A call for consensus in defining efficacy in clinical trials for opioid addiction: combined results from a systematic review and qualitative study in patients receiving pharmacological assisted therapy for opioid use disorder

Brittany B Dennis, Nitika Sanger, Monica Bawor, Leen Naji, Carolyn Plater, Andrew Worster, Julia Woo, Anuja Bhalerao, Natasha Baptist-Mohseni, Alannah Hillmer, Danielle Rice, Kim Corace, Brian Hutton, Peter Tugwell, Lehana Thabane, Zainab Samaan, Brittany B Dennis, Nitika Sanger, Monica Bawor, Leen Naji, Carolyn Plater, Andrew Worster, Julia Woo, Anuja Bhalerao, Natasha Baptist-Mohseni, Alannah Hillmer, Danielle Rice, Kim Corace, Brian Hutton, Peter Tugwell, Lehana Thabane, Zainab Samaan

Abstract

Background: Given the complex nature of opioid addiction treatment and the rising number of available opioid substitution and antagonist therapies (OSAT), there is no 'gold standard' measure of treatment effectiveness, and each successive trial measures a different set of outcomes which reflect success in arbitrary or opportune terms. We sought to describe the variation in current outcomes employed across clinical trials for opioid addiction, as well as determine whether a discrepancy exists between the treatment targets that patients consider important and how treatment effectiveness is measured in the literature.

Methods: We searched nine commonly used databases (e.g., EMBASE, MEDLINE) from inception to August 1, 2015. Outcomes used across trials were extracted and categorized according to previously established domains. To evaluate patient-reported goals of treatment, semi-structured interviews were conducted with 18 adults undergoing methadone treatment.

Results: We identified 60 trials eligible for inclusion. Once outcomes were categorized into eight broad domains (e.g., abstinence/substance abuse), we identified 21 specific outcomes with furthermore 53 subdomains and 118 measurements. Continued opioid use and treatment retention were the most commonly reported measures (46%, n = 28). The majority of patients agreed that abstinence from opioids was a primary goal in their treatment, although they also stressed goals under-reported in clinical trials.

Conclusions: There is inconsistency in the measures used to evaluate the effectiveness of OSATs. Individual and population level decision making is being guided by a standard of effect considered useful to researchers yet in direct conflict with what patients deem important.

Trial registration: PROSPERO, CRD42013006507.

Keywords: Clinical trials; Efficacy; Methodology; Opioid addiction; Patient important outcomes; Treatment effectiveness.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram
Fig. 2
Fig. 2
First ranked treatment goals among patients receiving OSAT. Patients ranking of treatment goals from a “pre-determined” list provided during the qualitative interview. Patients were asked to rank which aspect of recovery was most important to their addiction treatment goals. Patients were allowed to rank up to four items. The figure illustrates the first ranked items

References

    1. Deshpande PR, Rajan S, Sudeepthi BL, Abdul Nazir CP. Patient-reported outcomes: a new era in clinical research. Perspect Clin Res. 2011;2:137–144. doi: 10.4103/2229-3485.86879.
    1. Montori VM, Wang YG, Alonso-Coello P, Bhagra S. Systematic evaluation of the quality of randomized controlled trials in diabetes. Diabetes Care. 2006;29:1833–1838. doi: 10.2337/dc06-0077.
    1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th ed.). 2013. 10.1176/appi.books.9780890425596.
    1. Mattick Richard P, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev. 2009. 10.1002/14651858.CD002209.pub2.
    1. Hedrich D, et al. The effectiveness of opioid maintenance treatment in prison settings: a systematic review. Addiction. 2012;107:501–517. doi: 10.1111/j.1360-0443.2011.03676.x.
    1. Li Y, Kantelip J-P, Gerritsen-van Schieveen P, Davani S. Interindividual variability of methadone response. Mol Diagn Ther. 2008;12:109–124. doi: 10.1007/BF03256276.
    1. Dennis BB, Naji L, Bawor M, Bonner A, Varenbut M, Daiter J, Plater C, Pare G, Marsh DC, Worster A, Desai D. The effectiveness of opioid substitution treatments for patients with opioid dependence: a systematic review and multiple treatment comparison protocol. Syst Rev. 2014;3:105. doi: 10.1186/2046-4053-3-105.
    1. Shamseer L, et al. Preferred reporting items for systematic review and meta-analysis protocols (prisma-p) 2015: Elaboration and explanation. BMJ. 2015;349:g7647. doi: 10.1136/bmj.g7647.
    1. McLellan AT, et al. The fifth edition of the Addiction Severity Index. J Subst Abus Treat. 1992;9:199–213. doi: 10.1016/0740-5472(92)90062-S.
    1. Marsden John, Gossop Michael, Stewart Duncan, Best David, Farrell Michael, Lehmann Petra, Edwards Carolyn, Strang John. The Maudsley Addiction Profile (MAP): a brief instrument for assessing treatment outcome. Addiction. 1998;93(12):1857–1867. doi: 10.1046/j.1360-0443.1998.9312185711.x.
    1. Woo J, et al. “Dont judge a book by its cover”: a qualitative study of methadone patients’ experiences of stigma. Subst Abus Res Treat. 2017. 10.1177/1178221816685087.
    1. von Elm E, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ. 2007;335:806–808. doi: 10.1136/.
    1. Ahmadi J, Ahmadi K. Controlled trial of maintenance treatment of intravenous buprenorphine dependence. Ir J Med Sci. 2003;172:171–173. doi: 10.1007/BF02915283.
    1. van den Brink W, et al. Medical prescription of heroin to treatment resistant heroin addicts: two randomised controlled trials. BMJ. 2003;327:310. doi: 10.1136/bmj.327.7410.310.
    1. Ling W, Wesson DR, Charuvastra C, Klett CJ. A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence. Arch Gen Psychiatry. 1996;53:401–407. doi: 10.1001/archpsyc.1996.01830050035005.
    1. Schottenfeld RS, Chawarski MC, Mazlan M. Maintenance treatment with buprenorphine and naltrexone for heroin dependence in Malaysia: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;371:2192–2200. doi: 10.1016/S0140-6736(08)60954-X.
    1. Johnson RE, et al. A placebo controlled clinical trial of buprenorphine as a treatment for opioid dependence. Drug Alcohol Depend. 1995;40:17–25. doi: 10.1016/0376-8716(95)01186-2.
    1. Ahmadi J, Moosavinasab M, Babaee M, Firoozabadi A, Mohagheghzadeh M, et al. F. H. Treatment of heroin dependence. Ger J Psychiatry. 2004;7:1–5.
    1. Ahmadi J. A controlled trial of buprenorphine treatment for opium dependence: the first experience from Iran. Drug Alcohol Depend. 2002;66:111–114. doi: 10.1016/S0376-8716(01)00202-2.
    1. Yancovitz SR, et al. A randomized trial of an interim methadone maintenance clinic. Am J Public Heal. 1991;81:1185–1191. doi: 10.2105/AJPH.81.9.1185.
    1. Sees KL, et al. Methadone maintenance vs 180-day psychosocially enriched detoxification for treatment of opioid dependence: a randomized controlled trial. JAMA. 2000;283:1303–1310. doi: 10.1001/jama.283.10.1303.
    1. Strain EC, Stitzer ML, Liebson IA, Bigelow GE. Comparison of buprenorphine and methadone in the treatment of opioid dependence. Am J Psychiatry. 1994;151:1025–1030. doi: 10.1176/ajp.151.7.1025.
    1. 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;11:641–653. doi: 10.1017/S146114570700836X.
    1. March JC, Oviedo-Joekes E, Perea-Milla E, Carrasco F. Controlled trial of prescribed heroin in the treatment of opioid addiction. J Subst Abus Treat. 2006;31:203–211. doi: 10.1016/j.jsat.2006.04.007.
    1. Comer SD, et al. Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2006;63:210–218. doi: 10.1001/archpsyc.63.2.210.
    1. Eder H, et al. Comparative study of the effectiveness of slow-release morphine and methadone for opioid maintenance therapy. Addiction (Abingdon, England) 2005;100:1101–1109. doi: 10.1111/j.1360-0443.2005.001128.x.
    1. Eissenberg T, et al. Dose-related efficacy of levomethadyl acetate for treatment of opioid dependence. A randomized clinical trial. JAMA. 1997;277:1945–1951. doi: 10.1001/jama.1997.03540480045037.
    1. Jaffe JH, et al. Methadyl acetate vs methadone. A double-blind study in heroin users. JAMA. 1972;222:437–442. doi: 10.1001/jama.1972.03210040013004.
    1. Kamien JB, Branstetter SA, Amass L. Buprenorphine-naloxone versus methadone maintenance therapy: A randomised double-blind trial with opioid-dependent patients. Heroin Addict Relat Clin Probl. 2008;10:5–18.
    1. King VL, et al. A 12-month controlled trial of methadone medical maintenance integrated into an adaptive treatment model. J Subst Abus Treat. 2006;31:385–393. doi: 10.1016/j.jsat.2006.05.014.
    1. Oviedo-Joekes E, et al. Diacetylmorphine versus methadone for the treatment of opioid addiction. N Engl J Med. 2009;361:777–786. doi: 10.1056/NEJMoa0810635.
    1. Oviedo-Joekes E, March JC, Romero M, Perea-Milla E. The Andalusian trial on heroin-assisted treatment: a 2 year follow-up. Drug Alcohol Rev. 2010;29:75–80. doi: 10.1111/j.1465-3362.2009.00100.x.
    1. Potter JS, et al. Buprenorphine/naloxone and methadone maintenance treatment outcomes for opioid analgesic, heroin, and combined users: findings from starting treatment with agonist replacement therapies (START) J Stud Alcohol Drugs. 2013;74:605–613. doi: 10.15288/jsad.2013.74.605.
    1. Robertson JR, et al. Addressing the efficacy of dihydrocodeine versus methadone as an alternative maintenance treatment for opiate dependence: A randomized controlled trial. Addiction. 2006;101:1752–1759. doi: 10.1111/j.1360-0443.2006.01603.x.
    1. Saxon AJ, et al. Buprenorphine/Naloxone and methadone effects on laboratory indices of liver health: a randomized trial. Drug Alcohol Depend. 2013;128:71–76. doi: 10.1016/j.drugalcdep.2012.08.002.
    1. Anglin MD, Conner BT, Annon J, Longshore D. Levo-alpha-acetylmethadol (LAAM) versus methadone maintenance: 1-year treatment retention, outcomes and status. Addiction. 2007;102:1432–1442. doi: 10.1111/j.1360-0443.2007.01935.x.
    1. Schwartz RP, Kelly SM, O’Grady KE, Gandhi D, Jaffe JH. Interim methadone treatment compared to standard methadone treatment: 4-month findings. J Subst Abus Treat. 2011;41:21–29. doi: 10.1016/j.jsat.2011.01.008.
    1. Schwartz RP, et al. A randomized controlled trial of interim methadone maintenance. Arch Gen Psychiatry. 2006;63:102–109. doi: 10.1001/archpsyc.63.1.102.
    1. Strain EC, Stitzer ML, Liebson IA, Bigelow GE. Buprenorphine versus methadone in the treatment of opioid dependence: self-reports, urinalysis, and addiction severity index. J Clin Psychopharmacol. 1996;16:58–67. doi: 10.1097/00004714-199602000-00010.
    1. Wolstein J, et al. A randomized, open-label trial comparing methadone and Levo-Alpha-Acetylmethadol (LAAM) in maintenance treatment of opioid addiction. Pharmacopsychiatry. 2009;42:1–8. doi: 10.1055/s-0028-1083818.
    1. Ling W, Charuvastra VC, Kaim SC, Klett CJ. Methadyl acetate and methadone as maintenance treatments for heroin addicts: a Veterans Administration cooperative study. Arch Gen Psychiatry. 1976;33:709–720. doi: 10.1001/archpsyc.1976.01770060043007.
    1. White JM, et al. Relationship between LAAM-methadone preference and treatment outcomes. Drug Alcohol Depend. 2002;66:295–301. doi: 10.1016/S0376-8716(02)00007-8.
    1. Kosten TR, Schottenfeld R, Ziedonis D, Falcioni J. Buprenorphine versus methadone maintenance for opioid dependence. J Nerv Ment Dis. 1993;181:358–364. doi: 10.1097/00005053-199306000-00004.
    1. Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Arch Intern Med. 2007;167:2469–2475. doi: 10.1001/archinte.167.22.2469.
    1. Woody GE, et al. Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trial. JAMA. 2008;300:2003–2011. doi: 10.1001/jama.2008.574.
    1. Kakko J, Svanborg KD, Kreek MJ, Heilig M. 1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial. Lancet. 2003;361:662–668. doi: 10.1016/S0140-6736(03)12600-1.
    1. Fischer G, et al. Buprenorphine versus methadone maintenance for the treatment of opioid dependence. Addiction (Abingdon, England) 1999;94:1337–1347. doi: 10.1046/j.1360-0443.1999.94913376.x.
    1. Krook AL, et al. A placebo-controlled study of high dose buprenorphine in opiate dependents waiting for medication-assisted rehabilitation in Oslo, Norway. Addiction. 2002;97:533–542. doi: 10.1046/j.1360-0443.2002.00090.x.
    1. Ling W, et al. Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial. Addiction. 1998;93:475–486. doi: 10.1046/j.1360-0443.1998.9344753.x.
    1. Lintzeris N, et al. Implementing buprenorphine treatment in community settings in Australia: experiences from the Buprenorphine Implementation Trial. Am J Addict. 2004;13(Suppl 1):S29–S41. doi: 10.1080/10550490490440799.
    1. Mattick RP, et al. Buprenorphine versus methadone maintenance therapy: a randomized double-blind trial with 405 opioid-dependent patients. Addiction. 2003;98:441–452. doi: 10.1046/j.1360-0443.2003.00335.x.
    1. Neri S, et al. Randomized clinical trial to compare the effects of methadone and buprenorphine on the immune system in drug abusers. Psychopharmacology. 2005;179:700–704. doi: 10.1007/s00213-005-2239-x.
    1. Shufman EN, et al. The efficacy of naltrexone in preventing reabuse of heroin after detoxification. Biol Psychiatry. 1994;35:935–945. doi: 10.1016/0006-3223(94)91240-8.
    1. Pani PP, Maremmani I, Pirastu R, Tagliamonte A, Gessa GL. Buprenorphine: a controlled clinical trial in the treatment of opioid dependence. Drug Alcohol Depend. 2000;60:39–50. doi: 10.1016/S0376-8716(00)80006-X.
    1. Schottenfeld RS, Pakes JR, Kosten TR. Prognostic factors in Buprenorphine- versus methadone-maintained patients. J Nerv Ment Dis. 1998;186:35–43. doi: 10.1097/00005053-199801000-00006.
    1. Preston KL, Umbricht A, Epstein DH. Methadone dose increase and abstinence reinforcement for treatment of continued heroin use during methadone maintenance. Arch Gen Psychiatry. 2000;57:395–404. doi: 10.1001/archpsyc.57.4.395.
    1. Schottenfeld RS, et al. Methadone versus buprenorphine with contingency management or performance feedback for cocaine and opioid dependence. Am J Psychiatry. 2005;162:340–349. doi: 10.1176/appi.ajp.162.2.340.
    1. Fudala PJ, et al. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med. 2003;349:949–958. doi: 10.1056/NEJMoa022164.
    1. Strain EC, Stitzer ML, Liebson IA, Bigelow GE. Dose-response effects of methadone in the treatment of opioid dependence. Ann Intern Med. 1993;119:23–27. doi: 10.7326/0003-4819-119-1-199307010-00004.
    1. Hartnoll RL, et al. Evaluation of heroin maintenance in controlled trial. Arch Gen Psychiatry. 1980;37:877–884. doi: 10.1001/archpsyc.1980.01780210035003.
    1. Strang J, et al. Supervised injectable heroin or injectable methadone versus optimised oral methadone as treatment for chronic heroin addicts in England after persistent failure in orthodox treatment (RIOTT): a randomised trial. Lancet. 2010;375:1885–1895. doi: 10.1016/S0140-6736(10)60349-2.
    1. Zaks A, Fink M, Freedman AM. Levomethadyl in maintenance treatment of opiate dependence. JAMA. 1972;220:811–813. doi: 10.1001/jama.1972.03200060039005.
    1. Strain EC, Bigelow GE, Liebson IA, Stitzer ML. Moderate- vs high-dose methadone in the treatment of opioid dependence: a randomized trial. JAMA. 1999;281:1000–1005. doi: 10.1001/jama.281.11.1000.
    1. Petitjean S, et al. Double-blind randomized trial of buprenorphine and methadone in opiate dependence. Drug Alcohol Depend. 2001;62:97–104. doi: 10.1016/S0376-8716(00)00163-0.
    1. Guo S. Efficacy of naltrexone hydrochloride for preventing relapse among opiate dependent patients after detoxification. Hong Kong J Psychiatry. 2001;11:2–8.
    1. Krupitsky EM, et al. Naltrexone for heroin dependence treatment in St. Petersburg, Russia. J Subst Abus Treat. 2004;26:285–294. doi: 10.1016/j.jsat.2004.02.002.
    1. San L, Pomarol G, Peri JM, Olle JM, Cami J. Follow-up after a six-month maintenance period on naltrexone versus placebo in heroin addicts. Br J Addict. 1991;86:983–990. doi: 10.1111/j.1360-0443.1991.tb01859.x.
    1. Krupitsky EM, et al. Naltrexone with or without fluoxetine for preventing relapse to heroin addiction in St. Petersburg, Russia. J Subst Abus Treat. 2006;31:319–328. doi: 10.1016/j.jsat.2006.05.005.
    1. Giacomuzzi SM, Ertl M, Kemmler G, Riemer Y, Vigl A. Sublingual buprenorphine and methadone maintenance treatment: a three-year follow-up of quality of life assessment. Scientific World J. 2005;5:452–468. doi: 10.1100/tsw.2005.52.
    1. Haasen C, et al. Heroin-assisted treatment for opioid dependence: randomised controlled trial. Br J Psychiatry. 2007;191:55–62. doi: 10.1192/bjp.bp.106.026112.
    1. Johnson RE, Jaffe JH, Fudala PJ. A controlled trial of buprenorphine treatment for opioid dependence. JAMA. 1992;267:2750–2755. doi: 10.1001/jama.1992.03480200058024.
    1. Krupitsky E, et al. Randomized trial of long-acting sustained-release naltrexone implant vs oral naltrexone or placebo for preventing relapse to opioid dependence. Arch Gen Psychiatry. 2012;69:973–981. doi: 10.1001/archgenpsychiatry.2012.1a.
    1. Dennis BB, et al. Opioid substitution and antagonist therapy trials exclude the common addiction patient: a systematic review and analysis of eligibility criteria. Trials. 2015;16:1. doi: 10.1186/1745-6215-16-1.
    1. Bruneau J, et al. Management of opioid use disorders: a national clinical practice guideline. Can Med Assoc J. 2018;190:E247–E257. doi: 10.1503/cmaj.170958.
    1. Methadone maintenance treatment program standards and clinical guidelines. The College of Physicians and Surgeons of Ontario; 2011.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する