Internal and Emergency Medicine

, Volume 14, Issue 8, pp 1271–1278 | Cite as

High-dose lormetazepam dependence: strange case of Dr. Jekyll and Mr. Hyde

  • Marco Faccini
  • Stefano TamburinEmail author
  • Rebecca Casari
  • Laura Morbioli
  • Fabio Lugoboni


High-dose benzodiazepine (BZD) abuse is emerging as a substance use disorder (SUD). The aim of the study is to explore the impact of high-dose lormetazepam (LMZ) abuse and the characteristics of patients affected by this SUD in a tertiary referral addiction unit. We have retrospectively evaluated 1112 patients admitted to the Addiction Medicine Unit, Verona University Hospital, Italy for detoxification from high-dose BZD dependence. LMZ was the most common BZD, with an increasing prevalence from January 2003 to June 2018. Socio-demographic (more women; higher age and education) and clinical features (higher daily diazepam dosage equivalent, BZD abuse duration, age of first BZD intake; BZD prescribed more frequently for sleep disorders; less frequent history of other SUDs, previous/active alcohol, previous opioids abuse; more frequent overall major psychiatric diseases and major depression; less-frequent bipolar disorders and other psychoses, personality disorders, and more than one psychiatric disease) of LMZ vs. other BZD abusers significantly differed. 96.7% LMZ abusers took oral solution, while two-thirds of other BZD abusers took tablets. Oral solution, BZD abuse duration and prescription of BZD for sleep disorders increased, while history of other SUDs, previous/active alcohol and active cannabinoids SUD reduced the risk of high-dose LMZ vs. other BZDs abuse. The large prevalence of high-dose LMZ abusers in Italy may be strongly related to the availability and characteristics of oral formulation that may transform the innocuous Dr. Jekyll tablets into an evil Mr. Hyde. Restriction to the market of LMZ oral formulation might reduce the risk of high-dose abuse.


Benzodiazepine (BZD) Lormetazepam Abuse Addiction Oral solution Substance use disorders (SUDs) 




Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest.

Statement of human and animal rights

The study was conducted according to the Declaration of Helsinki and approved by the ethics committee of the Verona University Hospital.

Informed consent

All the patients gave written informed consent to the study.


  1. 1.
    Lader M (2011) Benzodiazepines revisited-will we ever learn? Addiction 106:2086–2109PubMedGoogle Scholar
  2. 2.
    Janhsen K, Roser P, Hoffmann K (2015) The problems of long-term treatment with benzodiazepines and related substances. Prescribing practice, epidemiology and the treatment of withdrawal. Dtsch Arztebl Int 112:1–7PubMedCentralGoogle Scholar
  3. 3.
    Soyka M (2017) Treatment of benzodiazepine dependence. N Engl J Med 376:1147–1157PubMedGoogle Scholar
  4. 4.
    Kurko TA, Saastamoinen LK, Tähkäpää S, Tuulio-Henriksson A, Taiminen T, Tiihonen J, Airaksinen MS, Hietala J (2015) Long-term use of benzodiazepines: definitions, prevalence and usage patterns—a systematic review of register-based studies. Eur Psychiatry 30:1037–1047PubMedGoogle Scholar
  5. 5.
    Faccini M, Leone R, Opri S, Casari R, Resentera C, Morbioli L, Conforti A, Lugoboni F (2016) Slow subcutaneous infusion of flumazenil for the treatment of long-term, high-dose benzodiazepine users: a review of 214 cases. J Psychopharmacol 30:1047–1053PubMedGoogle Scholar
  6. 6.
    Liebrenz M, Schneider M, Buadze A, Gehring MT, Dube A, Caflisch C (2015) High-dose benzodiazepine dependence: a qualitative study of patients' perceptions on initiation, reasons for use, and obtainment. PLoS ONE 10:e0142057PubMedPubMedCentralGoogle Scholar
  7. 7.
    Lugoboni F, Mirijello A, Faccini M, Casari R, Cossari A, Musi G, Bissoli G, Quaglio G, Addolorato G (2014) Quality of life in a cohort of high-dose benzodiazepine dependent patients. Drug Alcohol Depend 142:105–109PubMedGoogle Scholar
  8. 8.
    Tamburin S, Federico A, Faccini M, Casari R, Morbioli L, Sartore V, Mirijello A, Addolorato G, Lugoboni F (2017) Determinants of quality of life in high-dose benzodiazepine misusers. Int J Environ Res Public Health 14:38PubMedCentralGoogle Scholar
  9. 9.
    Federico A, Tamburin S, Maier A, Faccini M, Casari R, Morbioli L, Lugoboni F (2017) Multifocal cognitive dysfunction in high-dose benzodiazepine users: a cross-sectional study. Neurol Sci 38:137–142PubMedGoogle Scholar
  10. 10.
    Petitjean S, Ladewig D, Meier CR, Amrein R, Wiesbeck GA (2007) Benzodiazepine prescribing to the Swiss adult population: results from a national survey of community pharmacies. Int Clin Psychopharmacol 22:292–298PubMedGoogle Scholar
  11. 11.
    Cosci F, Guidi J, Balon R, Fava GA (2015) Clinical methodology matters in epidemiology: not all benzodiazepines are the same. Psychother Psychosom 84:262–264Google Scholar
  12. 12.
    Cloos JM, Bocquet V, Rolland-Portal I, Koch P, Chouinard G (2015) Hypnotics and triazolobenzodiazepines—best predictors of high-dose benzodiazepine use: results from the Luxembourg National Health Insurance Registry. Psychother Psychosom 84:273–283Google Scholar
  13. 13.
    Ozawa M, Nakada Y, Sugimachi K, Akai T, Yamaguchi M (1991) Interaction of the hypnotic lormetazepam with central benzodiazepine receptor subtypes omega 1, omega 2 and omega 3. Nihon Yakurigaku Zasshi 98:399–408PubMedGoogle Scholar
  14. 14.
    Kaufmann WA, Humpel C, Alheid GF, Marksteiner J (2003) Compartmentation of alpha 1 and alpha 2 GABA(A) receptor subunits within rat extended amygdala: implications for benzodiazepine action. Brain Res 964:91–99PubMedGoogle Scholar
  15. 15.
    Zecca L, Reina L, Scaglione F, Ferrario P, Pirola R, Ceccarelli G, Ciampini M, Fraschini F (1985) Relative bioavailability in humans for oral tablets and solutions of lormetazepam. Arzneimittelforschung 35:1870–1872PubMedGoogle Scholar
  16. 16.
    Guerra P, Soto A, Carcas AJ, Sancho A, Cassinello A, Frias-Iniesta J (2002) Comparison of lormetazepam solution and capsules in healthy volunteers. early exposure and drug pharmacokinetics. Clin Drug Invest 22:859–866Google Scholar
  17. 17.
    Ancolio C, Tardieu S, Soubrouillard C, Alquier C, Pradel V, Micallef J, Blin O (2004) A randomized clinical trial comparing doses and efficacy of lormetazepam tablets or oral solution for insomnia in a general practice setting. Hum Psychopharmacol 19:129–134PubMedGoogle Scholar
  18. 18.
    Faccini M, Leone R, Pajusco B, Quaglio G, Casari R, Albiero A, Donati M, Lugoboni F (2012) Lormetazepam addiction: data analysis from an Italian medical unit for addiction. Risk Manag Healthc Policy 5:43–48PubMedPubMedCentralGoogle Scholar
  19. 19.
    Tamburin S, Faccini M, Casari R, Federico A, Morbioli L, Franchini E, Bongiovanni LG, Lugoboni F (2017) Low risk of seizures with slow flumazenil infusion and routine anticonvulsant prophylaxis for high-dose benzodiazepine dependence. J Psychopharmacol 31:1369–1373PubMedGoogle Scholar
  20. 20.
    American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Press, Washington (text revision) Google Scholar
  21. 21.
    Galanter M, Kleber HD (2008) The American psychiatric publishing textbook of substance abuse treatment, 4th edn. American Psychiatric Publishers, ArlingtonGoogle Scholar
  22. 22.
    First MB, Spitzer RL, Gibbon M, Williams JBW (2002) Structured clinical interview for DSM-IV-TR Axis I disorders, patient edition (SCID-I/P). Biometrics Research, New York State Psychiatric Institute, New YorkGoogle Scholar
  23. 23.
    Zanarini M, Frankenburg F, Sickel A, Yong L (1996) The diagnostic interview for DSM-IV personality disorders (DIPD-IV). McLean Hospital, BelmontGoogle Scholar
  24. 24.
    Hosmer DW, Lemeshow S (2000) Applied logistic regression, 2nd edn. Wiley, New YorkGoogle Scholar
  25. 25.
    Hermos JA, Young MM, Lawler EV, Rosenbloom D, Fiore LD (2007) Long-term, high-dose benzodiazepine prescriptions in veteran patients with PTSD: influence of preexisting alcoholism and drug-abuse diagnoses. J Trauma Stress 20:909–914PubMedGoogle Scholar
  26. 26.
    Agenzia Italiana del Farmaco (AIFA) (2018) The Medicines Utilisation Monitoring Centre. National Report on Medicines use in Italy. Year 2017. Rome: Italian Medicines Agency. Accessed 3 Feb 2019.
  27. 27.
    Vicente-Sánchez MP, Macías-Saint-Gerons D, de la Fuente-Honrubia C, González-Bermejo D, Montero-Corominas D, Catalá-López F (2013) Trends of use of anxiolytics and hypnotics in Spain from 2000 to 2011. Rev Esp Salud Publica 87:247–255PubMedGoogle Scholar
  28. 28.
    Baldwin DS, Aitchison K, Bateson A, Curran HV, Davies S, Leonard B, Nutt DJ, Stephens DN, Wilson S (2013) Benzodiazepines: risks and benefits: a reconsideration. J Psychopharmacol 27:967–971PubMedGoogle Scholar
  29. 29.
    Hoffmann F (2013) Benefits and risks of benzodiazepines and Z-drugs: comparison of perceptions of GPs and community pharmacists in Germany. Ger Med Sci 2013(11):10Google Scholar
  30. 30.
  31. 31.
    Tan KR, Brown M, Labouèbe G, Yvon C, Creton C, Fritschy JM, Rudolph U, Lüscher C (2010) Neural bases for addictive properties of benzodiazepines. Nature 463:769–774PubMedCentralGoogle Scholar
  32. 32.
    Tan KR, Rudolph U, Luscher C (2011) Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci 34:188–197PubMedPubMedCentralGoogle Scholar
  33. 33.
    Cheng T, Wallace DM, Ponteri B, Tuli M (2018) Valium without dependence? Individual GABAA receptor subtype contribution toward benzodiazepine addiction, tolerance, and therapeutic effects. Neuropsychiatr Dis Treat 14:1351–1361PubMedPubMedCentralGoogle Scholar
  34. 34.
    Calixto E (2016) GABA withdrawal syndrome: GABAA receptor, synapse, neurobiological implications and analogies with other abstinences. Neuroscience 313:57–72PubMedGoogle Scholar
  35. 35.
    Fang SY, Chen CY, Chang IS, Wu EC, Chang CM, Lin KM (2009) Predictors of the incidence and discontinuation of long-term use of benzodiazepines: a population-based study. Drug Alcohol Depend 104:140–146PubMedGoogle Scholar
  36. 36.
    Italian Ministry of Health (2017) Alcohol: guide to use. Rome: Italian Ministry of Health. Accessed 27 Sep 2018
  37. 37.
    Cosci F, Mansueto G, Faccini M, Casari R, Lugoboni F (2016) Socio-demographic and clinical characteristics of benzodiazepine long-term users: Results from a tertiary care center. Compr Psychiatry 69:211–215PubMedGoogle Scholar
  38. 38.
    Magrini N, Vaccheri A, Parma E, D'Alessandro R, Bottoni A, Occhionero M, Montanaro N (1996) Use of benzodiazepines in the Italian general population: prevalence, pattern of use and risk factors for use. Clin Pharmacol 50:19–25Google Scholar
  39. 39.
    Olfson M, King M, Schoenbaum M (2015) Benzodiazepine use in the United States. JAMA Psychiatry 72:136–142PubMedGoogle Scholar
  40. 40.
    Van Der Waals FW, Mohrs J, Foets M (1993) Sex differences among recipients of benzodiazepines in Dutch general practice. BMJ 307:363–366PubMedPubMedCentralGoogle Scholar
  41. 41.
    Pélissolo A, Notides C, Lépine JP, Bisserbe JC (1999) Anxiolytic and hypnotic use by general hospital inpatients: the impact of psychopathology and general medical conditions. Gen Hosp Psychiatry 21:79–86PubMedGoogle Scholar
  42. 42.
    Kazim M, Abar A, Hanif M, Mansoor S, Tahir S, Mehmood A, Yousafzai AW (2015) Pattern of benzodiazepine prescription in internal medicine outpatients at a tertiary care hospital in Pakistan. Postgrad Med Inst 29:38–42Google Scholar
  43. 43.
    Donoghue J, Lader M (2010) Usage of benzodiazepines: a review. Psychiatry Clin Pract 14:78–87Google Scholar
  44. 44.
    Tamburin S, Federico A, Morbioli L, Faccini M, Casari R, Zamboni L, Briguglio G, Lugoboni F (2017) Screening for adult attention deficit/hyperactivity disorder in high-dose benzodiazepine dependent patients. Am J Addict 26:610–614PubMedGoogle Scholar
  45. 45.
    O'Brien PL, Karnell LH, Gokhale M, Kenneth Pack BS, Campopiano M, Zur J (2017) Prescribing of benzodiazepines and opioids to individuals with substance use disorders. Drug Alcohol Depend 178:223–230PubMedGoogle Scholar
  46. 46.
    Bramness JG, Skurtveit S, Furu K, Engeland A, Sakshaug S, Rønning M (2006) Changes in sale and use of flunitrazepam in Norway after 1999. Tidsskr Nor Laegeforen 126:589–590PubMedGoogle Scholar
  47. 47.
    Mounteney J, Haugland S (2009) Earlier warning: a multi-indicator approach to monitoring trends in the illicit use of medicines. Int J Drug Policy 20:161–169PubMedGoogle Scholar

Copyright information

© Società Italiana di Medicina Interna (SIMI) 2019

Authors and Affiliations

  1. 1.Addiction Medicine Unit, Department of MedicineVerona University HospitalVeronaItaly
  2. 2.Department of Neurosciences, Biomedicine and Movement SciencesUniversity of VeronaVeronaItaly

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