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A meta-analysis comparing the effectiveness of buprenorphine and methadone
Journal of Substance Abuse 12 (2000) 405 ± 414
A meta-analysis comparing the effectiveness of buprenorphine and methadone$ Steven L. Westa, Keri K. O'Neala, Carolyn W. Grahamb,* a
Texas Tech University, Lubbock, TX, USA Department of Child, Family, and Consumer Sciences, California State University-Fresno, 5300 North Campus Drive, M/S FF12, Fresno, CA 93740-8019, USA
b
Abstract Increases in the use of illicit opiates have refocused attention on these drugs. One outgrowth of this attention has been the increased consideration of pharmacotherapies to provide alternatives to methadone maintenance. Buprenorphine is one new tool used in the attenuation of illicit opiate use. Like methadone, buprenorphine produces cross-tolerance to other opiates. However, it may have advantages over methadone including a longer duration, limited withdrawal syndrome, and increased safety. Buprenorphine's ability to serve as a replacement drug for illicit opiate use is well documented, and efforts have recently been made to compare the drug with methadone. The purpose of this study was to provide a meta-analysis of all available research reporting a controlled comparison of buprenorphine and methadone. This analysis provided a rating of the comparative efficacy of each drug, thus giving clinicians an additional guide when selecting an appropriate course of treatment. Findings suggest a relative equality in the efficacy of buprenorphine and methadone, although patients receiving methadone were less likely to test positive for illicit opiate use. Past experience with methadone maintenance acted as a moderating variable, however, such that those receiving buprenorphine were more likely to stay drug-free in studies that included patients with prior methadone experience. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Buprenorphine; Methadone; Opiate relapse; Treatment
$ Portions of this research were presented in a poster at the 7th Annual Meeting of the Society for Prevention Research, New Orleans, LA, June 1999. * Corresponding author. Tel.: +1-559-278-8755; fax: +1-559-278-7824. E-mail address: [email protected] (C.W. Graham).
0899-3289/01/$ ± see front matter D 2001 Elsevier Science Inc. All rights reserved. PII: S 0 8 9 9 - 3 2 8 9 ( 0 1 ) 0 0 0 5 4 - 2
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1. Introduction A resurgence of opiate use and abuse has refocused national attention on this historically abused class of drugs. It has been estimated that roughly 810,000 or more individuals in the US are heroin users (American Methadone Treatment Association [AMTA], 1999). While nearly 162,000 people are engaged in methadone maintenance (AMTA, 1999), research has suggested that over 650,000 are in need of treatment due to an unresponsiveness to methadone or traditional counseling (AMTA, 1999; Ling, Wesson, Charuvastra, & Klett, 1996). Figures such as these have prompted researchers to seek alternative treatment modalities. Historically, few medications have been available in the US for maintenance treatment of opiate abuse. These have included methadone, naltrexone, and l-a-acetylmethadol (LAAM). Naltrexone is an opioid antagonist that effectively blocks receptor sites at doses of 50 mg/day (Litten & Allen, 1999), and has found additional use as an adjunct treatment for alcoholism. However, the retention rates of opioid-abusing patients in naltrexone maintenance has been notably poor. Retention rates of less than 30% after 6 months has been reported, possibly due to poor compliance arising for the drug's lack of narcotic side effects (Jaffe, 1995; Meandizga & Kosten, 1994). LAAM, another recent entry into the maintenance arena, is a long-lasting opioid agonist requiring dosing on 2- to 3-day intervals (Mattick, Oliphant, Ward, and Hall, 1998; Ward, Hall, & Mattick, 1999). This longer duration has the added benefits of lowering treatment costs and the risk of diversion (Ward et al., 1999). Despite this, LAAM use requires a longer stabilization period during which the risk of overdose is substantially increased (Ward et al., 1999). Based in part to these problems, and to the problems of the stigma associated with maintenance treatment and limited funding in general, neither of these therapies have true widespread use. Methadone is the most common pharmacological maintenance medication for opiate abuse available in the US (Alterman, McLellan, O'Brien, & McKay, 1998). Over the last three decades, the benefits of methadone maintenance for opiate abuse have been well-documented. Noted advantages have included decreases in criminal behavior, reduced illicit opiate use, improved retention in treatment programs, lower rates of HIV infection, and increased social functioning (Ball & Ross, 1993; Hubbard & Marsden, 1986; Newman, 1987; Plomp, Van Der Hek, & Ader, 1996; Schottenfeld & Kleber, 1995; Senay & Uchtenagen, 1990). Currently, methadone is available in approximately 750 to 800 clinics in the US (Ling, Rawson, & Compton, 1994). Despite these facts, the use of methadone, like LAAM and naltrexone, has not been without problems. Take-home methadone is subject to diversion for resale, and has a higher potential for overdose than clinically supervised administration, a method itself limited by higher costs (Cooper, 1992; Newman, 1987). Patients frequently note that daily methadone use is inconvenient and interferes with daily life activities (Cooper, 1992; Ling et al., 1994). There have been reports indicating that withdrawal from methadone is difficult, and that a variety of negative physical side effects are associated with its use (Cooper, 1992; Mello & Mendelson, 1985). Recently, research has also questioned the ability of normal-dose methadone in facilitating total abstinence from illicit opiates among individuals using the
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currently available higher-grade heroin found in most urban areas (Alterman et al., 1998). Although reduction in illicit use is still evident, available clinical studies have suggested that methadone maintenance with such clients is less effective than in previous years (Bickel & Amass, 1995; Morral, Igushi, Belding, & Lamb, 1997; O'Brien & McKay, 1998). As a result, there is often limited patient and community satisfaction with methadone use. These problems, coupled with the same social problems hindering the expansion of LAAM and naltrexone use, helped lead in part to the development of buprenorphine. Recent development of the partial m-opioid agonist buprenorphine has given clinicians a new tool in treating illicit opiate abuse. Buprenorphine is a mixed opioid agonist/antagonist that has received wide attention in both the experimental (e.g., Foltin & Fischman, 1996) and clinical treatment (e.g., Johnson, Jaffe, & Fudala, 1992) of opiate addiction. Researched initially for its safety and efficacy (Strain, Stitzer, Liebson, & Bigelow, 1994a; Strain, Stitzer, Liebson, & Bigelow, 1994b), recent efforts have been made to compare buprenorphine with the established opiate replacement drug methadone. Like methadone, buprenorphine produces cross-tolerance to other opiates. However, buprenorphine may have advantages over methadone including a longer duration of action, limited withdrawal syndrome after discontinuation, and an increased safety profile (e.g., full m-opioid agonists are more likely to cause depressed respiratory functioning) (Bickel et al., 1988; Johnson et al., 1992). Buprenorphine has been found to reduce heroin self-administration (Mello & Mendelson, 1985; Mello, Mendelson, & Kuehnle, 1982; Strain et al., 1994a, 1994b) in both experimental and clinical settings. Early research indicated that buprenorphine's duration of action was similar to that of methadone, but at much smaller doses (2 mg of buprenorphine vs. 30 mg methadone), a fact which may be due to buprenorphine's lengthy disassociation from receptor sites due to its high affinity for the m-opioid receptor (Kosten, Schottenfeld, Ziedonis, & Falcioni, 1993; McQuay & Moore, 1995). The purpose of this meta-analysis was to provide a quantitative evaluation of all available research articles reporting a controlled clinical comparison of buprenorphine and methadone. Such an analysis provides a rating of the comparative efficacy of each drug, thus giving clinicians an additional guide when selecting an appropriate course of action with opiate-abusing clients. A meta-analysis is an effective and efficient procedure for determining the combined significance of existing studies. To date, a variety of clinical studies are available in the research literature. However, no comprehensive meta-analytic evaluations have been completed. 2. Methods 2.1. Literature search In an effort to obtain articles for the present study, a search of the MEDLINE and PsychInfo computerized databases was conducted in the Summer of 2000. The subject headings ``buprenorphine,'' ``opiate addiction,'' ``methadone,'' ``drug treatment,'' and
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``maintenance'' were used independently and in combination with one another (i.e., ``methadone'' with ``maintenance'' and ``buprenorphine'' with ``drug treatment''). The reference lists of relevant articles and reviews were also examined in an effort to obtain as many reports as possible. The abstracts of references and the articles themselves were then evaluated for inclusion in the present analysis. No time limit was constrained on the search, and studies were examined dating from 1974 (the earliest date in which the word ``buprenorphine'' appeared in the databases) to 2000. Using these methods, over 1595 articles were initially obtained, the majority of which were investigations into the pharmacological properties of the drug. The use of criteria for inclusion provides a way to compare studies with similar methods and obtain a better understanding of the efficacy of a treatment plan. Studies were included in the meta-analysis if they satisfied each of the three following selection criteria. Any study that failed to meet one or all three of these criteria was purposefully excluded. Using the following three selection guidelines, the original list of references was refined to nine reports that met the inclusion criteria (see Table 1). 2.2. Criteria for inclusion (1) The article provided a controlled comparison of buprenorphine and methadone in the treatment of opiate addiction. If the participants in the research were reported to have coexisting psychiatric disorders or reported a primary drug of abuse other than an opiate, the study was not included in the present meta-analysis. As noted by Brewer, Catalano, Haggerty, Gainey, and Fleming (1998), it is important to distinguish different subtypes of substance users and individuals with coexisting psychiatric disorders. These differences result in variations in drug use and psychological functioning among selected individuals that may unduly influence the results obtained for any particular treatment. Since buprenorphine is not currently approved for general use in the US, this criterion was selected in an attempt to provide a clear rating of effectiveness with its primary intended population. However, due to the limited number of studies with subjects who abused only opiates and the prevalence of polydrug use among opiate abusers, articles were included which noted the use of other substances in their sample. Such articles were only included if the primary drug of abuse was an opiate. (2) The study included quantified information about treatment efficacy in regard to continued illicit opiate use. The various articles obtained used an assortment of ways to rate treatment efficacy including retention rates, self-report of illicit opiate use, and urine toxicology screening. As discussed below in detail, the only common outcome measure across all of the studies was urinalysis. (3) The treatment program in each study provided data on the total number of individuals testing positive and negative for illicit opiate use within each group (buprenorphine or methadone maintenance) at the end of the study period. 2.3. Calculation of effect sizes Effect sizes were calculated using the procedures outlined by Rosenthal (1991). For the current analysis, the calculation of an effect size was based on the number of individuals who
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Table 1 Primary articles included in the present analysis Author (year)
Sample
Johnson et al. (1992)
162 male and female opiate abusers
Kosten et al. (1993)
125 male and female opiate abusers
Strain et al. (1994a)
51 male and female opiate and cocaine abusers 164 male and female opiate abusers
Strain et al. (1994b)
Ling et al. (1996)
225 male and female opiate abusers
Schottenfeld et al. (1997)
116 male and female opiate abusers
Eder et al. (1998)
34 (gender not specified) opiate abusers
Uehlinger et al. (1998)
58 male and female opiate abusers
Fischer et al. (1999)
60 male and female opiate abusers
Treatment type 25-week, outpatient program (buprenorphine 8 mg daily vs. methadone 20 and 60 mg daily) 24-week outpatient program (buprenorphine 2 and 6 mg daily vs. methadone 35 and 65 mg daily) 24-week outpatient program (buprenorphine 8 to 16 mg daily vs. methadone 50 to 90 mg daily) 24-week outpatient program [buprenorphine 8 mg (variable administration) vs. methadone 50 mg (variable administration)] 52-week outpatient program (buprenorphine 8 mg daily vs. methadone 30 and 80 mg daily) 24-week outpatient program (buprenorphine 4 and 12 mg daily vs. methadone 20 and 65 mg daily) 24-week outpatient (buprenorphine to 8 mg daily vs. methadone variable administration daily) 6-week outpatient (buprenorphine 4 ± 16 mg daily vs. methadone 30 ± 120 mg daily) 24-week outpatient program [buprenorphine 2 and 8 mg daily vs. methadone (up to 80 mg daily)]
Statistic used in meta-analysis
Effect size
2
.1670
c2
.2154
c2
.0524
c2
.0733
c2
.1204
c2
.0025
c2
.00a
c2
.00a
c2
.4637
c
A negative symbol ( ) by an effect size denotes a greater efficacy for methadone. a Assumed effect size.
had and had not tested positive for illicit use by means of a urine toxicology screen (the only common outcome measure for all studies). However, none of the studies provided sufficient information to compute an effect size from their reported statistical techniques. In lieu of this information, calculation of effect sizes for the present study had to be conducted via chisquare tests derived from the total sample size, the size of each treatment group, and the
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number of participants retained within each treatment group in the study. In two cases, a total lack of information necessary to make such a calculation was present (Eder et al., 1998; Uehlinger et al., 1998). In both cases, however, it was noted that a nonsignificant difference existed between the buprenorphine and methadone groups. Hence, the common procedure of entering an effect size of zero in such cases (e.g., Das Eiden & Reifman, 1996) was used for these two studies in the present analysis. Meta-analyses are commonly presented in the form of both correlation coefficients (r) and by the difference in the means of the treatment and control conditions divided by the pooled standard deviation (Cohen's d) (Das Eiden & Reifman, 1996). Since both are ratings of effect size, they can readily be converted into one another, and, if not provided in the original analyses, they can be calculated using F, t, and c2 statistics as well as by means and standard deviations (Rosenthal, 1991). Since effect sizes were not provided in any of the original articles in this analysis, the appropriate data (in this case c2 statistics) were obtained and converted first into the r statistic using the method described by Rosenthal (1991). We then converted the effect size r to Cohen's d to provide a comparison rating for those more familiar with this statistic. Primary reliance on the effect size r was used since the validity of the assumptions made when calculating Cohen's d have been called into question (Greenland, 1998). Briefly, the method for calculating d involves the use of standard deviation units that may in fact vary across individual studies. This may result in over- or underestimation of effect size since the resulting comparative results are, in fact, nonequivalent. Since many meta-analytic studies report this statistic, we included the d in this study for comparative purposes only. Tests of significance require that effect sizes be independent (Amato & Keith, 1991). Therefore, if two or more effect sizes were generated within the same outcome category (i.e., if varying doses of the same drug were compared against one another), we used the mean effect size in the current study. Although this procedure allowed for the inclusion of studies with varying dosages, it is problematic due to possible error of using pooled or averaged data when there are differential effectiveness levels. 3. Results The average unweighted mean effect size across all studies was r = .0460 (d = .0921), with the negative sign for both statistics indicating a better outcome for methadone treatment (vs. buprenorphine). Using the guidelines developed by Cohen (1988), the obtained effect sizes are both below the level that is normally considered small. Further, the test of cumulative significance used to indicate whether or not a difference exists between the groups was not significant (Z = 1.2760, ns). To determine whether or not the obtained effect sizes were more spread out than would be expected by chance, a test of heterogeneity was performed. Results indicated that the obtained effect sizes were clearly more diffuse than would be anticipated (c2 = 25.42, df = 6, P < .001). A significant result indicates that the effect sizes are not homogenous across studies and it is necessary to further analyze the data in an attempt to account for the heterogeneity. Therefore,
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focused tests were conducted to assess whether individual study characteristics were acting as moderating variables and contributing to the differentiation across studies. Focused tests are appropriate to use in the current analysis when common variables are utilized throughout the original studies. Therefore, upon finding that the test of heterogeneity was significant, the first task was to determine what, if any, shared characteristics existed. This post hoc examination of the original articles allowed for one focused test to be performed based on previous experience with methadone maintenance programs. This characteristic was chosen because it was the one shared characteristic across all studies which could potentially alter the results obtained by any one individual study and/or the overall analysis. For the purpose of this test, studies were weighted either as (1) for prior experience with methadone maintenance or ( 1) for no past experience with methadone maintenance. A significant result would indicate a between-study difference for those who have had prior methadone maintenance experience and those who have not. Many of the reports (Eder et al., 1998; Johnson et al., 1992; Ling et al., 1996; Schottenfeld, Pakes, Oliveto, Ziedonis, & Kosten, 1997; Uehlinger et al., 1998) provided no clear information about prior methadone maintenance experience, and thus could not be used in this focused test. This highlights the difficult and often arbitrary nature of conducting such an analysis. Focused tests are limited to the types of common characteristics discernable from the original articles. When such information is absent, as in five cases in the current study, any conclusions drawn from the results are tempered by the uncertainty of how the excluded studies could have influenced the outcome of the test. Although not the case in the present analysis, the decision to include studies in one focused group as opposed to another can also be a matter of judgment and hence, add potential subjectivity or bias to the test. Consequently, only four studies were available for the analysis. The results of the focused test were significant (Z = 3.99, P < .01), noting that studies with patients having a history of methadone treatment were also the studies wherein buprenorphine tended to be more effective. 4. Discussion A high degree of variability was apparent in the findings of the individual studies included in the present analysis. This lack of consistency may be due, in part, to the lack of uniformity both in research design and reporting in these studies. A focused test was conducted to determine if commonalties existed across studies and assessed the potential effect of prior methadone maintenance experience. The significant result indicated that a difference existed between studies that included subjects with past methadone maintenance experience vs. those with no prior experience. Those studies containing patients with prior methadone experience were also the ones where buprenorphine proved to be more effective. Such a finding implies that clinicians should consider prior methadone experience when determining the appropriate course of treatment. It may be that individuals in treatment for recurrent opiate use who have had experience with methadone are less likely to be maintained on a similar regimen. However, such a conclusion is speculative, as future research is necessary to clarify this
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finding and note other potential factors at play. The limited information available at this time and the particularly small number of studies available for the focused test prevents the ability to generalize to broader clinical populations. The current analysis is limited by the fact that the included studies also did not use uniform dosages of either buprenorphine or methadone. In many cases, individual reports contained data on clients receiving differing dose levels of a particular medication over time. Likewise, the articles included here also contained reports with two different dosage levels of both methadone and buprenorphine. Due to the limited information provided, it was frequently unclear what particular dose levels were being provided. To conduct the meta-analysis, the present research contained information on all buprenorphine vs. all methadone levels. This amalgamation provided the best statistical test given the limited number of studies available and the wide variation in reported doses. Future efforts comparing these two treatments should convey information on dosage levels more clearly. As evidenced by the limited number of studies qualifying for inclusion in the present analysis, many questions remain to be answered. Factors such as ethnicity and gender were not addressed in the primary studies reported here and thus were unavailable for examination via focused tests. Similarly, other variables such as age, length of history of use, and precise information on previous treatment experiences were also not addressed. Once variables such as these are taken into account, a broader understanding of the similarities and differences of these two pharmacotherapies will emerge. The current findings suggest a relative equality in the efficacy of buprenorphine and methadone. Although the effect sizes of the methadone groups were slightly larger than those of the buprenorphine groups, this effect was virtually nonexistent and was not statistically significant. This suggests that for all practical purposes these two medications can be used with equal success. However, there are other aspects of these medications that may impact clinician choice. Buprenorphine has consistently been shown to be a safer alternative to methadone due to its better safety profile (i.e., less likelihood of respiratory depression and sedation) and more limited withdrawal syndrome (i.e., limited withdrawal effects even during abrupt discontinuation) (Bickel et al., 1988; Johnson et al., 1992). Moreover, this analysis indicates that buprenorphine can be used as an effective alternative to traditional methadone maintenance. Based on these findings, clinicians can base their choice of maintenance medications on factors related to safety and patient compliance. References Alterman, A. I., McLellan, A. T., O'Brien, C. P., & McKay, J. R. (1998). Differential therapies and options. In: R. J. Frances, & S. I. Miller (Eds.), Clinical textbook of addictive disorders ((2nd ed.) pp. 447 ± 478). New York: Guilford Press. Amato, P. R., & Keith, B. (1991). Parental divorce and the well-being of children: a meta-analysis. Psychological Bulletin, 110 (1), 26 ± 46. American Methadone Treatment Association. (1999). Methadone maintenance program and census in the U.S.. New York: American Methadone Treatment Association.
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A meta-analysis comparing the effectiveness of buprenorphine and methadone$ Steven L. Westa, Keri K. O'Neala, Carolyn W. Grahamb,* a
Texas Tech University, Lubbock, TX, USA Department of Child, Family, and Consumer Sciences, California State University-Fresno, 5300 North Campus Drive, M/S FF12, Fresno, CA 93740-8019, USA
b
Abstract Increases in the use of illicit opiates have refocused attention on these drugs. One outgrowth of this attention has been the increased consideration of pharmacotherapies to provide alternatives to methadone maintenance. Buprenorphine is one new tool used in the attenuation of illicit opiate use. Like methadone, buprenorphine produces cross-tolerance to other opiates. However, it may have advantages over methadone including a longer duration, limited withdrawal syndrome, and increased safety. Buprenorphine's ability to serve as a replacement drug for illicit opiate use is well documented, and efforts have recently been made to compare the drug with methadone. The purpose of this study was to provide a meta-analysis of all available research reporting a controlled comparison of buprenorphine and methadone. This analysis provided a rating of the comparative efficacy of each drug, thus giving clinicians an additional guide when selecting an appropriate course of treatment. Findings suggest a relative equality in the efficacy of buprenorphine and methadone, although patients receiving methadone were less likely to test positive for illicit opiate use. Past experience with methadone maintenance acted as a moderating variable, however, such that those receiving buprenorphine were more likely to stay drug-free in studies that included patients with prior methadone experience. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Buprenorphine; Methadone; Opiate relapse; Treatment
$ Portions of this research were presented in a poster at the 7th Annual Meeting of the Society for Prevention Research, New Orleans, LA, June 1999. * Corresponding author. Tel.: +1-559-278-8755; fax: +1-559-278-7824. E-mail address: [email protected] (C.W. Graham).
0899-3289/01/$ ± see front matter D 2001 Elsevier Science Inc. All rights reserved. PII: S 0 8 9 9 - 3 2 8 9 ( 0 1 ) 0 0 0 5 4 - 2
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1. Introduction A resurgence of opiate use and abuse has refocused national attention on this historically abused class of drugs. It has been estimated that roughly 810,000 or more individuals in the US are heroin users (American Methadone Treatment Association [AMTA], 1999). While nearly 162,000 people are engaged in methadone maintenance (AMTA, 1999), research has suggested that over 650,000 are in need of treatment due to an unresponsiveness to methadone or traditional counseling (AMTA, 1999; Ling, Wesson, Charuvastra, & Klett, 1996). Figures such as these have prompted researchers to seek alternative treatment modalities. Historically, few medications have been available in the US for maintenance treatment of opiate abuse. These have included methadone, naltrexone, and l-a-acetylmethadol (LAAM). Naltrexone is an opioid antagonist that effectively blocks receptor sites at doses of 50 mg/day (Litten & Allen, 1999), and has found additional use as an adjunct treatment for alcoholism. However, the retention rates of opioid-abusing patients in naltrexone maintenance has been notably poor. Retention rates of less than 30% after 6 months has been reported, possibly due to poor compliance arising for the drug's lack of narcotic side effects (Jaffe, 1995; Meandizga & Kosten, 1994). LAAM, another recent entry into the maintenance arena, is a long-lasting opioid agonist requiring dosing on 2- to 3-day intervals (Mattick, Oliphant, Ward, and Hall, 1998; Ward, Hall, & Mattick, 1999). This longer duration has the added benefits of lowering treatment costs and the risk of diversion (Ward et al., 1999). Despite this, LAAM use requires a longer stabilization period during which the risk of overdose is substantially increased (Ward et al., 1999). Based in part to these problems, and to the problems of the stigma associated with maintenance treatment and limited funding in general, neither of these therapies have true widespread use. Methadone is the most common pharmacological maintenance medication for opiate abuse available in the US (Alterman, McLellan, O'Brien, & McKay, 1998). Over the last three decades, the benefits of methadone maintenance for opiate abuse have been well-documented. Noted advantages have included decreases in criminal behavior, reduced illicit opiate use, improved retention in treatment programs, lower rates of HIV infection, and increased social functioning (Ball & Ross, 1993; Hubbard & Marsden, 1986; Newman, 1987; Plomp, Van Der Hek, & Ader, 1996; Schottenfeld & Kleber, 1995; Senay & Uchtenagen, 1990). Currently, methadone is available in approximately 750 to 800 clinics in the US (Ling, Rawson, & Compton, 1994). Despite these facts, the use of methadone, like LAAM and naltrexone, has not been without problems. Take-home methadone is subject to diversion for resale, and has a higher potential for overdose than clinically supervised administration, a method itself limited by higher costs (Cooper, 1992; Newman, 1987). Patients frequently note that daily methadone use is inconvenient and interferes with daily life activities (Cooper, 1992; Ling et al., 1994). There have been reports indicating that withdrawal from methadone is difficult, and that a variety of negative physical side effects are associated with its use (Cooper, 1992; Mello & Mendelson, 1985). Recently, research has also questioned the ability of normal-dose methadone in facilitating total abstinence from illicit opiates among individuals using the
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currently available higher-grade heroin found in most urban areas (Alterman et al., 1998). Although reduction in illicit use is still evident, available clinical studies have suggested that methadone maintenance with such clients is less effective than in previous years (Bickel & Amass, 1995; Morral, Igushi, Belding, & Lamb, 1997; O'Brien & McKay, 1998). As a result, there is often limited patient and community satisfaction with methadone use. These problems, coupled with the same social problems hindering the expansion of LAAM and naltrexone use, helped lead in part to the development of buprenorphine. Recent development of the partial m-opioid agonist buprenorphine has given clinicians a new tool in treating illicit opiate abuse. Buprenorphine is a mixed opioid agonist/antagonist that has received wide attention in both the experimental (e.g., Foltin & Fischman, 1996) and clinical treatment (e.g., Johnson, Jaffe, & Fudala, 1992) of opiate addiction. Researched initially for its safety and efficacy (Strain, Stitzer, Liebson, & Bigelow, 1994a; Strain, Stitzer, Liebson, & Bigelow, 1994b), recent efforts have been made to compare buprenorphine with the established opiate replacement drug methadone. Like methadone, buprenorphine produces cross-tolerance to other opiates. However, buprenorphine may have advantages over methadone including a longer duration of action, limited withdrawal syndrome after discontinuation, and an increased safety profile (e.g., full m-opioid agonists are more likely to cause depressed respiratory functioning) (Bickel et al., 1988; Johnson et al., 1992). Buprenorphine has been found to reduce heroin self-administration (Mello & Mendelson, 1985; Mello, Mendelson, & Kuehnle, 1982; Strain et al., 1994a, 1994b) in both experimental and clinical settings. Early research indicated that buprenorphine's duration of action was similar to that of methadone, but at much smaller doses (2 mg of buprenorphine vs. 30 mg methadone), a fact which may be due to buprenorphine's lengthy disassociation from receptor sites due to its high affinity for the m-opioid receptor (Kosten, Schottenfeld, Ziedonis, & Falcioni, 1993; McQuay & Moore, 1995). The purpose of this meta-analysis was to provide a quantitative evaluation of all available research articles reporting a controlled clinical comparison of buprenorphine and methadone. Such an analysis provides a rating of the comparative efficacy of each drug, thus giving clinicians an additional guide when selecting an appropriate course of action with opiate-abusing clients. A meta-analysis is an effective and efficient procedure for determining the combined significance of existing studies. To date, a variety of clinical studies are available in the research literature. However, no comprehensive meta-analytic evaluations have been completed. 2. Methods 2.1. Literature search In an effort to obtain articles for the present study, a search of the MEDLINE and PsychInfo computerized databases was conducted in the Summer of 2000. The subject headings ``buprenorphine,'' ``opiate addiction,'' ``methadone,'' ``drug treatment,'' and
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``maintenance'' were used independently and in combination with one another (i.e., ``methadone'' with ``maintenance'' and ``buprenorphine'' with ``drug treatment''). The reference lists of relevant articles and reviews were also examined in an effort to obtain as many reports as possible. The abstracts of references and the articles themselves were then evaluated for inclusion in the present analysis. No time limit was constrained on the search, and studies were examined dating from 1974 (the earliest date in which the word ``buprenorphine'' appeared in the databases) to 2000. Using these methods, over 1595 articles were initially obtained, the majority of which were investigations into the pharmacological properties of the drug. The use of criteria for inclusion provides a way to compare studies with similar methods and obtain a better understanding of the efficacy of a treatment plan. Studies were included in the meta-analysis if they satisfied each of the three following selection criteria. Any study that failed to meet one or all three of these criteria was purposefully excluded. Using the following three selection guidelines, the original list of references was refined to nine reports that met the inclusion criteria (see Table 1). 2.2. Criteria for inclusion (1) The article provided a controlled comparison of buprenorphine and methadone in the treatment of opiate addiction. If the participants in the research were reported to have coexisting psychiatric disorders or reported a primary drug of abuse other than an opiate, the study was not included in the present meta-analysis. As noted by Brewer, Catalano, Haggerty, Gainey, and Fleming (1998), it is important to distinguish different subtypes of substance users and individuals with coexisting psychiatric disorders. These differences result in variations in drug use and psychological functioning among selected individuals that may unduly influence the results obtained for any particular treatment. Since buprenorphine is not currently approved for general use in the US, this criterion was selected in an attempt to provide a clear rating of effectiveness with its primary intended population. However, due to the limited number of studies with subjects who abused only opiates and the prevalence of polydrug use among opiate abusers, articles were included which noted the use of other substances in their sample. Such articles were only included if the primary drug of abuse was an opiate. (2) The study included quantified information about treatment efficacy in regard to continued illicit opiate use. The various articles obtained used an assortment of ways to rate treatment efficacy including retention rates, self-report of illicit opiate use, and urine toxicology screening. As discussed below in detail, the only common outcome measure across all of the studies was urinalysis. (3) The treatment program in each study provided data on the total number of individuals testing positive and negative for illicit opiate use within each group (buprenorphine or methadone maintenance) at the end of the study period. 2.3. Calculation of effect sizes Effect sizes were calculated using the procedures outlined by Rosenthal (1991). For the current analysis, the calculation of an effect size was based on the number of individuals who
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Table 1 Primary articles included in the present analysis Author (year)
Sample
Johnson et al. (1992)
162 male and female opiate abusers
Kosten et al. (1993)
125 male and female opiate abusers
Strain et al. (1994a)
51 male and female opiate and cocaine abusers 164 male and female opiate abusers
Strain et al. (1994b)
Ling et al. (1996)
225 male and female opiate abusers
Schottenfeld et al. (1997)
116 male and female opiate abusers
Eder et al. (1998)
34 (gender not specified) opiate abusers
Uehlinger et al. (1998)
58 male and female opiate abusers
Fischer et al. (1999)
60 male and female opiate abusers
Treatment type 25-week, outpatient program (buprenorphine 8 mg daily vs. methadone 20 and 60 mg daily) 24-week outpatient program (buprenorphine 2 and 6 mg daily vs. methadone 35 and 65 mg daily) 24-week outpatient program (buprenorphine 8 to 16 mg daily vs. methadone 50 to 90 mg daily) 24-week outpatient program [buprenorphine 8 mg (variable administration) vs. methadone 50 mg (variable administration)] 52-week outpatient program (buprenorphine 8 mg daily vs. methadone 30 and 80 mg daily) 24-week outpatient program (buprenorphine 4 and 12 mg daily vs. methadone 20 and 65 mg daily) 24-week outpatient (buprenorphine to 8 mg daily vs. methadone variable administration daily) 6-week outpatient (buprenorphine 4 ± 16 mg daily vs. methadone 30 ± 120 mg daily) 24-week outpatient program [buprenorphine 2 and 8 mg daily vs. methadone (up to 80 mg daily)]
Statistic used in meta-analysis
Effect size
2
.1670
c2
.2154
c2
.0524
c2
.0733
c2
.1204
c2
.0025
c2
.00a
c2
.00a
c2
.4637
c
A negative symbol ( ) by an effect size denotes a greater efficacy for methadone. a Assumed effect size.
had and had not tested positive for illicit use by means of a urine toxicology screen (the only common outcome measure for all studies). However, none of the studies provided sufficient information to compute an effect size from their reported statistical techniques. In lieu of this information, calculation of effect sizes for the present study had to be conducted via chisquare tests derived from the total sample size, the size of each treatment group, and the
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number of participants retained within each treatment group in the study. In two cases, a total lack of information necessary to make such a calculation was present (Eder et al., 1998; Uehlinger et al., 1998). In both cases, however, it was noted that a nonsignificant difference existed between the buprenorphine and methadone groups. Hence, the common procedure of entering an effect size of zero in such cases (e.g., Das Eiden & Reifman, 1996) was used for these two studies in the present analysis. Meta-analyses are commonly presented in the form of both correlation coefficients (r) and by the difference in the means of the treatment and control conditions divided by the pooled standard deviation (Cohen's d) (Das Eiden & Reifman, 1996). Since both are ratings of effect size, they can readily be converted into one another, and, if not provided in the original analyses, they can be calculated using F, t, and c2 statistics as well as by means and standard deviations (Rosenthal, 1991). Since effect sizes were not provided in any of the original articles in this analysis, the appropriate data (in this case c2 statistics) were obtained and converted first into the r statistic using the method described by Rosenthal (1991). We then converted the effect size r to Cohen's d to provide a comparison rating for those more familiar with this statistic. Primary reliance on the effect size r was used since the validity of the assumptions made when calculating Cohen's d have been called into question (Greenland, 1998). Briefly, the method for calculating d involves the use of standard deviation units that may in fact vary across individual studies. This may result in over- or underestimation of effect size since the resulting comparative results are, in fact, nonequivalent. Since many meta-analytic studies report this statistic, we included the d in this study for comparative purposes only. Tests of significance require that effect sizes be independent (Amato & Keith, 1991). Therefore, if two or more effect sizes were generated within the same outcome category (i.e., if varying doses of the same drug were compared against one another), we used the mean effect size in the current study. Although this procedure allowed for the inclusion of studies with varying dosages, it is problematic due to possible error of using pooled or averaged data when there are differential effectiveness levels. 3. Results The average unweighted mean effect size across all studies was r = .0460 (d = .0921), with the negative sign for both statistics indicating a better outcome for methadone treatment (vs. buprenorphine). Using the guidelines developed by Cohen (1988), the obtained effect sizes are both below the level that is normally considered small. Further, the test of cumulative significance used to indicate whether or not a difference exists between the groups was not significant (Z = 1.2760, ns). To determine whether or not the obtained effect sizes were more spread out than would be expected by chance, a test of heterogeneity was performed. Results indicated that the obtained effect sizes were clearly more diffuse than would be anticipated (c2 = 25.42, df = 6, P < .001). A significant result indicates that the effect sizes are not homogenous across studies and it is necessary to further analyze the data in an attempt to account for the heterogeneity. Therefore,
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focused tests were conducted to assess whether individual study characteristics were acting as moderating variables and contributing to the differentiation across studies. Focused tests are appropriate to use in the current analysis when common variables are utilized throughout the original studies. Therefore, upon finding that the test of heterogeneity was significant, the first task was to determine what, if any, shared characteristics existed. This post hoc examination of the original articles allowed for one focused test to be performed based on previous experience with methadone maintenance programs. This characteristic was chosen because it was the one shared characteristic across all studies which could potentially alter the results obtained by any one individual study and/or the overall analysis. For the purpose of this test, studies were weighted either as (1) for prior experience with methadone maintenance or ( 1) for no past experience with methadone maintenance. A significant result would indicate a between-study difference for those who have had prior methadone maintenance experience and those who have not. Many of the reports (Eder et al., 1998; Johnson et al., 1992; Ling et al., 1996; Schottenfeld, Pakes, Oliveto, Ziedonis, & Kosten, 1997; Uehlinger et al., 1998) provided no clear information about prior methadone maintenance experience, and thus could not be used in this focused test. This highlights the difficult and often arbitrary nature of conducting such an analysis. Focused tests are limited to the types of common characteristics discernable from the original articles. When such information is absent, as in five cases in the current study, any conclusions drawn from the results are tempered by the uncertainty of how the excluded studies could have influenced the outcome of the test. Although not the case in the present analysis, the decision to include studies in one focused group as opposed to another can also be a matter of judgment and hence, add potential subjectivity or bias to the test. Consequently, only four studies were available for the analysis. The results of the focused test were significant (Z = 3.99, P < .01), noting that studies with patients having a history of methadone treatment were also the studies wherein buprenorphine tended to be more effective. 4. Discussion A high degree of variability was apparent in the findings of the individual studies included in the present analysis. This lack of consistency may be due, in part, to the lack of uniformity both in research design and reporting in these studies. A focused test was conducted to determine if commonalties existed across studies and assessed the potential effect of prior methadone maintenance experience. The significant result indicated that a difference existed between studies that included subjects with past methadone maintenance experience vs. those with no prior experience. Those studies containing patients with prior methadone experience were also the ones where buprenorphine proved to be more effective. Such a finding implies that clinicians should consider prior methadone experience when determining the appropriate course of treatment. It may be that individuals in treatment for recurrent opiate use who have had experience with methadone are less likely to be maintained on a similar regimen. However, such a conclusion is speculative, as future research is necessary to clarify this
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finding and note other potential factors at play. The limited information available at this time and the particularly small number of studies available for the focused test prevents the ability to generalize to broader clinical populations. The current analysis is limited by the fact that the included studies also did not use uniform dosages of either buprenorphine or methadone. In many cases, individual reports contained data on clients receiving differing dose levels of a particular medication over time. Likewise, the articles included here also contained reports with two different dosage levels of both methadone and buprenorphine. Due to the limited information provided, it was frequently unclear what particular dose levels were being provided. To conduct the meta-analysis, the present research contained information on all buprenorphine vs. all methadone levels. This amalgamation provided the best statistical test given the limited number of studies available and the wide variation in reported doses. Future efforts comparing these two treatments should convey information on dosage levels more clearly. As evidenced by the limited number of studies qualifying for inclusion in the present analysis, many questions remain to be answered. Factors such as ethnicity and gender were not addressed in the primary studies reported here and thus were unavailable for examination via focused tests. Similarly, other variables such as age, length of history of use, and precise information on previous treatment experiences were also not addressed. Once variables such as these are taken into account, a broader understanding of the similarities and differences of these two pharmacotherapies will emerge. The current findings suggest a relative equality in the efficacy of buprenorphine and methadone. Although the effect sizes of the methadone groups were slightly larger than those of the buprenorphine groups, this effect was virtually nonexistent and was not statistically significant. This suggests that for all practical purposes these two medications can be used with equal success. However, there are other aspects of these medications that may impact clinician choice. Buprenorphine has consistently been shown to be a safer alternative to methadone due to its better safety profile (i.e., less likelihood of respiratory depression and sedation) and more limited withdrawal syndrome (i.e., limited withdrawal effects even during abrupt discontinuation) (Bickel et al., 1988; Johnson et al., 1992). Moreover, this analysis indicates that buprenorphine can be used as an effective alternative to traditional methadone maintenance. Based on these findings, clinicians can base their choice of maintenance medications on factors related to safety and patient compliance. References Alterman, A. I., McLellan, A. T., O'Brien, C. P., & McKay, J. R. (1998). Differential therapies and options. In: R. J. Frances, & S. I. Miller (Eds.), Clinical textbook of addictive disorders ((2nd ed.) pp. 447 ± 478). New York: Guilford Press. Amato, P. R., & Keith, B. (1991). Parental divorce and the well-being of children: a meta-analysis. Psychological Bulletin, 110 (1), 26 ± 46. American Methadone Treatment Association. (1999). Methadone maintenance program and census in the U.S.. New York: American Methadone Treatment Association.
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