Maintenance treatment for opioid dependence with slow-release oral morphine: a randomized cross-over, non-inferiority study versus methadone

Thilo Beck, Christian Haasen, Uwe Verthein, Stephan Walcher, Christoph Schuler, Markus Backmund, Christian Ruckes, Jens Reimer, Thilo Beck, Christian Haasen, Uwe Verthein, Stephan Walcher, Christoph Schuler, Markus Backmund, Christian Ruckes, Jens Reimer

Abstract

Aims: To compare the efficacy of slow-release oral morphine (SROM) and methadone as maintenance medication for opioid dependence in patients previously treated with methadone.

Design: Prospective, multiple-dose, open label, randomized, non-inferiority, cross-over study over two 11-week periods. Methadone treatment was switched to SROM with flexible dosing and vice versa according to period and sequence of treatment.

Setting: Fourteen out-patient addiction treatment centres in Switzerland and Germany.

Participants: Adults with opioid dependence in methadone maintenance programmes (dose ≥50 mg/day) for ≥26 weeks.

Measurements: The efficacy end-point was the proportion of heroin-positive urine samples per patient and period of treatment. Each week, two urine samples were collected, randomly selected and analysed for 6-monoacetyl-morphine and 6-acetylcodeine. Non-inferiority was concluded if the two-sided 95% confidence interval (CI) in the difference of proportions of positive urine samples was below the predefined boundary of 10%.

Findings: One hundred and fifty-seven patients fulfilled criteria to form the per protocol population. The proportion of heroin-positive urine samples under SROM treatment (0.20) was non-inferior to the proportion under methadone treatment (0.15) (least-squares mean difference 0.05; 95% CI = 0.02, 0.08; P > 0.01). The 95% CI fell within the 10% non-inferiority margin, confirming the non-inferiority of SROM to methadone. A dose-dependent effect was shown for SROM (i.e. decreasing proportions of heroin-positive urine samples with increasing SROM doses). Retention in treatment showed no significant differences between treatments (period 1/period 2: SROM: 88.7%/82.1%, methadone: 91.1%/88.0%; period 1: P = 0.50, period 2: P = 0.19). Overall, safety outcomes were similar between the two groups.

Conclusions: Slow-release oral morphine appears to be at least as effective as methadone in treating people with opioid use disorder.

Keywords: Dose-response; maintenance treatment; methadone; opioid addiction; retention rate; slow-release oral morphine.

© 2013 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.

Figures

Figure 1
Figure 1
Randomization of patients and treatment completion per period
Figure 2
Figure 2
Dose–response: correlation of the proportion of heroin-positive urine samples and quartiles of mean daily doses (data presented as least-square means and corresponding 95% confidence interval (CI), per protocol (PP) population, n = 157)

References

    1. World Health Organization/United Nations Office on Drugs and Crime/Joint United Nations Programme on HIV/AIDS (WHO/UNDOC/UNAIDS) 2004. WHO/UNDOC/UNAIDS position paper. Available at: (accessed 7 February 2012) (archived at on 24 December 2013)
    1. Amato L, Minozzi S, Davoli M, Vecchi S. Psychosocial combined with agonist maintenance treatments versus agonist maintenance treatments alone for treatment of opioid dependence. Cochrane Database Syst Rev. 2011;(10) CD004147.
    1. Kreek MJ. Neurobiological basis for use of opioid agonist maintenance in the treatment of heroin addiction. In: Waal H, Haga E, editors. Maintenance Treatment of Heroin Addiction. Oslo: Cappelen Akademisk Forlag; 2003. pp. 10–39.
    1. Amato L, Davoli M, Perucci CA, Ferri M, Faggiano F, Mattick RP. An overview of systematic reviews of the effectiveness of opiate maintenance therapies: available evidence to inform clinical practice and research. J Subst Abuse Treat. 2005;28:321–329.
    1. Dyer KR, White JM. Patterns of symptom complaints in methadone maintenance patients. Addiction. 1997;92:1445–1455.
    1. Brown R, Kraus C, Flemming M, Reddy S. Methadone: applied pharmacology and use as adjunctive treatment in chronic pain. Postgrad Med J. 2004;80:654–659.
    1. Woody GE. New horizons: sustained release morphine as agonist treatment. Addiction. 2005;100:1758–1759.
    1. Haasen C, van den Brink W. Innovations in agonist maintenance treatment of opioid-dependent patients. Curr Opin Psychiatry. 2006;19:631–636.
    1. White JM, Lopatko OV. Opioid maintenance: a comparative review of pharmacological strategies. Expert Opin Pharmacother. 2007;8:1–11.
    1. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008;11:133–153.
    1. Borg L, Kravets I, Kreek MJ. The pharmacology of long-acting as contrasted with short-acting opioids. In: Ries RK, Fiellin DA, Miller SC, Saitz R, editors. Principles of Addiction Medicine. 4. Philadelphia: Lipincott Williams & Wilkins; 2009. pp. 117–131.
    1. Dole VP, Nyswander M. A medical treatment for diacetylmorphine (heroin) addiction. A clinical trial with methadone hydrochloride. JAMA. 1965;193:646–650.
    1. Broomhead A, West R, Eglinton L, Jones M, Bubner R, Sienko D, et al. Comparative single-dose pharmacokinetics of sustained-release and modified-release morphine sulfate capsules under fed and fasting conditions. Clin Drug Invest. 1997;13:162–170.
    1. Hagen NA, Thirlwell M, Eisenhoffer J, Quigley P, Harsanyi Z, Darke A. Efficacy, safety, and steady-state pharmacokinetics of once-a-day controlled-release morphine (MS Contin XL) in cancer pain. J Pain Symptom Manage. 2005;29:80–90.
    1. Fischer G, Presslich O, Diamant K, Schneider C, Pezawas L, Kasper S. Oral morphine-sulphate in the treatment of opiate dependent patients. Alcoholism. 1996;32:35–43.
    1. Mitchell TB, White JM, Somogyi AA, Bochner F. Slow-release morphine versus methadone: a crossover comparison of patient outcomes and acceptability as maintenance pharmacotherapies for opioid dependence. Addiction. 2004;99:940–945.
    1. Kraigher D, Jagsch R, Gombas W, Ortner R, Eder H, Primorac A, et al. Use of slow-release oral morphine for the treatment of opioid dependence. Eur Addict Res. 2005;11:145–151.
    1. Eder H, Jagsch R, Kraigher D, Primorac A, Ebner N, Fischer G. Comparative study of the effectiveness of slow-release morphine and methadone for opioid maintenance therapy. Addiction. 2005;100:1101–1109.
    1. Hermann P, Wagner W, Lindenbauer B. Safety and efficacy of oral prolonged release morphine for the maintenance therapy for opioid dependence—results of a pilot study in outpatients. Suchtmed Forsch Praxis. 2005;7:215–220.
    1. Vasilev GN, Alexieva DZ, Pavlova RZ. Safety and efficacy of oral slow release morphine for maintenance treatment in heroin addicts: a 6-month open non comparative study. Eur Addict Res. 2006;12:53–60.
    1. 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;103:1837–1846.
    1. Bond AJ, Reed KD, Beavan P, Strang J. After the randomized injectable opiate treatment trial: post-trial investigation of slow-release oral morphine as an alternative opiate maintenance medication. Drug Alcohol Rev. 2012;31:492–498.
    1. Giacomuzzi S, Kemmler G, Ertl M, Riemer Y. Opioid addicts at admission vs. slow-release oral morphine, methadone, and sublingual buprenorphine maintenance treatment participants. Subst Use Misuse. 2006;41:223–244.
    1. Jegu J, Gallini A, Soler P. Slow-release oral morphine for opioid maintenance treatment: a systematic review. Br J Clin Pharmacol. 2011;71:832–843.
    1. Mattick RP, Kimber J, Breen C, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev. 2008;(2) CD002207. doi: .
    1. Senn S. Cross-over trial in drug development: theory and practice. J Stat Plan Inference. 2001;96:29–40.
    1. D’Agostino RB, Sr, Massaro JM, Sullivan LM. Non-inferiority trials: design concepts and issues—the encounters of academic consultants in statistics. Stat Med. 2003;22:169–186.
    1. Matsumoto M, Nishimura T. Mersenne twister: a 623-dimensionally equidistributed uniform pseudo-random number generator. ACM Trans Model Comput Simul. 1998;8:3–30.
    1. Sturm S, Hammann F, Drew J, Maurer HH, Scholer A. An automated screening method for drugs and toxic compounds in human serum and urine using liquid chromatography–tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2010;878:2726–2732.
    1. Scott IA. Non-inferiority trials: determining whether alternative treatments are good enough. Med J Aust. 2009;190:326–330.
    1. Donovan DM, Bigelow GE, Brigham GS, Carroll KM, Cohen AJ, Gardin JG, et al. Primary outcome indices in illicit drug dependence treatment research: systematic approach to selection and measurement of drug use end-points in clinical trials. Addiction. 2012;107:694–708.
    1. Reisfield GM, Goldberger BA, Bertholf RL. ‘False-positive’ and ‘false-negative’ test results in clinical urine drug testing. Bioanalysis. 2009;1:937–952.
    1. Stefanidou M, Athanaselis S, Spiliopoulou C, Dona A, Maravelias C. Biomarkers of opiate use. Int J Clin Pract. 2010;64:1712–1718.
    1. Jones B, Jarvis P, Lewis JA, Ebbutt AF. Trials to assess equivalence: the importance of rigorous methods. BMJ. 1996;313:36–39.
    1. Lange S, Freitag G. Choice of delta: requirements and reality—results of a systematic review. Biomed J. 2005;47:12–27.
    1. European Medicines Agency (EMEA) 2005. pp. 1–11. Guideline on the choice of the non-inferiority margin. Doc.Ref.: EMEA/CPMP/EWP/2158/99, 27 July. (Accessed 14 February 2012) (archived at on 24 December 2013)
    1. Hung HM, Wang SJ, O’Neill R. A regulatory perspective on choice of margin and statistical inference issue in non-inferiority trials. Biomed J. 2005;47:28–36.
    1. Food and Drug Administration (FDA) Guidance for industry non-inferiority clinical trials. Washington, DC: US Department of Health and Human Services; 2010.
    1. Strain EC, Stitzer ML, Liebson I, Bigelow GE. Dose–response effects of methadone in the treatment of opioid dependence. Ann Intern Med. 1993;119:23–27.
    1. Bammer G, Dobler-Mikola A, Fleming PM, Strang J, Uchtenhagen A. The heroin prescribing debate: integrating science and politics. Science. 1999;284:1277–1278.
    1. Gossop M. Randomised and controlled, but irrelevant? In: Waal H, Haga E, editors. Maintenance Treatment of Heroin Addiction—Evidence at the Crossroads. Oslo: Cappelen Akademisk Forlag; 2003. pp. 91–105.
    1. Freemantle N, Blonde L, Bolinder B, Gerber RA, Hobbs FD, Martinez L, et al. Real-world trials to answer real-world questions. Pharmacoeconomics. 2005;23:747–754.
    1. Kane JM. Issues in clinical trial designs. In: Davis KL, Charney D, Coyle JT, Nemeroff CH, editors. Neuropharmacology: The Fifth Generation of Progress. Brentwood, TN: American College of Neuropsychopharmacology; 2002. pp. 537–546.
    1. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) 2000. Reviewing current practice in drug-substitution treatment in the European Union. Insights Series, number 3. Lisbon: EMCDDA.
    1. Casati A, Sedefov R, Pfeiffer-Gerchel T. Misuse of medicines in the European Union: a systematic review of the literature. Eur Addict Res. 2012;18:228–245.
    1. Dale-Perera A, Goulão J, Stöver H. Quality of care provided to patients receiving opioid maintenance treatment in Europe: results from the EQUATOR analysis. Heroin Addict Relat Clin Probl. 2012;14:23–38.
    1. Beer B, Rabl W, Libiseller K, Giacomuzzi S, Riemer Y, Pavlic M. Impact of slow-release oral morphine on drug abusing habits in Austria. Neuropsychiatr. 2010;24:108–117.

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