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COMMENTARY
Commentary on Hser et al. (2014):To retain or not to retain—open questions in opioid maintenance therapy
Methadone, buprenorphine and the buprenorphine/ naloxone combination are established first-line medications for the treatment of opioid dependence [1–4], but may have different indications in different people. Furthermore, in several countries oral or intravenous diamorphine or oral morphine treatment are used for maintenance treatment in special subgroups of opioiddependent patients [5,6]. In this issue, Hser et al. [7] present data from an important study in 1267 opioid-dependent individuals randomized to open-label buprenorphine/naloxone or methadone treatment. Three findings are of relevance: first, the treatment completion rate was much higher with methadone than with buprenorphine/naloxone (74 versus 46%); secondly, the completion rate with buprenorphine/naloxone increased linearly as the dose was increased, reaching 60% with doses of 30–32 mg/day—higher doses than are usually given in clinical practice or studies (see [8]); and thirdly, buprenorphine/naloxone was associated with a lower rate of continued illicit drug use. A number of other studies, but not all [9], have also shown somewhat better retention rates for methadone than for buprenorphine [10], although a 28% difference is striking. Retention rates are relevant for opioid maintenance treatment (no patients, no success), but vary considerably between treatment settings. Naturalistic long-term studies do not indicate that methadone has a higher retention rate than buprenorphine [11]. One should keep in mind that regulatory authorities stipulate that the primary outcome of an opioid maintenance drug must be decreased opioid consumption. Retention per se is not the goal and may vary. Retention depends upon many setting variables: supervised versus unsupervised dosage, strict versus less strict urinary controls, take-home supply versus daily clinic attendance, zero or maximum tolerance with respect to alcohol intake, etc. Not surprisingly, many patients favour less controlling settings; such settings may show better treatment retention, but not necessarily reduced opioid use. Largely unsupervised settings that use a maximum dose are lax about performing urine analyses and in which physicians and social workers do not ask too many questions may meet many patients’ wishes more than stricter settings, but they do not guarantee long-term success. In other words, retention is important, but it is just one aspect of opioid maintenance treatment. However, in special treatment situations, e.g. the treatment of pregnant opioiddependent women, retention rate is very important, more so than in other patient groups [12]. In line with the © 2013 Society for the Study of Addiction
results of Hser et al., a recent study showed that in pregnant women the retention rate is higher with methadone than with buprenorphine [13]. The results of this study also highlight again the essential role of the induction phase in initiating opioid maintenance therapy. The greatest differences in retention rates emerged within the first weeks of treatment. Stepped-care approaches may be helpful [14]. One may speculate whether the results presented by Hser et al. fit into a differential typology of opioid users, often heard among clinicians but not well established, that affects the choice of opioid maintenance drug: methadone may be more appropriate for the long-term addict with a high level of physical dependence, while buprenorphine may be better for the more motivated, possibly abstinenceorientated patient, because it is easier to taper off. Future studies may address this question in more detail. Buprenorphine and methadone also differ in their elimination and pharmacological interactions, which may facilitate clinical decisions [15,16]. A final comment on buprenorphine dosing: the data from Hser et al. are in line with other findings indicating better retention with higher buprenorphine dosage [17], but they are not supported by neuroimaging studies. Just a handful of opioid receptor positron emission tomography (PET) studies have been performed with buprenorphine. Greenwald et al. [18] demonstrated that 16 mg buprenorphine reduced mu-opioid receptor availability by 85–92%, while 32 mg reduced it by 94–98%, with minimal interindividual variability. Similar findings for 16 mg were published by Zubieta et al. [19]. These data make it difficult to understand why 32 mg buprenorphine may be more effective than 16 mg (or 20–24 mg). However, we are treating patients, not PET scans. Clinical data show the way! Nevertheless, basic research may address the question of why a higher dose than needed for maximum receptor binding may work better than we expect on the basis of opioid receptor PET studies. Acknowledgement The authors thank Jacquie Klesing, Board-Certified Editor in the Life Sciences (ELS), for editing assistance with this commentary. Declaration of interests Michael Soyka has received unrestricted research grants or has worked as a consultant for Lundbeck, Prempharm, Addiction, 109, 88–89
Commentary
Essex, Sanofi Aventis and Reckitt Benckiser. Thomas Hillemacher has received unrestricted research grants or has worked as a consultant for Lundbeck, Servier, Otsuka, BMS, Jansen and Astra Zeneca. Keywords Buprenorphine, dependence, opioids, therapy.
methadone,
8.
opioid 9.
MICHAEL SOYKA1,2 & THOMAS HILLEMACHER3
Department of Psychiatry, Ludwig Maximilian University, Nussbaumstr 7, 80336 Munich, Germany,1 Private Hospital Meiringen, PO Box 612, 3860 Meiringen, Switzerland2 and Center for Addiction Research, Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.3 E-mail: [email protected]
10.
11.
12.
References 1. Kleber H. D., Weiss R. D., Anton R. F. Jr, George T. P., Greenfield S. F., Kosten T. R. et al. Treatment of patients with substance use disorders, second edition. American Psychiatric Association. Am J Psychiatry 2007; 164: 5–123. 2. Soyka M., Kranzler H. R., van den Brink W., Krystal J., Moller H. J., Kasper S. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of substance use and related disorders. Part 2: opioid dependence. World J Biol Psychiatry 2011; 12: 160– 87. 3. Lingford-Hughes A. R., Welch S., Peters L., Nutt D. J. BAP updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP. J Psychopharmacol 2012; 26: 899–952. 4. World Health Organization. Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. Geneva: World Health Organization; 2009. 5. Haasen C., Verthein U., Degkwitz P., Berger J., Krausz M., Naber D. Heroin-assisted treatment for opioid dependence: randomised controlled trial. Br J Psychiatry 2007; 191: 55–62. 6. Kastelic A., Dubajic G., Strbad E. Slow-release oral morphine for maintenance treatment of opioid addicts intolerant to methadone or with inadequate withdrawal suppression. Addiction 2008; 103: 1837–46. 7. Hser Y., Saxon A. J., Huang D., Hasson A., Thomas C., Hillhouse M. et al. Treatment retention among patients randomized to buprenorphine/naloxone compared to
© 2013 Society for the Study of Addiction
13.
14.
15.
16.
17.
18.
19.
89
methadone in a multi-site trial. Addiction 2014; 109: 79–87. European Medicines Agency. Suboxone, buprenorphine/ naloxone. 2013. Available at: http://www.ema.europa .eu/ema/index.jsp?curl=pages/medicines/human/ medicines/000697/human_med_001067.jsp&mid =WC0b01ac058001d124 (accessed 13 October, 2013). Soyka M., Zingg C., Koller G., Kuefner H. Retention rate and substance use in methadone and buprenorphine maintenance therapy and predictors of outcome: results from a randomized study. Int J Neuropsychopharmacol 2008; 11: 641–53. Mattick R. P., Kimber J., Breen C., Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev 2008; 16: CD002207. Wittchen H. U., Trader A., Klotsche J., Backmund M., Buhringer G., Rehm J. T. et al. [The role of the maintenance drug and its dose on long-term outcome in opioid maintenance therapy]. Suchtmed 2011; 13: 263–8. Heberlein A., Leggio L., Stichtenoth D., Hillemacher T. The treatment of alcohol and opioid dependence in pregnant women. Curr Opin Psychiatry 2012; 25: 559–64. Jones H. E., Kaltenbach K., Heil S. H., Stine S. M., Coyle M. G., Arria A. M. et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med 2010; 363: 2320–31. Kakko J., Gronbladh L., Svanborg K. D., von Wachenfeldt J., Ruck C., Rawlings B. et al. A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial. Am J Psychiatry 2007; 164: 797–803. Gruber V. A., McCance-Katz E. F. Methadone, buprenorphine, and street drug interactions with antiretroviral medications. Curr HIV/AIDS Rep 2010; 7: 152–60. McCance-Katz E. F. Drug interactions associated with methadone, buprenorphine, cocaine, and HIV medications: implications for pregnant women. Life Sci 2011; 88: 953–8. Fareed A., Vayalapalli S., Casarella J., Drexler K. Effect of buprenorphine dose on treatment outcome. J Addict Dis 2012; 31: 8–18. Greenwald M. K., Johanson C. E., Moody D. E., Woods J. H., Kilbourn M. R., Koeppe R. A. et al. Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroindependent volunteers. Neuropsychopharmacology 2003; 28: 2000–9. Zubieta J., Greenwald M. K., Lombardi U., Woods J. H., Kilbourn M. R., Jewett D. M. et al. Buprenorphine-induced changes in mu-opioid receptor availability in male heroindependent volunteers: a preliminary study. Neuropsychopharmacology 2000; 23: 326–34.
Addiction, 109, 88–89
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
COMMENTARY
Commentary on Hser et al. (2014):To retain or not to retain—open questions in opioid maintenance therapy
Methadone, buprenorphine and the buprenorphine/ naloxone combination are established first-line medications for the treatment of opioid dependence [1–4], but may have different indications in different people. Furthermore, in several countries oral or intravenous diamorphine or oral morphine treatment are used for maintenance treatment in special subgroups of opioiddependent patients [5,6]. In this issue, Hser et al. [7] present data from an important study in 1267 opioid-dependent individuals randomized to open-label buprenorphine/naloxone or methadone treatment. Three findings are of relevance: first, the treatment completion rate was much higher with methadone than with buprenorphine/naloxone (74 versus 46%); secondly, the completion rate with buprenorphine/naloxone increased linearly as the dose was increased, reaching 60% with doses of 30–32 mg/day—higher doses than are usually given in clinical practice or studies (see [8]); and thirdly, buprenorphine/naloxone was associated with a lower rate of continued illicit drug use. A number of other studies, but not all [9], have also shown somewhat better retention rates for methadone than for buprenorphine [10], although a 28% difference is striking. Retention rates are relevant for opioid maintenance treatment (no patients, no success), but vary considerably between treatment settings. Naturalistic long-term studies do not indicate that methadone has a higher retention rate than buprenorphine [11]. One should keep in mind that regulatory authorities stipulate that the primary outcome of an opioid maintenance drug must be decreased opioid consumption. Retention per se is not the goal and may vary. Retention depends upon many setting variables: supervised versus unsupervised dosage, strict versus less strict urinary controls, take-home supply versus daily clinic attendance, zero or maximum tolerance with respect to alcohol intake, etc. Not surprisingly, many patients favour less controlling settings; such settings may show better treatment retention, but not necessarily reduced opioid use. Largely unsupervised settings that use a maximum dose are lax about performing urine analyses and in which physicians and social workers do not ask too many questions may meet many patients’ wishes more than stricter settings, but they do not guarantee long-term success. In other words, retention is important, but it is just one aspect of opioid maintenance treatment. However, in special treatment situations, e.g. the treatment of pregnant opioiddependent women, retention rate is very important, more so than in other patient groups [12]. In line with the © 2013 Society for the Study of Addiction
results of Hser et al., a recent study showed that in pregnant women the retention rate is higher with methadone than with buprenorphine [13]. The results of this study also highlight again the essential role of the induction phase in initiating opioid maintenance therapy. The greatest differences in retention rates emerged within the first weeks of treatment. Stepped-care approaches may be helpful [14]. One may speculate whether the results presented by Hser et al. fit into a differential typology of opioid users, often heard among clinicians but not well established, that affects the choice of opioid maintenance drug: methadone may be more appropriate for the long-term addict with a high level of physical dependence, while buprenorphine may be better for the more motivated, possibly abstinenceorientated patient, because it is easier to taper off. Future studies may address this question in more detail. Buprenorphine and methadone also differ in their elimination and pharmacological interactions, which may facilitate clinical decisions [15,16]. A final comment on buprenorphine dosing: the data from Hser et al. are in line with other findings indicating better retention with higher buprenorphine dosage [17], but they are not supported by neuroimaging studies. Just a handful of opioid receptor positron emission tomography (PET) studies have been performed with buprenorphine. Greenwald et al. [18] demonstrated that 16 mg buprenorphine reduced mu-opioid receptor availability by 85–92%, while 32 mg reduced it by 94–98%, with minimal interindividual variability. Similar findings for 16 mg were published by Zubieta et al. [19]. These data make it difficult to understand why 32 mg buprenorphine may be more effective than 16 mg (or 20–24 mg). However, we are treating patients, not PET scans. Clinical data show the way! Nevertheless, basic research may address the question of why a higher dose than needed for maximum receptor binding may work better than we expect on the basis of opioid receptor PET studies. Acknowledgement The authors thank Jacquie Klesing, Board-Certified Editor in the Life Sciences (ELS), for editing assistance with this commentary. Declaration of interests Michael Soyka has received unrestricted research grants or has worked as a consultant for Lundbeck, Prempharm, Addiction, 109, 88–89
Commentary
Essex, Sanofi Aventis and Reckitt Benckiser. Thomas Hillemacher has received unrestricted research grants or has worked as a consultant for Lundbeck, Servier, Otsuka, BMS, Jansen and Astra Zeneca. Keywords Buprenorphine, dependence, opioids, therapy.
methadone,
8.
opioid 9.
MICHAEL SOYKA1,2 & THOMAS HILLEMACHER3
Department of Psychiatry, Ludwig Maximilian University, Nussbaumstr 7, 80336 Munich, Germany,1 Private Hospital Meiringen, PO Box 612, 3860 Meiringen, Switzerland2 and Center for Addiction Research, Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.3 E-mail: [email protected]
10.
11.
12.
References 1. Kleber H. D., Weiss R. D., Anton R. F. Jr, George T. P., Greenfield S. F., Kosten T. R. et al. Treatment of patients with substance use disorders, second edition. American Psychiatric Association. Am J Psychiatry 2007; 164: 5–123. 2. Soyka M., Kranzler H. R., van den Brink W., Krystal J., Moller H. J., Kasper S. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of substance use and related disorders. Part 2: opioid dependence. World J Biol Psychiatry 2011; 12: 160– 87. 3. Lingford-Hughes A. R., Welch S., Peters L., Nutt D. J. BAP updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP. J Psychopharmacol 2012; 26: 899–952. 4. World Health Organization. Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. Geneva: World Health Organization; 2009. 5. Haasen C., Verthein U., Degkwitz P., Berger J., Krausz M., Naber D. Heroin-assisted treatment for opioid dependence: randomised controlled trial. Br J Psychiatry 2007; 191: 55–62. 6. Kastelic A., Dubajic G., Strbad E. Slow-release oral morphine for maintenance treatment of opioid addicts intolerant to methadone or with inadequate withdrawal suppression. Addiction 2008; 103: 1837–46. 7. Hser Y., Saxon A. J., Huang D., Hasson A., Thomas C., Hillhouse M. et al. Treatment retention among patients randomized to buprenorphine/naloxone compared to
© 2013 Society for the Study of Addiction
13.
14.
15.
16.
17.
18.
19.
89
methadone in a multi-site trial. Addiction 2014; 109: 79–87. European Medicines Agency. Suboxone, buprenorphine/ naloxone. 2013. Available at: http://www.ema.europa .eu/ema/index.jsp?curl=pages/medicines/human/ medicines/000697/human_med_001067.jsp&mid =WC0b01ac058001d124 (accessed 13 October, 2013). Soyka M., Zingg C., Koller G., Kuefner H. Retention rate and substance use in methadone and buprenorphine maintenance therapy and predictors of outcome: results from a randomized study. Int J Neuropsychopharmacol 2008; 11: 641–53. Mattick R. P., Kimber J., Breen C., Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev 2008; 16: CD002207. Wittchen H. U., Trader A., Klotsche J., Backmund M., Buhringer G., Rehm J. T. et al. [The role of the maintenance drug and its dose on long-term outcome in opioid maintenance therapy]. Suchtmed 2011; 13: 263–8. Heberlein A., Leggio L., Stichtenoth D., Hillemacher T. The treatment of alcohol and opioid dependence in pregnant women. Curr Opin Psychiatry 2012; 25: 559–64. Jones H. E., Kaltenbach K., Heil S. H., Stine S. M., Coyle M. G., Arria A. M. et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med 2010; 363: 2320–31. Kakko J., Gronbladh L., Svanborg K. D., von Wachenfeldt J., Ruck C., Rawlings B. et al. A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial. Am J Psychiatry 2007; 164: 797–803. Gruber V. A., McCance-Katz E. F. Methadone, buprenorphine, and street drug interactions with antiretroviral medications. Curr HIV/AIDS Rep 2010; 7: 152–60. McCance-Katz E. F. Drug interactions associated with methadone, buprenorphine, cocaine, and HIV medications: implications for pregnant women. Life Sci 2011; 88: 953–8. Fareed A., Vayalapalli S., Casarella J., Drexler K. Effect of buprenorphine dose on treatment outcome. J Addict Dis 2012; 31: 8–18. Greenwald M. K., Johanson C. E., Moody D. E., Woods J. H., Kilbourn M. R., Koeppe R. A. et al. Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroindependent volunteers. Neuropsychopharmacology 2003; 28: 2000–9. Zubieta J., Greenwald M. K., Lombardi U., Woods J. H., Kilbourn M. R., Jewett D. M. et al. Buprenorphine-induced changes in mu-opioid receptor availability in male heroindependent volunteers: a preliminary study. Neuropsychopharmacology 2000; 23: 326–34.
Addiction, 109, 88–89
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
