CNS Drugs

, Volume 33, Issue 7, pp 649–657 | Cite as

Outcome Assessment in Trials of Pharmacological Treatments for Alcohol Use Disorders: Fair and Strict Testing

  • Susanne RösnerEmail author
  • Michael Soyka
Review Article


Outcome assessment in the pharmacological treatment of alcohol use disorders (AUDs) faces specific challenges resulting from low adherence to treatment, high rates of dropout, and the susceptibility of patient self-reports to bias. This review discusses methodological issues in planning, conducting, and interpreting clinical trials on AUD treatment against the background of the principle of ‘strictness and fairness’ of testing. Threats to fairness include factors that limit the implementation of an intervention, such as low compliance and early treatment termination. In turn, fairness of testing is increased by factors that support the degree to which an intervention is implemented, such as the use of adequate pretreatments and the matching of psychosocial and pharmacological treatment strategies. Furthermore, selecting outcomes on the basis of an intervention’s mechanism of action and including continuous outcomes as sensitive measures of drinking change further increases fairness by increasing the likelihood that the data will adequately reflect the effects of the intervention. On the other hand, strictness of testing is increased by all measures that limit the influence of confounders that could potentially lead to an overestimation of effects. The use of a side effect-mimicking placebo to prevent an unmasking of blinding and the repeated assessment of alcohol biomarkers to validate drinking self-reports might be valid strategies to further increase the strictness of testing by limiting risks of bias in trials of AUD treatment.



The authors thank Jacquie Klesing, Board-certified Editor in the Life Sciences (ELS), for editing assistance with the manuscript.

Compliance with Ethical Standards


No funding was received for the preparation of this review.

Conflict of interest

Susanne Rösner and Michael Soyka declare that they have no conflict of interest related to the content of this review.


  1. 1.
    Grant BF, Goldstein RB, Saha TD, Chou SP, Jung J, Zhang H, et al. Epidemiology of DSM-5 alcohol use disorder: results from the National epidemiologic survey on alcohol and related conditions III. JAMA Psychiatry. 2015;72(8):757–66.Google Scholar
  2. 2.
    Kranzler HR, Soyka M. Diagnosis and pharmacotherapy of alcohol use disorder: a review. JAMA. 2018;320(8):815–24.Google Scholar
  3. 3.
    Rehm J, Dawson D, Frick U, Gmel G, Roerecke M, Shield KD, et al. Burden of disease associated with alcohol use disorders in the United States. Alcohol Clin Exp Res. 2014;38(4):1068–77.Google Scholar
  4. 4.
    Donoghue K, Elzerbi C, Saunders R, Whittington C, Pilling S, Drummond C. The efficacy of acamprosate and naltrexone in the treatment of alcohol dependence, Europe versus the rest of the world: a meta-analysis. Addiction. 2015;110(6):920–30.Google Scholar
  5. 5.
    Maisel NC, Blodgett JC, Wilbourne PL, Humphreys K, Finney JW. Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: when are these medications most helpful? Addiction. 2013;108(2):275–93.Google Scholar
  6. 6.
    Brorson HH, Ajo Arnevik E, Rand-Hendriksen K, Duckert F. Drop-out from addiction treatment: a systematic review of risk factors. Clin Psychol Rev. 2013;33(8):1010–24.Google Scholar
  7. 7.
    Raes V, De Jong CA, De Bacquer D, Broekaert E, De Maeseneer J. The effect of using assessment instruments on substance-abuse outpatients’ adherence to treatment: a multi-centre randomised controlled trial. BMC Health Serv Res. 2011;11:123.Google Scholar
  8. 8.
    Matthews S, Dwyer R, Snoek A. Stigma and self-stigma in addiction. J Bioeth Inq. 2017;14(2):275–86.Google Scholar
  9. 9.
    Schomerus G, Matschinger H, Angermeyer MC. Attitudes towards alcohol dependence and affected individuals: persistence of negative stereotypes and illness beliefs between 1990 and 2011. Eur Addict Res. 2014;20(6):293–9.Google Scholar
  10. 10.
    Yoshino A, Kato M. Influence of social desirability response set on self-report for assessing the outcome of treated alcoholics. Alcohol Clin Exp Res. 1995;19(6):1517–9.Google Scholar
  11. 11.
    Rosner S, Hackl-Herrwerth A, Leucht S, Lehert P, Vecchi S, Soyka M. Acamprosate for alcohol dependence. Cochrane Database Syst Rev. 2010;9:CD004332.Google Scholar
  12. 12.
    Allen JP. Measuring outcome in interventions for alcohol dependence and problem drinking: executive summary of a conference sponsored by the National Institute on alcohol abuse and alcoholism. Alcohol Clin Exp Res. 2003;27(10):1657–60.Google Scholar
  13. 13.
    Westermann R, Hager W. Error probabilities in educational and psychological research. J Educ Stat. 1986;11:117–46.Google Scholar
  14. 14.
    Moos RH, Moos BS. Rates and predictors of relapse after natural and treated remission from alcohol use disorders. Addiction. 2006;101(2):212–22.Google Scholar
  15. 15.
    Witkiewitz K, Finney JW, Harris AH, Kivlahan DR, Kranzler HR. Guidelines for the reporting of treatment trials for alcohol use disorders. Alcohol Clin Exp Res. 2015;39(9):1571–81.Google Scholar
  16. 16.
    Jonas DE, Amick HR, Feltner C, Bobashev G, Thomas K, Wines R, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA. 2014;311(18):1889–900.Google Scholar
  17. 17.
    Shen WW. Anticraving therapy for alcohol use disorder: a clinical review. Neuropsychopharmacol Rep. 2018;38(3):105–16.Google Scholar
  18. 18.
    Minozzi S, Saulle R, Rosner S. Baclofen for alcohol use disorder. Cochrane Database Syst Rev. 2018;11:CD012557.Google Scholar
  19. 19.
    Pierce M, Sutterland A, Beraha EM, Morley K, van den Brink W. Efficacy, tolerability, and safety of low-dose and high-dose baclofen in the treatment of alcohol dependence: a systematic review and meta-analysis. Eur Neuropsychopharmacol. 2018;28(7):795–806.Google Scholar
  20. 20.
    Mutschler J, Grosshans M, Soyka M, Rosner S. Current findings and mechanisms of action of disulfiram in the treatment of alcohol dependence. Pharmacopsychiatry. 2016;49(4):137–41.Google Scholar
  21. 21.
    Rosner S, Grosshans M, Mutschler JH. Disulfiram: Aktuelle Befunde und Wirkmechanismen. Suchtmedizin. 2014;16(2):47–52.Google Scholar
  22. 22.
    Skinner MD, Lahmek P, Pham H, Aubin HJ. Disulfiram efficacy in the treatment of alcohol dependence: a meta-analysis. PLoS One. 2014;9(2):e87366.Google Scholar
  23. 23.
    Bujarski S, O’Malley SS, Lunny K, Ray LA. The effects of drinking goal on treatment outcome for alcoholism. J Consult Clin Psychol. 2013;81(1):13–22.Google Scholar
  24. 24.
    Hasin DS, Wall M, Witkiewitz K, Kranzler HR, Falk D, Litten R, et al. Change in non-abstinent WHO drinking risk levels and alcohol dependence: a 3 year follow-up study in the US general population. Lancet Psychiatry. 2017;4(6):469–76.Google Scholar
  25. 25.
    European Medicines Agency. Guideline on the development of medicinal products for the treatment of alcohol dependence. London: European Medicines Agency; 2010.Google Scholar
  26. 26.
    Palpacuer C, Duprez R, Huneau A, Locher C, Boussageon R, Laviolle B, et al. Pharmacologically controlled drinking in the treatment of alcohol dependence or alcohol use disorders: a systematic review with direct and network meta-analyses on nalmefene, naltrexone, acamprosate, baclofen and topiramate. Addiction. 2018;113(2):220–37.Google Scholar
  27. 27.
    Bakhshi E, McArdle B, Mohammad K, Seifi B, Biglarian A. Let continuous outcome variables remain continuous. Comput Math Methods Med. 2012;2012:639124.Google Scholar
  28. 28.
    MacCallum RC, Zhang S, Preacher KJ, Rucker DD. On the practice of dichotomization of quantitative variables. Psychol Methods. 2002;7(1):19–40.Google Scholar
  29. 29.
    Yoo B. The impact of dichotomization in longitudinal data analysis: a simulation study. Pharm Stat. 2010;9(4):298–312.Google Scholar
  30. 30.
    Witkiewitz K, Hallgren KA, Kranzler HR, Mann KF, Hasin DS, Falk DE, et al. Clinical validation of reduced alcohol consumption after treatment for alcohol dependence using the World Health Organization risk drinking levels. Alcohol Clin Exp Res. 2017;41(1):179–86.Google Scholar
  31. 31.
    Tiffany ST, Friedman L, Greenfield SF, Hasin DS, Jackson R. Beyond drug use: a systematic consideration of other outcomes in evaluations of treatments for substance use disorders. Addiction. 2012;107(4):709–18.Google Scholar
  32. 32.
    Carr AJ, Gibson B, Robinson PG. Measuring quality of life: is quality of life determined by expectations or experience? BMJ. 2001;322(7296):1240–3.Google Scholar
  33. 33.
    Donovan DM, Kivlahan DR, Doyle SR, Longabaugh R, Greenfield SF. Concurrent validity of the Alcohol Use Disorders Identification Test (AUDIT) and AUDIT zones in defining levels of severity among out-patients with alcohol dependence in the COMBINE study. Addiction. 2006;101(12):1696–704.Google Scholar
  34. 34.
    Becker SJ, Curry JF, Yang C. Longitudinal association between frequency of substance use and quality of life among adolescents receiving a brief outpatient intervention. Psychol Addict Behav. 2009;23(3):482–90.Google Scholar
  35. 35.
    Sobell LC, Sobell MB. Timeline follow-back: a technique for assessing self-reported alcohol consumption. Totowa: Human Press; 1992.Google Scholar
  36. 36.
    Miller WR. Form 90. A structured assessment interview for drinking and related behaviors: test manual. Bethesda: National Institute on Alcohol Abuse and Alcoholism; 1996.Google Scholar
  37. 37.
    Shiffman S. Ecological momentary assessment (EMA) in studies of substance use. Psychol Assess. 2009;21(4):486–97.Google Scholar
  38. 38.
    Simons JS, Wills TA, Emery NN, Marks RM. Quantifying alcohol consumption: self-report, transdermal assessment, and prediction of dependence symptoms. Addict Behav. 2015;50:205–12.Google Scholar
  39. 39.
    Maisto SA, Conigliaro JC, Gordon AJ, McGinnis KA, Justice AC. An experimental study of the agreement of self-administration and telephone administration of the timeline followback interview. J Stud Alcohol Drugs. 2008;69(3):468–71.Google Scholar
  40. 40.
    Pedersen ER, Grow J, Duncan S, Neighbors C, Larimer ME. Concurrent validity of an online version of the timeline followback assessment. Psychol Addict Behav. 2012;26(3):672–7.Google Scholar
  41. 41.
    Del Boca FK, Darkes J. The validity of self-reports of alcohol consumption: state of the science and challenges for research. Addiction. 2003;98(Suppl 2):1–12.Google Scholar
  42. 42.
    Finney JW, Moyer A, Swearingen CE. Outcome variables and their assessment in alcohol treatment studies: 1968–1998. Alcohol Clin Exp Res. 2003;27(10):1671–9.Google Scholar
  43. 43.
    Andresen-Streichert H, Muller A, Glahn A, Skopp G, Sterneck M. Alcohol biomarkers in clinical and forensic contexts. Dtsch Arztebl Int. 2018;115(18):309–15.Google Scholar
  44. 44.
    Ingall GB. Alcohol biomarkers. Clin Lab Med. 2012;32(3):391–406.Google Scholar
  45. 45.
    Tavakoli HR, Hull M, Michael Okasinski L. Review of current clinical biomarkers for the detection of alcohol dependence. Innov Clin Neurosci. 2011;8(3):26–33.Google Scholar
  46. 46.
    Cabezas J, Lucey MR, Bataller R. Biomarkers for monitoring alcohol use. Clin Liver Dis. 2016;2:59–63.Google Scholar
  47. 47.
    Karns-Wright TE, Roache JD, Hill-Kapturczak N, Liang Y, Mullen J, Dougherty DM. Time delays in transdermal alcohol concentrations relative to breath alcohol concentrations. Alcohol Alcohol. 2017;52(1):35–41.Google Scholar
  48. 48.
    Swift R. Transdermal alcohol measurement for estimation of blood alcohol concentration. Alcohol Clin Exp Res. 2000;24(4):422–3.Google Scholar
  49. 49.
    Voas RB, DuPont RL, Talpins SK, Shea CL. Towards a national model for managing impaired driving offenders. Addiction. 2011;106(7):1221–7.Google Scholar
  50. 50.
    Dougherty DM, Hill-Kapturczak N, Liang Y, Karns TE, Cates SE, Lake SL, et al. Use of continuous transdermal alcohol monitoring during a contingency management procedure to reduce excessive alcohol use. Drug Alcohol Depend. 2014;142:301–6.Google Scholar
  51. 51.
    Roache JD, Karns-Wright TE, Goros M, Hill-Kapturczak N, Mathias CW, Dougherty DM. Processing transdermal alcohol concentration (TAC) data to detect low-level drinking. Alcohol. 2018. Scholar
  52. 52.
    Koffarnus MN, Bickel WK, Kablinger AS. Remote alcohol monitoring to facilitate incentive-based treatment for alcohol use disorder: a randomized trial. Alcohol Clin Exp Res. 2018;42(12):2423–31.Google Scholar
  53. 53.
    Deci EL, Koestner R, Ryan RM. A meta-analytic review of experiments examining the effects of extrinsic rewards on intrinsic motivation. Psychol Bull. 1999;125(6):627–68 (discussion 92–700).Google Scholar
  54. 54.
    Kwako LE, Momenan R, Litten RZ, Koob GF, Goldman D. Addictions neuroclinical assessment: a neuroscience-based framework for addictive disorders. Biol Psychiatry. 2016;80(3):179–89.Google Scholar
  55. 55.
    Ray LA, Bujarski S, Roche DJO, Magill M. Overcoming the “valley of death” in medications development for alcohol use disorder. Alcohol Clin Exp Res. 2018;42(9):1612–22.Google Scholar
  56. 56.
    Cook TD, Campbell DT. Quasi-experimentation: design and analysis issues for field settings. Chicago: Rand McNally; 1979.Google Scholar
  57. 57.
    Del Re AC, Maisel NC, Blodgett JC, Finney JW. Intention-to-treat analyses and missing data approaches in pharmacotherapy trials for alcohol use disorders. BMJ Open. 2013;3(11):e003464.Google Scholar
  58. 58.
    Heinala P, Alho H, Kiianmaa K, Lonnqvist J, Kuoppasalmi K, Sinclair JD. Targeted use of naltrexone without prior detoxification in the treatment of alcohol dependence: a factorial double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2001;21(3):287–92.Google Scholar
  59. 59.
    O’Malley SS, Jaffe AJ, Chang G, Schottenfeld RS, Meyer RE, Rounsaville B. Naltrexone and coping skills therapy for alcohol dependence. A controlled study. Arch Gen Psychiatry. 1992;49(11):881–7.Google Scholar
  60. 60.
    Witkiewitz K, Falk DE, Kranzler HR, Litten RZ, Hallgren KA, O’Malley SS, et al. Methods to analyze treatment effects in the presence of missing data for a continuous heavy drinking outcome measure when participants drop out from treatment in alcohol clinical trials. Alcohol Clin Exp Res. 2014;38(11):2826–34.Google Scholar
  61. 61.
    Stout RL. Methodological and statistical considerations in measuring alcohol treatment effects. Alcohol Clin Exp Res. 2003;27(10):1686–91.Google Scholar
  62. 62.
    Lehert P. Review and discussion of statistical analysis of controlled clinical trials in alcoholism. Alcohol Alcohol Suppl. 1993;2:157–63.Google Scholar
  63. 63.
    Moncrieff J. A comparison of antidepressant trials using active and inert placebos. Int J Methods Psychiatr Res. 2003;12(3):117–27.Google Scholar
  64. 64.
    Jensen JS, Bielefeldt AO, Hrobjartsson A. Active placebo control groups of pharmacological interventions were rarely used but merited serious consideration: a methodological overview. J Clin Epidemiol. 2017;87:35–46.Google Scholar
  65. 65.
    Rosner S, Hackl-Herrwerth A, Leucht S, Vecchi S, Srisurapanont M, Soyka M. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev. 2010;12:CD001867.Google Scholar
  66. 66.
    Litten RZ, Castle IJ, Falk D, Ryan M, Fertig J, Chen CM, et al. The placebo effect in clinical trials for alcohol dependence: an exploratory analysis of 51 naltrexone and acamprosate studies. Alcohol Clin Exp Res. 2013;37(12):2128–37.Google Scholar
  67. 67.
    Khan A, Detke M, Khan SR, Mallinckrodt C. Placebo response and antidepressant clinical trial outcome. J Nerv Ment Dis. 2003;191(4):211–8.Google Scholar
  68. 68.
    Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the food and drug administration. PLoS Med. 2008;5(2):e45.Google Scholar
  69. 69.
    Anton RF, O’Malley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006;295(17):2003–17.Google Scholar
  70. 70.
    Fertig JB, Ryan ML, Falk DE, Litten RZ, Mattson ME, Ransom J, et al. A double-blind, placebo-controlled trial assessing the efficacy of levetiracetam extended-release in very heavy drinking alcohol-dependent patients. Alcohol Clin Exp Res. 2012;36(8):1421–30.Google Scholar
  71. 71.
    Chan AW, Tetzlaff JM, Altman DG, Dickersin K, Moher D. SPIRIT 2013: new guidance for content of clinical trial protocols. Lancet. 2013;381(9861):91–2.Google Scholar
  72. 72.
    International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline: Statistical Principles for Clinical Trials E9. London: European Medicines Agency; 1998.Google Scholar
  73. 73.
    Heffner JL, Tran GQ, Johnson CS, Barrett SW, Blom TJ, Thompson RD, et al. Combining motivational interviewing with compliance enhancement therapy (MI-CET): development and preliminary evaluation of a new, manual-guided psychosocial adjunct to alcohol-dependence pharmacotherapy. J Stud Alcohol Drugs. 2010;71(1):61–70.Google Scholar
  74. 74.
    Schulz KF, Grimes DA. Sample size slippages in randomised trials: exclusions and the lost and wayward. Lancet. 2002;359(9308):781–5.Google Scholar
  75. 75.
    Spieth PM, Kubasch AS, Penzlin AI, Illigens BM, Barlinn K, Siepmann T. Randomized controlled trials—a matter of design. Neuropsychiatr Dis Treat. 2016;12:1341–9.Google Scholar
  76. 76.
    Hallgren KA, Witkiewitz K. Missing data in alcohol clinical trials: a comparison of methods. Alcohol Clin Exp Res. 2013;37(12):2152–60.Google Scholar
  77. 77.
    Jackson D, White IR, Mason D, Sutton S. A general method for handling missing binary outcome data in randomized controlled trials. Addiction. 2014;109(12):1986–93.Google Scholar
  78. 78.
    Klemperer EM, Hughes JR, Naud S. Study characteristics influence the efficacy of substance abuse treatments: a meta-analysis of medications for alcohol use disorder. Drug Alcohol Depend. 2018;190:229–34.Google Scholar
  79. 79.
    Sobell MB, Sobell LC. Controlled drinking after 25 years: how important was the great debate? Addiction. 1995;90(9):1149–53 (discussion 57–77).Google Scholar
  80. 80.
    Jones JD, Comer SD, Kranzler HR. The pharmacogenetics of alcohol use disorder. Alcohol Clin Exp Res. 2015;39(3):391–402.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Forel ClinicAddiction Treatment CenterEllikon an der ThurSwitzerland
  2. 2.Psychiatric HospitalUniversity of MunichMunichGermany
  3. 3.Medical Park ChiemseeblickBernauGermany

Personalised recommendations