it acts as a potent mu-opioid (i.e. morphine-like) agonist at low doses. However, as the dose of buprenorphine is increased, it produces maximal agonist effects that are less than that expected from a full mu-opioid agonist. Further, as a result of its partial agonist properties, a high dose of buprenorphine may cause opioid-like withdrawal signs and symptoms (i.e. appearing to function as an opioid antagonist) in persons who have a high level of physical dependence on other opioids.
However, like methadone and LAAM (but unlike naltrexone), buprenorphine also has the disadvantage that it can be abused (Pickworth et al., 1993, Strain et al., 1997, Comer et al., 2002a, Comer and Collins, 2002b). Because this liability could significantly impact the ultimate role of buprenorphine in the treatment of opioid dependence (Agar et al., 2001), a combination product of buprenorphine and naloxone (Suboxone®) was developed. By reducing the abuse liability of buprenorphine, it can be made acceptable for use by clinicians outside of opioid treatment programs (i.e. office-based treatment setting). If buprenorphine were available through the traditional opioid treatment program system, it is likely that additional numbers of new patients entering the treatment delivery system would be limited (as appeared to be the initial case with LAAM). The US Food and Drug Administration approved buprenorphine and buprenorphine/naloxone on 8 October 2002 for the treatment of opioid dependence. Therefore, it is available in new treatment delivery sites such as office-based practices and this should result in an increase in the number of patients accessing treatment.
Office-based care will be possible due to a change in legislation driving the delivery of narcotic addiction treatment (Jaffe and O'Keeffe, 2003). Congress passed the Children's Health Act of 2000 (P.L. 106-310) on 17 October 2000. Title XXXV of this law provides a “Waiver Authority for Physicians Who Dispense or Prescribe Certain Narcotic Drugs for Maintenance Treatment or Detoxification Treatment” of opioid-dependent individuals. This part of the law is known as the Drug Addiction Treatment Act (2000) (Boatwright, 2002). Under this law physicians can treat opioid-dependent patients from their office with FDA approved schedule III, IV and V narcotics by notifying the Department of Health and Human services (DHSS) (through the Center for Substance Abuse Treatment (CSAT)) of their intent to treat. To qualify, a physician must be board or ASAM certified in addiction medicine or have 8 h of training in the treatment of opioid-dependent patients and be able to provide or refer patients to appropriate ancillary services (e.g. psychiatric, counselling, vocational education, etc.) (Clark, 2001). Further, physicians who obtain this waiver may treat a maximum of 30 patients at a time. Physicians who meet the above requirements will be able to treat patients from their office with buprenorphine or buprenorphine/naloxone because both of these tablet formulations are schedule III narcotics approved for the treatment of opioid dependence. It is hoped that this office-based system will help to destigmatize opioid dependence treatment, reduce barriers for patient entry into treatment, and move addiction treatment into mainstream medicine (Schnoll, 2001).
This paper provides an overview on the use of buprenorphine in the outpatient treatment of opioid dependence. It begins with a brief review of the pharmacology of buprenorphine, and the interested reader can find a more extensive discussion of buprenorphine's pharmacology in this (e.g. Walsh and Eissenberg, 2003) and other sources (Bickel and Amass, 1995). The subsequent sections address issues of starting (i.e. inducting), maintaining (i.e. maintenance), and reducing the dose (i.e. dose reduction, medical withdrawl, detoxification or dose tapering) in patients treated with buprenorphine. Issues associated with special populations are addressed in the final section.
Section snippets
Overview
Buprenorphine is generally described as a mixed agonist–antagonist opioid. Specifically, it has been characterized as a partial agonist at the mu receptor, and an antagonist at the kappa receptor. Thus, intrinsic activity differs at these two opioid receptors. Buprenorphine has low intrinsic activity (and high affinity) at the mu receptor (Martin et al., 1976, Jasinski et al., 1978). That is, it binds tightly to this receptor, but it does not “turn on” this receptor as completely as a full
Overview
Buprenorphine is available as tablets containing either buprenorphine alone (sometimes referred to as monotherapy tablets) or combined with naloxone (combination therapy tablets). It is expected that patients maintained on buprenorphine will be given the tablet containing both buprenorphine and naloxone. Experience from two national evaluations of the combination therapy tablet suggests that direct induction with combination therapy is acceptable to a majority of street heroin users (L. Amass,
Overview
Numerous studies have tested the efficacy and safety of buprenorphine during relatively short (i.e. 1 year or less) maintenance treatment episodes (e.g. Johnson et al., 1992, Johnson et al., 2000, Kosten et al., 1993, Strain et al., 1994, Ling et al., 1996, Schottenfeld et al., 1997, Schottenfeld et al., 2000, Uehlinger et al., 1998, Fischer et al., 1999, Mattick et al., 1999, Pani et al., 2000, Amass et al., 2000a, Petitjean et al., 2001, Perez de los Cobos et al., 2000, Ahmadi, 2002). Most of
Overview
While numerous outpatient clinical trials have tested the efficacy of maintenance buprenorphine, there have been relatively few controlled systematic studies of buprenorphine medical withdrawal (“detoxification” or “dose reduction”). For a complete review of this topic, see Gowing et al. (2002). Abrupt discontinuation of buprenorphine appears to produce a mild to moderate withdrawal syndrome (Jasinski et al., 1978, Jasinski et al., 1983, Seow et al., 1986, Kosten and Kleber, 1988, Fudala et
Overview
Few studies have been designed to specifically assess the effects of buprenorphine in special populations. Several studies have reported results in special populations as secondary outcome measures.
Gender
It is possible there may be differences between men and women in the response to buprenorphine. For example, in one clinical trial it was found that, early in treatment, men had fewer opiate positive urine specimens than women (Johnson et al., 1995a). However, another study found that women treated
Summary
Buprenorphine is an effective, safe medication for use in the treatment of opioid dependence. It has a unique pharmacologic profile, and understanding its pharmacologic effects helps in understanding and guiding its clinical use. Like other medications for medical disorders, its optimal use will depend upon appropriate and adequate dosing and the concurrent delivery of non-medication services that directly and indirectly address the underlying disorder (opioid dependence). However, because of
Acknowledgements
This work was supported by USPHS grants R01-DA12220 and P50-DA 05273 (Rolley E. Johnson), K02-DA00332 and R01-DA08045 (Eric C. Strain), and R01-DA11160 and R01-DA13638 (Leslie Amass) from the National Institute on Drug Abuse.
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At the time of the writing of this review Dr Johnson was Professor, Department of Psychiatry and Behavioral Science, Johns Hopkins University School of Medicine. He joined Reckitt Benckiser Pharmaceuticals, Inc. as Vice-President for Clinical, Scientific and Regulatory Affairs on 1 January 2003.