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EMCDDA. New report highlights public health risks and increasing availability of ‘designer benzodiazepines’ in Europe 

New benzodiazepines, which are not controlled by international drug laws, come under the spotlight today in a new report released by the EU drugs agency (EMCDDA) (1). Often marketed as ‘designer benzodiazepines’, these substances are sold as ‘legal’ replacements for controlled benzodiazepines and are becoming increasingly available in Europe. They are monitored by the agency as new psychoactive substances (NPS) through the EU Early Warning System (EWS).

The EMCDDA currently monitors 30 new benzodiazepines, over 80% of which were detected for the first time between 2014 and 2020. Despite this relatively large number, the new benzodiazepine market in Europe is currently dominated by etizolam and flualprazolam — although this may change, as both substances were placed under international control in November 2020. In 2019, 1 240 seizures of new benzodiazepines were reported by the EU Member States (around 5% of NPS seizures). (EMCDDA, News release No 6/2021, Lissabon, 09.06.2021

https://www.emcdda.europa.eu/news/2021/6/report-highlights-public-health-risks-and-increasing-availability-designer-benzodiazepines-europe_en

EMCDDA. New benzodiazepines in Europe – a review

Summary

This report provides a technical review of the current body of knowledge regarding new benzodiazepines that are monitored by the EU Early Warning System. The aims of this report are to strengthen situational awareness of new benzodiazepines in Europe, and to help stakeholders prepare for and respond to public health and social threats caused by such substances. (EMCDDA, Lissabon, Juni 2021)

https://www.emcdda.europa.eu/system/files/publications/13759/TD0221596ENN_002.pdf

Benzodiazepine Use in Opioid Maintenance Treatment Programme: Risks and Clinical Outcomes. 

Oliveira C, Filipe R, Meira J, Sampaio L, Teixeira L, Rodrigues J, Nunes I, Tavares J. 

Acta Med Port. 2021 Mar 1;34(3):209-216. doi: 10.20344/amp.13181. Epub 2021 Mar 1. PMID: 33971116.

https://actamedicaportuguesa.com/revista/index.php/amp/article/view/13181/6273

Relationship between benzodiazepine prescription, aggressive behavior, and behavioral disinhibition: a retrospective study in a Swiss prison. 

Baggio, S., Starcevic, V., Heller, P. et al. 

Harm Reduct J 18, 58 (2021). doi.org/10.1186/s12954-021-00504-5

https://harmreductionjournal.biomedcentral.com/articles/10.1186/s12954-021-00504-5

Doc-Hopping bei Benzodiazepin- und Pregabalinverordnungen

Wie lässt sich vermeiden, dass Patienten verschiedene Praxen aufsuchen, um an möglichst große mengen bestimmter medikamente zu kommen? (R.Ullmann in KVHH Journal, 12/2020, Seiten 26/27)

https://www.kvhh.net/_Resources/Persistent/3/e/a/4/3ea4979c6d3f19755778b20928ee0c42525cf8e7/12_20_www_KVH_Journal_RZ02.pdf

A high-resolution in vivo atlas of the human brain's benzodiazepine binding site of GABAA receptors. 

Nørgaard M, Beliveau V, Ganz M, Svarer C, Pinborg LH, Keller SH, Jensen PS, Greve DN, Knudsen GM. 

Neuroimage. 2021 Feb 18;232:117878. doi: 10.1016/j.neuroimage.2021.117878. Epub ahead of print. PMID: 33610745.

https://www.sciencedirect.com/science/article/pii/S1053811921001555

Opioid overdose reduced in patients taking buprenorphine

Study indicates the drug is effective in opioid users who also take benzodiazepines for anxiety, other conditions. (Washington University School of Medicine, 02.03.2021)

https://medicine.wustl.edu/news/buprenorphine-protects-against-opioid-overdoses-even-in-benzodiazepine-users/

Kanada. A Deadly Synthetic Street Drug Called ‘Benzo Dope’ Is on the Rise

The emerging drug contains two highly-potent highs, fentanyl and etizolam, and has been linked to a string of drug deaths in Canada. (Vice, UK, 02.03.2021)

https://www.vice.com/en/article/3anmy5/a-deadly-synthetic-street-drug-called-benzo-dope-is-on-the-rise

Concurrent use of opioids and benzodiazepines/Z-drugs in Alberta, Canada and the risk of hospitalisation and death: a case cross-over study. 

Sharma V, Simpson SH, Samanani S, Jess E, Eurich DT. 

BMJ Open. 2020 Nov 20;10(11):e038692. doi: 10.1136/bmjopen-2020-038692. PMID: 33444187; PMCID: PMC7682464.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682464/

Benzodiazepines: the time for systematic change is now. 

Schmitz, A. (2021)

Addiction, 116: 219– 221. doi.org/10.1111/add.15095.

https://onlinelibrary.wiley.com/doi/10.1111/add.15095

Compassionate Use: Statt Propofol und Midazolam: Klinik testet Remimazolam

Berlin - In einigen italienischen Krankenhäusern werden verschiedene Wirkstoffe zur Sedierung von Covid-Patienten knapp. Nun wurde mit Remimazolam im Zuge eines Compassionate-Use-Programms ein weiterer Wirkstoff zur Verfügung gestellt, um den Engpass zu lockern. (apotheke adhoc, 02.02.2020)

https://www.apotheke-adhoc.de/nachrichten/detail/internationales/statt-propofol-und-midazolam-klinik-testet-remimazolam-italien-compassionate-use-fuer-remimazolam/

Association Between Benzodiazepine Use With or Without Opioid Use and All-Cause Mortality in the United States, 1999-2015. 

Xu KY, Hartz SM, Borodovsky JT, Bierut LJ, Grucza RA.

JAMA Netw Open. 2020;3(12):e2028557. doi:10.1001/jamanetworkopen.2020.28557

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2773826

Benzodiazepine: FDA will Warnungen vor Abhängigkeit verschärfen

Silver Spring/Maryland – Ein offenbar zunehmender Missbrauch von Benzodiazepinen veranlasst die Arzneimittelbehörde FDA dazu, die Fachinformationen zu verschärfen. Diese sollen künftig umrahmte Warnhinweise enthalten. (aerzteblatt.de, 15.10.2020)

https://www.aerzteblatt.de/nachrichten/116832/Benzodiazepine-FDA-will-Warnungen-vor-Abhaengigkeit-verschaerfen

Concurrent Use of Benzodiazepine by Heroin Users-What Are the Prevalence and the Risks Associated with This Pattern of Use?. 

Yamamoto T, Dargan PI, Dines A, et al. 

J Med Toxicol. 2019;15(1):4-11. doi:10.1007/s13181-018-0674-4

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314928/

Mixing meds: Weighing the pros and cons of adding benzodiazepines to buprenorphine treatment for individuals with opioid use disorder

Benzodiazepines (a class of sedative medications best known by brand names like Valium, Xanax, and Klonopin) may be prescribed to patients who are receiving buprenorphine treatment for opioid use disorder (an opioid agonist medication best known in formulation with naloxone, marketed as Suboxone). Clinicians accept that there are both risks, and potential benefits associated with combining these medications. To help aid clinical recommendations, Park and colleagues examined some of the risks and benefits associated with prescribing buprenorphine and benzodiazepines together using government records from the state of Massachusetts. (Recovery Research Institute, USA, Juni 2020)

https://www.recoveryanswers.org/research-post/mixing-benzodiazepines-buprenorphine-opioid-use-disorder/

An expanding world of new psychoactive substances-designer benzodiazepines.

Zawilska JB, Wojcieszak J.

Neurotoxicology. 2019 Jul;73:8-16. doi: 10.1016/j.neuro.2019.02.015.

Abstract

https://www.sciencedirect.com/science/article/abs/pii/S0161813X19300178

Combining opioids and benzodiazepines: effects on mortality and severe adverse respiratory events.

Boon M, van Dorp E, Broens S, Overdyk F.

Ann Palliat Med. 2020 Mar;9(2):542-557. doi: 10.21037/apm.2019.12.09. 

http://apm.amegroups.com/article/view/35734/29319

A serious adverse drug reaction probably induced by clonazepam: a case report of myotoxicity.

Han X, Wang J.

BMC Pharmacol Toxicol. 2019 Nov 5;20(1):64. doi: 10.1186/s40360-019-0366-y.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833282/

Problematic Medication With Benzodiazepines, "Z-drugs", and Opioid Analgesics.

Buth S, Holzbach R, Martens MS, Neumann-Runde E, Meiners O, Verthein U.

Dtsch Arztebl Int. 2019 Sep 13;116(37):607-614. doi: 10.3238/arztebl.2019.0607.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819700/

nal von minden: Drug-Screen® 7-Aminoclonazepam Schnelltest

Zum Nachweis von 7-Aminoclonazepam in Urin, Cut-off: 200 ng/mL

https://www.nal-vonminden.com/de/fileupload/index/download?id=133

Benzodiazepine: Fluch und Segen - Was Benzodiazepine im Körper bewirken

Daniela Beer, “Product Manager Toxicology“, nal von minden GmbH

Benzodiazepine- Fluch und Segen - Was Benzodiazepine im Körper bewirken - D.Beer

Benzodiazepines for treatment of patients with delirium excluding those who are cared for in an intensive care unit.

Li Y, Ma J, Jin Y, Li N, Zheng R, Mu W, Wang J, Si J, Chen J, Shang H. 

Cochrane Database of Systematic Reviews 2020, Issue 2. Art. No.: CD012670. DOI: 10.1002/14651858.CD012670.pub2

Abstract

https://www.cochrane.org/CD012670/DEMENTIA_use-benzodiazepines-treat-adults-delirium-excluding-patients-being-cared-intensive-care-units-icu

Is Long-Term Benzodiazepine Use a Risk Factor for Cognitive Decline? Results of a Systematic Review

Danilo Nader and Linda Gowing

Journal of Addiction, Volume 2020, Article ID 1569456, 10 pages, doi.org/10.1155/2020/1569456

https://www.hindawi.com/journals/jad/2020/1569456/

Prescription of benzodiazepines, z-drugs, and gabapentinoids and mortality risk in people receiving opioid agonist treatment: Observational study based on the UK Clinical Practice Research Datalink and Office for National Statistics death records.

Macleod J, Steer C, Tilling K, Cornish R, Marsden J, Millar T, Strang J, Hickman M.

PLoS Med. 2019 Nov 26;16(11):e1002965. doi: 10.1371/journal.pmed.1002965. 

https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002965

Clonazepam used as single antiepileptic drug to treat people with newly diagnosed epilepsy

Brigo F, Igwe SC, Bragazzi N, Lattanzi S. 

Cochrane Database of Systematic Reviews 2019, Issue 11. Art. No.: CD013028. DOI: 10.1002/14651858.CD013028.pub2

Certainty of the evidence

So far, the evidence on the efficacy and tolerability of clonazepam used as a single antiepileptic drug for the treatment of epilepsy is scarce and of very low certainty; hence insufficient to base decisions on its use in monotherapy.

Abstract

https://www.cochrane.org/CD013028/EPILEPSY_clonazepam-used-single-antiepileptic-drug-treat-people-newly-diagnosed-epilepsy

The Evolution of Designer Benzodiazepines - Challenges for detection and monitoring 

Maximo J. Marin, MD, and Xander M.R. van Wijk, PhD, DABCC  // Date: NOV.1.2019  // Source: Clinical Laboratory News; American Association for Clinical Chemistry (AACC)

https://www.aacc.org/publications/cln/articles/2019/november/the-evolution-of-designer-benzodiazepines

Anticholinergic and benzodiazepine medication use and risk of incident dementia: a UK cohort study.

Grossi CM, Richardson K, Fox C, Maidment I, Steel N, Loke YK, Arthur A, Myint PK, Campbell N, Boustani M, Robinson L, Brayne C, Matthews FE, Savva GM.

BMC Geriatr. 2019 Oct 21;19(1):276. doi: 10.1186/s12877-019-1280-2.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802337/

Association between benzodiazepines and suicide risk: a matched case-control study.

Cato V, Holländare F, Nordenskjöld A, Sellin T.

BMC Psychiatry. 2019 Oct 26;19(1):317. doi: 10.1186/s12888-019-2312-3.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815437/

Medicines associated with dependence or withdrawal: a mixed-methods public health review and national database study in England.

Marsden J, White M, Annand F, Burkinshaw P, Carville S, Eastwood B, Kelleher M, Knight J, O'Connor R, Tran A, Willey P, Greaves F, Taylor S.

Lancet Psychiatry. 2019 Nov;6(11):935-950. doi: 10.1016/S2215-0366(19)30331-1.

https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(19)30331-1/fulltext

Norwegen. 'The entire pharmaceutical compendium' in the treatment of substance use disorders

Jørg Mørland, Helge Waal

Tidsskr Nor Legeforen 2019, doi: 10.4045/tidsskr.18.0678

https://tidsskriftet.no/en/2019/02/kronikk/entire-pharmaceutical-compendium-treatment-substance-use-disorders

  1. Prediction of Drug-Drug Interactions Between Opioids and Overdosed Benzodiazepines Using Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation.
  2. Reduction of Benzodiazepine Use in Patients Prescribed Medical Cannabis.
  3. An Approach to Evaluate the Effects of Concomitant Prescribing of Opioids and Benzodiazepines on Veteran Deaths and Suicides.
  4. Originalarbeit: Problematische Medikation von Benzodiazepinen, Z-Substanzen und Opioid-Analgetika - Analyse von Verschreibungsdaten der Gesetzlichen Krankenversicherung der Jahre 2006–2016
  5. Considerations for the use of a loading dose of diazepam for the treatment of benzodiazepine dependence.