Cited by 409Substance Abuse Treatment and OutcomesSleep and related disordersOpioid Use Disorder Treatment

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Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data

Hajak, G., Müller, W. E., Wittchen, H. U., Pittrow, D., Kirch, W.·2003·Addiction

DOI 10.1046/j.1360-0443.2003.00491.x

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Abstract

AIMS: The non-benzodiazepine hypnotics zolpidem and zopiclone, which are indicated for short-term treatment of insomnia, were considered originally by physicians as almost devoid of abuse and dependence potential. Several recent publications, however, have suggested that both agents carry a significant risk of abuse. To substantiate and re-evaluate this situation, the world literature was reviewed for cases of dependence of both agents; these cases were analysed in order to identify certain underlying patterns, if evident. METHODS: A systematic review based on a Medline literature search was conducted including the years 1966-2002 to assemble all available clinical case reports that were analysed for typical features of abuse and dependence according to prespecified criteria. Only case reports were of interest, and clinical studies were excluded. No limitations as to language or publication year were applied. The terms 'zolpidem', 'zopiclone' and 'abuse', 'dependence', 'addiction', 'withdrawal' and 'intoxication' were used to identify relevant publications. Potentially relevant citations were retrieved and assessed for inclusion independently by two authors. RESULTS: A total of 36 cases for zolpidem were identified, most of them reported in recent years, and 22 cases for zopiclone. Both sexes were involved to a similar extent; and cases were reported in all age groups. In extreme cases, dose increases reached a factor of 30-120 above the recommended doses. The majority of patients had a history of former drug or alcohol abuse and/or other psychiatric conditions. CONCLUSION: On the basis of world-wide prescription numbers, which are approximately twofold higher for zolpidem (1,338,774,000 tablets from June 2001 to June 2002 in Europe, Japan and United States) than for zopiclone (664,897,000 tablets during the same period in Europe and Japan), the relative incidence of reported dependence similar for both drugs and remarkably lower than that of benzodiazepines used for the treatment of disturbed sleep. The findings offer the conclusion that zolpidem and zopiclone are relatively safe drugs. However, as both drugs are psychotropic drugs, patients with a history of abuse or dependence and those with psychiatric diseases seem to be at increased risk of abuse of these agents.

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Yurcheshen, M. E., Guttuso, T. J., McDermott, M., Holloway, R. G., & Perlis, M. L. (2009) · Journal of Women s Health · doi:10.1089/jwh.2008.1257 · Cited by 52
Adverse Reactions to Zolpidem
Inagaki, T., Miyaoka, T., Tsuji, S., Inami, Y., Nishida, A., & Horiguchi, J. (2010) · The Primary Care Companion to The Journal of Clinical Psychiatry · doi:10.4088/pcc.09r00849bro · Cited by 50
Emerging drugs for insomnia: new frontiers for old and novel targets
Sullivan, S. S., & Guilleminault, C. (2009) · Expert Opinion on Emerging Drugs · doi:10.1517/14728210903171948 · Cited by 50
“There is also the possibility of tolerance and lack of effectiveness over time, as well as dependence in some patients [25].”
Background
Pharmacoepidemiological characterisation of zolpidem and zopiclone usage
Victorri-Vigneau, C., Feuillet, F., Wainstein, L., Grall-Bronnec, M., Pivette, J., Chaslerie, A., Sébille, V., & Jolliet, P. (2013) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-013-1557-x · Cited by 49
Modest abuse-related subjective effects of zolpidem in drug-naive volunteers
Licata, S. C., Mashhoon, Y., MacLean, R. R., & Lukas, S. E. (2011) · Behavioural Pharmacology · doi:10.1097/fbp.0b013e328343d78a · Cited by 49
Prevalence and Predictors of Prescription Sleep Aid Use among Individuals with DSM-5 Insomnia: The Role of Hyperarousal
Pillai, V., Cheng, P., Kalmbach, D. A., Roehrs, T., Roth, T. G., & Drake, C. L. (2016) · SLEEP · doi:10.5665/sleep.5636 · Cited by 49
Effects of cognitive behavioral therapy for insomnia on subjective and objective measures of sleep and cognition
Perrault, A. A., Pomares, F. B., Smith, D., Cross, N. E., Gong, K., Maltezos, A., McCarthy, M., Madigan, E., Tarelli, L., McGrath, J. J., et al. (2022) · Sleep Medicine · doi:10.1016/j.sleep.2022.05.010 · Cited by 58
Raising awareness about sleep disorders
Jaiswal, S. J., Owens, R. L., & Malhotra, A. (2017) · Lung India · doi:10.4103/0970-2113.205331 · Cited by 54
“Lung India • Volume 34 • Issue 3 • May - June 2017 265 recommended due to issues with dependence, tolerance, as well as medication side effects.[69-71] Interestingly, cognitive behavioral therapy (CBT) has been shown to improve sleep quality, as measured by sleep efficiency, time spent in slow-wave sleep, and total sl…”
Background
On-site rapid screening of benzodiazepines in dietary supplements using pipette-tip micro-solid phase extraction coupled to ion mobility spectrometry
Sun, T., Ali, M. M., Wang, D., & Du, Z. (2019) · Journal of Chromatography A · doi:10.1016/j.chroma.2019.460547 · Cited by 48
Pharmacological Treatment of Insomnia in Alcohol Recovery: A Systematic Review
Kolla, B. P., Mansukhani, M. P., & Schneekloth, T. D. (2011) · Alcohol and Alcoholism · doi:10.1093/alcalc/agr073 · Cited by 44
Assessment of the Abuse Potential of the Orexin Receptor Antagonist, Suvorexant, Compared With Zolpidem in a Randomized Crossover Study
Schoedel, K. A., Sun, H., Sellers, E. M., Faulknor, J., Levy‐Cooperman, N., Li, X., Kennedy, W. P., Cha, J., Lewis, N. M., Liu, W., et al. (2016) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000000516 · Cited by 42
Mild cognitive impairment: associations with sleep disturbance, apolipoprotein e4, and sleep medications
Burke, S. L., Hu, T., Spadola, C., Li, T., Naseh, M., Burgess, A., & Cadet, T. J. (2018) · Sleep Medicine · doi:10.1016/j.sleep.2018.09.001 · Cited by 40
Neural Basis of Benzodiazepine Reward: Requirement for α2 Containing GABAA Receptors in the Nucleus Accumbens
Engin, E., Bakhurin, K. I., Smith, K. S., Hines, R. M., Reynolds, L. M., Tang, W., Sprengel, R., Moss, S. J., & Rudolph, U. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.41 · Cited by 40
“…compounds, have highlighted the role of the a1GABAARs in the self-administration of and the preference for benzodiazepines, as well as in the plastic changes in the VTA following benzodiazepine administration (eg, Hajak et al, 2003; Rowlett et al, 2005; Heikkinen et al, 2009; Tan et al, 2010).”
Background
The effects of repeated zolpidem treatment on tolerance, withdrawal-like symptoms, and GABAA receptor mRNAs profile expression in mice: Comparison with diazepam
Wright, B. T., Gluszek, C. F., & Heldt, S. A. (2014) · Psychopharmacology · doi:10.1007/s00213-014-3473-x · Cited by 41
“2012), numerous cases of zolpidem abuse and dependence have been reported in individuals using supratherapeutic doses (Hajak et al. 2003; Victorri-Vigneau et al. 2007).”
Background
Self-reported efficacy and tolerability of ramelteon 8 mg in older adults experiencing severe sleep-onset difficulty
Mini, L. J., Wang‐Weigand, S., & Zhang, J. (2007) · The American Journal of Geriatric Pharmacotherapy · doi:10.1016/j.amjopharm.2007.09.004 · Cited by 40
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BARBIERI, I. A., Oliveira, M. L. S., Bruckmann, F. D. S., Salles, T. D. R., Zancanaro, L. V., Silva, L. F. O., Dotto, G. L., Lima, E. C., Naushad, M., & Rhoden, C. R. B. (2023) · Journal of Molecular Liquids · doi:10.1016/j.molliq.2023.123657 · Cited by 39
Zopiclone’s Residual Effects on Actual Driving Performance in a Standardized Test: A Pooled Analysis of Age and Sex Effects in 4 Placebo-Controlled Studies
Leufkens, T., & Vermeeren, A. (2013) · Clinical Therapeutics · doi:10.1016/j.clinthera.2013.11.005 · Cited by 39
Do Subtype-Selective γ-Aminobutyric AcidA Receptor Modulators Have a Reduced Propensity to Induce Physical Dependence in Mice?
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Verbrauch von Zolpidem und Zopiclon auf Privatrezepten zwischen 1993 und 2007
Hoffmann, F., Scharffetter, W., & Glaeske, G. (2009) · Der Nervenarzt · doi:10.1007/s00115-008-2648-2 · Cited by 38
4-Fluorosulfonylpiperidines: Selective 5-HT2A ligands for the treatment of insomnia
Fish, L. R., Gilligan, M. T., Humphries, A. C., Ivarsson, M., Ladduwahetty, T., Merchant, K. J., O'Connor, D. V., Patel, S. S., Philipps, E., Vargas, H. M., et al. (2005) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2005.05.104 · Cited by 37
Prevalence and correlates of the misuse of z-drugs and benzodiazepines in the National Survey on Drug Use and Health
McHugh, R. K., Votaw, V. R., Trapani, E. W., & McCarthy, M. D. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1129447 · Cited by 38
A European Community Pharmacy-Based Survey to Investigate Patterns of Prescription Fraud through Identification of Falsified Prescriptions
Lapeyre‐Mestre, M., Gony, M., Carvajal, A., Saint-Gerons, D. M., Conforti, A., D’Incau, P., Heerdink, E. R., van der Stichele, R., Bergman, U., & The OSIAP Europe Study Group (2014) · European Addiction Research · doi:10.1159/000356812 · Cited by 36
Treating insomnia with medications
Pagel, J. F., Pandi-Perumal, S. R., & Monti, J. M. (2018) · Sleep Science and Practice · doi:10.1186/s41606-018-0025-z · Cited by 43
“While all hypnotics have abuse potential for individuals with addictive histories and personalities, these agents have been noted to have minimal additive potential (Hajak et al. 2003).”
Background
The Risk of Overdose With Concomitant Use of Z-Drugs and Prescription Opioids: A Population-Based Cohort Study
Szmulewicz, A., Bateman, B. T., Levin, R., & Huybrechts, K. F. (2021) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2020.20071038 · Cited by 56
Zolpidem abuse, dependence and withdrawal syndrome: sex as susceptibility factor for adverse effects
Cubała, W. J., Landowski, J., & Wichowicz, H. M. (2008) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2007.03028.x · Cited by 34
Rapid determination of benzodiazepines, zolpidem and their metabolites in urine using direct injection liquid chromatography–tandem mass spectrometry
Jeong, Y.-D., Kim, M. K., Suh, S. I., In, M. K., Kim, J. Y., & Paeng, K. (2015) · Forensic Science International · doi:10.1016/j.forsciint.2015.07.043 · Cited by 34
“BDZ often had unexpected side effects including a high potential for abuse [4].”
Background
Nonmedical use of benzodiazepines and Z‐drugs in the UK
Hockenhull, J., Black, J. C., Haynes, C. M., Rockhill, K. M., Dargan, P. I., Dart, R. C., & Wood, D. M. (2020) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.14397 · Cited by 34
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Long‐term Use of Z‐Hypnotics and Co‐medication with Benzodiazepines and Opioids
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Insomnia in Patients with Depression
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“cases of zolpidem-dependent patients, including the two above-mentioned cases, are described in literature (Hajak et al., 2003; Liappas et al., 2003; Boulanger-Rostowsky et al., 2004).”
Result
Severe Chronic Abuse of Zolpidem in Refractory Insomnia
Chiaro, G., Castelnovo, A., Bianco, G., Maffei, P., & Manconi, M. (2018) · Journal of Clinical Sleep Medicine · doi:10.5664/jcsm.7240 · Cited by 32
Insomnia
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Update on Insomnia after Mild Traumatic Brain Injury
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“While Z-drugs have a significantly lower incidence of dependence relative to benzodiazepines, there is still a risk of abuse especially in patients with a history of substance abuse, dependence, or psychiatric diseases [79].”
Background
Clinical Pharmacology of Sleep
Pandi-Perumal, S. R., & Monti, J. M. (2006) · Birkhäuser Basel eBooks · doi:10.1007/3-7643-7440-3 · Cited by 31

Authors: Hajak, G., Müller, W. E., Wittchen, H. U., Pittrow, D., & Kirch, W.
Affiliations: University of Regensburg (DE)
Goethe University Frankfurt (DE)
Technische Universität Dresden (DE)
Corresponding author: Hajak, G.
ORCID: Hajak, G.
Müller, W. E.
Venue: Addiction
Publisher: Wiley
Published: 2003-10
Volume: 98
Issue: 10
Pages: 1371-1378
ISSN: 0965-2140 (ISSN-L)
1360-0443
DOI: 10.1046/j.1360-0443.2003.00491.x
OpenAlex: W2116289594
Cited by: 404
References: 74
Citations by year: 2026: 3 · 2025: 7 · 2024: 10 · 2023: 19 · 2022: 11 · 2021: 16 · 2020: 29 · 2019: 21 · 2018: 17 · 2017: 13 · 2016: 25 · 2015: 13 · 2014: 27 · 2013: 19 · 2012: 20
FWCI: 2.30
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Addiction (publishedVersion)
PubMed (publishedVersion)
University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
Topics: Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
Keywords: zolpidem, zopiclone, non-benzodiazepine hypnotics, drug addiction, drug abuse, insomnia treatment, benzodiazepine alternatives, prescribing patterns, psychiatric comorbidity, withdrawal, drug safety
MeSH terms: Zolpidem, Adult, Aged, Female, Humans, Hypnotics and Sedatives, Male, Middle Aged, Piperazines, Pyridines, Substance-Related Disorders, Azabicyclo Compounds

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Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data

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