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Who Receives Nalmefene and How Does It Work in the Real World? A Single-Arm, Phase IV Study of Nalmefene in Alcohol Dependent Outpatients: Baseline and 1-Month Results

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A Letter to the Editor to this article was published on 23 February 2018

Abstract

Background

Alcohol dependence remains a major health problem from both a public health and clinical perspective. Harm reduction strategies have been increasingly recognized as suitable treatment goals. Nalmefene has been recently approved for this precise therapeutic indication after completion of phase III trials. However, more data from routine practice settings are needed in order to obtain evidence with high external validity. The aim of this study was to conduct a single-arm, phase IV study with alcohol-dependent outpatients starting nalmefene for the first time.

Methods

An observational, multisite, single-arm, phase IV study was conducted among adult alcohol-dependent outpatients who received nalmefene for the first time. The study consisted of four visits: baseline, 4 weeks (referred to as 1 month hereafter), 6 and 12 months. At each visit, drinking variables were obtained from the Timeline Followback regarding the previous month. Satisfaction with medication was also assessed for both patients and professionals, with the Medication Satisfaction Questionnaire. A repeated measures mixed model was performed for effectiveness analysis regarding drinking outcomes (reduction in total alcohol consumption and number of heavy drinking days). Regression analyses were performed in order to find predictors of response to nalmefene.

Results

A total of 110 patients were included, with 88 reporting data at the 1-month visit. On average, patients took nalmefene 68% of the days. The number of heavy drinking days decreased from 13.5 to 6.8 days/month, and total alcohol consumption decreased from 169 to 79 units. For both outcomes, significant reductions at 1 month were found, with no other significant variables reaching significance. Thirty-seven patients were considered medication responders, but given the high presence of low-risk drinkers in our sample, no significant predictors could be found. Satisfaction was globally high for both professionals and patients, and overall nalmefene was well tolerated, with no serious adverse events reported.

Conclusion

The data provided by this phase IV study suggest nalmefene is an effective, well-tolerated treatment for alcohol dependence in real-world, clinical settings.

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References

  1. Wittchen HU, Jacobi F, Rehm J, Gustavsson A, Svensson M, Jönsson B, et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur Neuropsychopharmacol. 2011;21(9):655–79.

    Article  CAS  PubMed  Google Scholar 

  2. Kohn R, Saxena S, Levav I, Saraceno B. The treatment gap in mental health care. Bull World Health Organ. 2004;82(11):858–66.

    PubMed  PubMed Central  Google Scholar 

  3. Merkx MJM, Schippers GM, Koeter MWJ, Vuijk PJ, Oudejans SCC, Stam RK, et al. Guidelines for allocating outpatient alcohol abusers to levels of care: predictive validity. Addict Behav. 2011;36(6):570–5.

    Article  PubMed  Google Scholar 

  4. Miller WR, Walters ST, Bennett ME. How effective is alcoholism treatment in the United States? J Stud Alcohol. 2001;62(2):211–20.

    Article  CAS  PubMed  Google Scholar 

  5. Agency EM. Guideline on the development of medicinal products for the treatment of alcohol dependence. European Medicines Agency 2010. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/03/WC500074898.pdf. Accessed 1 Sept 2017.

  6. Gastfriend DR, Garbutt JC, Pettinati HM, Forman RF. Reduction in heavy drinking as a treatment outcome in alcohol dependence. J Subst Abuse Treat. 2007;33(1):71–80.

    Article  PubMed  Google Scholar 

  7. Heilig M, Goldman D, Berrettini W, O’Brien CP. Pharmacogenetic approaches to the treatment of alcohol addiction. Nat Rev Neurosci. 2011;12(11):670–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Luquiens A, Reynaud M, Aubin HJ. Is controlled drinking an acceptable goal in the treatment of alcohol dependence? A survey of French alcohol specialists. Alcohol Alcohol. 2011;46(5):586–91.

    Article  CAS  PubMed  Google Scholar 

  9. Rehm J. The risks associated with alcohol use and alcoholism. Alcohol Res Health. 2011;34(2):135–43.

    PubMed  PubMed Central  Google Scholar 

  10. Dixon R, Gentile J, Hsu HB, Hsiao J, Howes J, Garg D, et al. Nalmefene: safety and kinetics after single and multiple oral doses of a new opioid antagonist. J Clin Pharmacol. 1987;27(3):233–9.

    Article  CAS  PubMed  Google Scholar 

  11. Gal TJ, DiFazio CA, Dixon R. Prolonged blockade of opioid effect with oral nalmefene. Clin Pharmacol Ther. 1986;40(5):537–42.

    Article  CAS  PubMed  Google Scholar 

  12. Emmerson PJ, Liu MR, Woods JH, Medzihradsky F. Binding affinity and selectivity of opioids at mu, delta and kappa receptors in monkey brain membranes. J Pharmacol Exp Ther. 1994;271(3):1630–7.

    CAS  PubMed  Google Scholar 

  13. Ingman K, Hagelberg N, Aalto S, Någren K, Juhakoski A, Karhuvaara S, et al. Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing. Neuropsychopharmacology. 2005;30(12):2245–53.

    Article  CAS  PubMed  Google Scholar 

  14. Bruijnzeel AW. kappa-Opioid receptor signaling and brain reward function. Brain Res Rev. 2009;62(1):127–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Garbutt JC. Efficacy and tolerability of naltrexone in the management of alcohol dependence. Curr Pharm Des. 2010;16(19):2091–7.

    Article  CAS  PubMed  Google Scholar 

  16. Swift RM. Naltrexone and nalmefene: any meaningful difference? Biol Psychiatry. 2013;73(8):700–1.

    Article  CAS  PubMed  Google Scholar 

  17. Mason BJ, Salvato FR, Williams LD, Ritvo EC, Cutler RB. A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch Gen Psychiatry. 1999;56(8):719–24.

    Article  CAS  PubMed  Google Scholar 

  18. Mason BJ, Ritvo EC, Morgan RO, Salvato FR, Goldberg G, Welch B, et al. A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nalmefene HCl for alcohol dependence. Alcohol Clin Exp Res. 1994;18(5):1162–7.

    Article  CAS  PubMed  Google Scholar 

  19. Anton RF, Pettinati H, Zweben A, Kranzler HR, Johnson B, Bohn MJ, et al. A multi-site dose ranging study of nalmefene in the treatment of alcohol dependence. J Clin Psychopharmacol. 2004;24(4):421–8.

    Article  CAS  PubMed  Google Scholar 

  20. Karhuvaara S, Simojoki K, Virta A, Rosberg M, Loyttyniemi E, Nurminen T, et al. Targeted nalmefene with simple medical management in the treatment of heavy drinkers: a randomized double-blind placebo-controlled multicenter study. Alcohol Clin Exp Res. 2007;31(7):1179–87.

    Article  CAS  PubMed  Google Scholar 

  21. Gual A, He Y, Torup L, van den Brink W, Mann K. A randomised, double-blind, placebo-controlled, efficacy study of nalmefene, as-needed use, in patients with alcohol dependence. Eur Neuropsychopharmacol. 2013;23(11):1432–42.

    Article  CAS  PubMed  Google Scholar 

  22. Mann K, Bladström A, Torup L, Gual A, van den Brink W. Extending the treatment options in alcohol dependence: a randomized controlled study of as-needed nalmefene. Biol Psychiatry. 2013;73(8):706–13.

    Article  CAS  PubMed  Google Scholar 

  23. van den Brink W, Aubin HJ, Bladstrom A, Torup L, Gual A, Mann K. Efficacy of as-needed nalmefene in alcohol-dependent patients with at least a high drinking risk level: results from a subgroup analysis of two randomized controlled 6-month studies. Alcohol Alcohol. 2013;48(5):570–8.

    Article  PubMed  PubMed Central  Google Scholar 

  24. van den Brink W, Sørensen P, Torup L, Mann K, Gual A, SENSE Study Group. Long-term efficacy, tolerability and safety of nalmefene as-needed in patients with alcohol dependence: a 1-year, randomised controlled study. J Psychopharmacol. 2014;28(8):733–44.

    Article  PubMed  Google Scholar 

  25. Pearson M, Coomber R. The challenge of external validity in policy-relevant systematic reviews: a case study from the field of substance misuse. Addiction. 2010;105(1):136–45.

    Article  PubMed  Google Scholar 

  26. Dekkers OM, von Elm E, Algra A, Romijn JA, Vandenbroucke JP. How to assess the external validity of therapeutic trials: a conceptual approach. Int J Epidemiol. 2010;39(1):89–94.

    Article  CAS  PubMed  Google Scholar 

  27. Rothwell PM. External validity of randomised controlled trials: “to whom do the results of this trial apply?”. Lancet. 2005;365(9453):82–93.

    Article  PubMed  Google Scholar 

  28. Hoertel N, de Maricourt P, Katz J, Doukhan R, Lavaud P, Peyre H, et al. Are participants in pharmacological and psychotherapy treatment trials for social anxiety disorder representative of patients in real-life settings? J Clin Psychopharmacol. 2014;34(6):697–703.

    Article  PubMed  Google Scholar 

  29. Uijen AA, Bakx JC, Mokkink HGA, van Weel C. Hypertension patients participating in trials differ in many aspects from patients treated in general practices. J Clin Epidemiol. 2007;60(4):330–5.

    Article  PubMed  Google Scholar 

  30. Persaud N, Mamdani MM. External validity: the neglected dimension in evidence ranking. J Eval Clin Pract. 2006;12(4):450–3.

    Article  PubMed  Google Scholar 

  31. Farahani P, Levine M, Gaebel K, Thabane L. Clinical data gap between phase III clinical trials [pre-marketing] and phase IV [post-marketing] studies: evaluation of etanercept in rheumatoid arthritis. Can J Clin Pharmacol. 2005;12(3):e254–63.

    PubMed  Google Scholar 

  32. Linden M. Phase-IV research: specifics, objectives and methodology. Pharmacopsychiatry. 1984;17(5):140–2.

    Article  CAS  PubMed  Google Scholar 

  33. Naudet F, Granger B, Braillon A. Cost-effectiveness of nalmefene: exaggerated expectations or fallacy? Alcohol Alcohol. 2016;51(5):623–4.

    Article  PubMed  Google Scholar 

  34. Soyka M, Friede M, Schnitker J. Comparing nalmefene and naltrexone in alcohol dependence: are there any differences? Results from an indirect meta-analysis—comment to Naudet. Pharmacopsychiatry. 2016;49(6):261–2.

    Article  CAS  PubMed  Google Scholar 

  35. Naudet F, Fitzgerald N, Braillon A. Nalmefene for alcohol dependence: a NICE decision? Lancet Psychiatry. 2016;3(12):1104–5.

    Article  PubMed  Google Scholar 

  36. Fitzgerald N, Angus K, Elders A, de Andrade M, Raistrick D, Heather N, et al. Weak evidence on nalmefene creates dilemmas for clinicians and poses questions for regulators and researchers. Addiction. 2016;111(8):1477–87.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Barrio P, Ortega L, Bona X, Gual A. Development, validation, and implementation of an innovative mobile app for alcohol dependence management: protocol for the SIDEAL trial. JMIR Res Protoc. 2016;5(1):e27.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Barrio P, Ortega L, López H, Gual A. Self-management and shared decision-making in alcohol dependence via a mobile app: a pilot study. Int J Behav Med. 2017;24(5):722–727.

  39. Sobell LC, Sobell MB. Timeline follow-back: a technique for assessing self-reported ethanol consumption. In: Litten RZ, Allen JP, editors. Measuring alcohol consumption: psychosocial and biological methods. Totowa: Humana Press; 1992. p. 41–72.

    Chapter  Google Scholar 

  40. Kalali A. Patient satisfaction with, and acceptability of, atypical antipsychotics. Curr Med Res Opin. 1999;15(2):135–7.

    Article  CAS  PubMed  Google Scholar 

  41. Vernon MK, Revicki DA, Awad AG, Dirani R, Panish J, Canuso CM, et al. Psychometric evaluation of the Medication Satisfaction Questionnaire [MSQ] to assess satisfaction with antipsychotic medication among schizophrenia patients. Schizophr Res. 2010;118(1–3):271–8.

    Article  PubMed  Google Scholar 

  42. Flensborg-Madsen T, Mortensen EL, Knop J, Becker U, Sher L, Grønbæk M. Comorbidity and temporal ordering of alcohol use disorders and other psychiatric disorders: results from a Danish register-based study. Compr Psychiatry. 2009;50(4):307–14.

    Article  PubMed  Google Scholar 

  43. Fein G. Psychiatric comorbidity in alcohol dependence. Neuropsychol Rev. 2015;25(4):456–75.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Monterosso JR, Flannery BA, Pettinati HM, Oslin DW, Rukstalis M, O’Brien CP, et al. Predicting treatment response to naltrexone: the influence of craving and family history. Am J Addict. 2001;10(3):258–68.

    Article  CAS  PubMed  Google Scholar 

  45. Garbutt JC, Greenblatt AM, West SL, Morgan LC, Kampov-Polevoy A, Jordan HS, et al. Clinical and biological moderators of response to naltrexone in alcohol dependence: a systematic review of the evidence. Addiction. 2014;109(8):1274–84.

    Article  PubMed  Google Scholar 

  46. Dundon WD, Pettinati HM, Lynch KG, Xie H, Varillo KM, Makadon C, et al. The therapeutic alliance in medical-based interventions impacts outcome in treating alcohol dependence. Drug Alcohol Depend. 2008;95(3):230–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Öjehagen A, Berglund M, Hansson L. The relationship between helping alliance and outcome in outpatient treatment of alcoholics: a comparative study of psychiatric treatment and multimodal behavioural therapy. Alcohol Alcohol. 1997;32(3):241–9.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Addictive Behaviors Unit, Clinic Hospital, University of Barcelona, Barcelona, Spain

    Pablo Barrio, Lluisa Ortega & Antoni Gual

  2. Addictive Behavior Unit, Psychiatry Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    Josep Guardia

  3. Addiction and Dual Diagnosis Unit, Psychiatric Service, Hospital Vall Hebron-ASPB, CIBERSAM and Psychiatric Department, Universidad Autónoma, Barcelona, Spain

    Carlos Roncero

  4. Addictive Behaviors Unit, Germanes Hospitalàries, Sant Boi, Barcelona, Spain

    Lara Yuguero

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  1. Pablo Barrio
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Corresponding author

Correspondence to Pablo Barrio.

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Funding

This study was funded by Lundbeck. The sponsor was involved in the study design, but not in data collection, analysis, manuscript writing, or the decision to submit the article for publication.

Conflict of interest

Dr. Barrio, Dr. Roncero, Dr. Guardia and Dr. Gual have received honoraria from Lundbeck. Dr. Barrio has also received honoraria from Pfizer. Dr. Roncero has also received honoraria from Janssen-Cilag, Otsuka, Server, GSK, Rovi, Astra, MSD and Sanofi. Dr. Yuguero and Dr. Ortega have no conflict of interest to declare.

Ethics approval

The study protocol, final approved informed consent document, and all supporting information were submitted to and approved by the institutional review boards of all participating centers.

Consent to participate

All participants provided written informed consent before taking part in study procedures. The study was conducted in accordance with the International Conference on Harmonisation and Good Clinical Practice and the principles of the Declaration of Helsinki.

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Barrio, P., Ortega, L., Guardia, J. et al. Who Receives Nalmefene and How Does It Work in the Real World? A Single-Arm, Phase IV Study of Nalmefene in Alcohol Dependent Outpatients: Baseline and 1-Month Results. Clin Drug Investig 38, 147–155 (2018). https://doi.org/10.1007/s40261-017-0590-4

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  • DOI: https://doi.org/10.1007/s40261-017-0590-4

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