Academiejaar

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1 Academiejaar Acute recreational drug and new psychoactive substance toxicity in the region of Ghent, Belgium: 12 months data collection A comparative study with the European Drug Emergencies Network (Euro-DEN) Project. Ibolya TÓTH Student number: Promotor 1: Dr. Cathelijne Lyphout Promotor 2: Prof. Dr. Peter De Paepe Master s dissertation submitted to obtain the specialty diploma in Emergency Medicine

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3 Academiejaar Acute recreational drug and new psychoactive substance toxicity in the region of Ghent, Belgium: 12 months data collection A comparative study with the European Drug Emergencies Network (Euro-DEN) Project. Ibolya TÓTH Student number: Promotor 1: Dr. Cathelijne Lyphout Promotor 2: Prof. Dr. Peter De Paepe Master s dissertation submitted to obtain the specialty diploma in Emergency Medicine

4 Acknowledgements I would like to thank my promotor, Dr Cathelijne Lyphout, from the bottom of my heart for the support and the guidance that she has offered me throughout this project. Without her patience and enthusiasm this project would not have been finished on time to the desired results. I would also like to show my gratitude and deepest respect to Prof Dr Peter De Paepe, my copromotor. In my eyes, his ideas made this project grow and they made me develop further throughout this intensive working process. Thank you to all my doctor colleagues from the emergency department of the University Hospital of Ghent for the consistent execution of the registrations that were indispensable for this master's dissertation. Special thanks to Mr Jeroen Deconinck and to Ms Anja Mariën, for their help in collecting the data from a complicated database. Furthermore, many thanks to drs. Anne-Marie Descamps, who helped me make this project more complete by adding valuable last minute data to my database and to Ms Alison Dines, the key contact person between me and the Euro-DEN project, for timely sharing the whole European dataset, knowing that I am working against a tight deadline. Last but not least I would like to shout out the warmest thank you to my other half who supported and helped me through this roller coaster of my life not letting me give up and with his inexhaustible love made me once more a better person. I dedicate this master s dissertation to my unborn child who stayed up long sleepless nights with me without causing any trouble.

5 Table of Contents Abstract... 3 Objective... 3 Methods... 3 Results... 3 Conclusion Introduction Global literature review Classical recreational drugs Novel psychoactive substances The Euro-DEN and the Euro-DEN Plus network The Euro-DEN network Euro-DEN Plus Network Methods and materials Definition and purpose of the study research Methods Case definition Definition of a recreational drug Identification and recruitment of patients Inclusion criteria Case exclusion criteria Data collection Demographic and outcome details Clinical features and initial vital signs Treatment Analytical drug screening methods Ethical approval The Belgian healthcare system: the insurance status and compensation eligibility of patients Results Number of presentations reported Demographics Time and date of presentations Drugs of abuse reported Toxicology screening Clinical features and recorded observations Treatment Outcomes Fatalities The patient s insurance status and reimbursement entitlement Discussion with comparison of Ghent University Hospital and the global Euro-DEN Plus centres cohorts Number of presenting patients Demographics Time of presentation Patterns of drugs associated with presentations (reported substances) Analytical confirmation Clinical features and parameters Treatment

6 4.8 Outcomes Patient s insurance status Limitations Future perspectives Conclusions List of abbreviations References Nederlandse samenvatting Doelstelling Methoden Resultaten Conclusie Appendices Appendix 1: Pre - formatted Excel spreadsheets Appendix 2: Copy of the informed consent (in Dutch) Table of Figures Figure 1 - The number of new substances detected each year... 9 Figure 2 - Location of Euro-DEN Plus centres before the approval of the Ghent University 14 Figure 3 - Presentations by age and gender - Ghent Figure 4 - Time of presentations Figure 5 - Presentations by day of the week Figure 6 - Most common reported drugs Figure 7 - Analyticel confirmation Figure 8 - Range of lactate (mmol/l) Figure 9 - Clinical features Figure 10 - Most frequently received treatment Figure 11 - Outcomes Ghent Figure 12 - Length of stay in hours Ghent Figure 13 - Compensation status of presentations with recreational drug use in UZGhent Figure 14 - Number of presentations per centre Figure 15 - Percentage of recreational drug users per ED attendances Figure 16 - Percentage of drug users in ED presentations per country Figure 17 - Most frequent seized drugs across Europe Figure 18 - Ten most common NPS in Europe Figure 19 - Lowest concious level Ghent Figure 20 - Length of stay in hours across Europe

7 Abstract Objective Recreational drug use and toxicity is a rapidly expanding problem with serious consequences and increasing death rates in Europe. Despite the potential for recreational drugs to cause significant morbidity and mortality, there was no standardised routine collection of data on acute recreational drug toxicity or hospital presentations at a national level in Europe. This is why the Euro-DEN project was founded in The University Hospital of Ghent joined the Euro-DEN project to gain insight into the impact of recreational drug use on the emergency services, to provide reliable evidence of the extent of recreational drug use and to gain a global view of the clinical and demographic features of these patients. Independent from the Euro-DEN project, the socio-economic origin of this population was analysed, relying on their insurance and high compensation status. Methods Presentations to the Emergency Department (ED) related to acute toxicity from recreational drug use between January 2017 and December 2017 were registered through a prospective data collection from the electronic medical records of the University Hospital of Ghent. A descriptive, comparative study was done to establish demographics, clinical features, treatment and insurance status of the presenting patients. Results There were 152 presentations identified with recreational drug use, constituting 0.45% of the total ED presentations. Men (73.03%), and the age group of years (52.63%) had the highest incidence. Single drug use was recorded in 52.6% of the presentations. The most commonly detected recreational drug was cannabis (18.9%), closely followed by cocaine (18.5%), MDMA (14.3%) and amphetamines (7.9%). There were two presentations with NPS use (1.31%). Alcohol was co-ingested in 53.3% of the cases. A total of 94 presentations (61.8%) were brought to the ED by ambulance. Treatment was given to 72.4% of the recruited population, 34.2% was admitted to the hospital, with most admissions to a specialised psychiatry ward (25%) followed by 7.9% admissions to the critical care unit. Two (1.31%) patients died. Analytical screening and confirmation was performed in 72.4% of the presentations, confirming the self reported drug in 89.09% of cases. Out of the total cohort, 3

8 94.7% had a healthcare insurance, 33.6% of the presentations were entitled to increased compensation and 5.3% had no insurance. The results of this registration regarding demographics and clinical features are comparable to the European cohort. There were some similarities between the treatments given across Europe and in our centre, but likely due the high incidence of heroin use identified in the global Euro-DEN cohort, which was significantly less in our centre, the treatment pattern differed. Similarly, we identified more intoxications with stimulant drugs like cocaine, amphetamines, methamphetamines and MDMA in our centre compared to the other sentinels. Conclusion By joining the Euro-DEN Plus project our centre is contributing to a better understanding of recreational drug use epidemiology, envisaging the design of more synergetic, dynamic and cost-effective interventions. Data on 152 presentations over a 12-month period provide a firsttime insight into acute recreational drug toxicity presentations in Ghent University Hospital. An improved registration system, ideally with analytical confirmation, could provide a better global overview of recreational drug use and a direct towards more in-depth research. Keywords: Recreational drug; acute recreational toxicity; Euro-DEN Plus project; insurance status Word count in this master s dissertation:

9 1 Introduction 1.1 Global literature review Addiction to drugs and alcohol is increasingly becoming a worldwide trend in lifestyle that is prevalent in rich and poor countries alike. Addiction to alcohol, drugs and cigarette smoking is now regarded as a major public health problem 1,2. Beyond that, recreational drug use is becoming more and more common all over the world. 1,3,4 According to the world drug report from 2017, it is estimated that a quarter of a billion people, between the ages of 15 and 64 years, or around 5% of the global adult population, used drugs at least once in More worrisome is the fact that about 29.5 million of those drug users, or 0.6% of the global adult population, suffer from drug use disorders 5. This means that their drug use is harmful to the point that they may experience drug dependence and require treatment. In comparison with the data from the 2004 World Drug Report (reporting on ) 6, when it was estimated that about 3% of the global population (185 million people) consumed illicit drugs annually, there is an increase in global drug use of at least 2%. More than 93 million or just over a quarter of 15 to 64-year-olds in the European Union are estimated to have tried illicit drugs during their lives 4,7. While opioids continue to be the most troublesome and deadly drugs of abuse worldwide (an estimated minimum of 190,000 in most cases avoidable premature deaths from drugs in general, the majority attributable to the use of opioids 5 ), other drugs of abuse are more and more frequently used and abused all over the world. For example, cocaine use appears to be increasing in the two largest markets, North America and Europe, with markedly increasing drug overdose cases between 2012 and 2015 (globally, DALYs disability-adjusted life years attributed to cocaine use disorders increased from 729,000 in 2005 to 999,000 in ). Over the last decade, there has also been an increased availability and usage of cannabis and novel psychoactive substances (NPS, also known as legal highs ) 8. The illicit manufacture of opioids and the availability of numerous research opioids, which were first synthesized in the 1970s and have structures distinct from those used in medical practice, are now posing serious public health concerns, in particular with the use of a combination of different opioids and other psychoactive substances 5. In many regions, an increasingly complex relationship between the use of heroin and synthetic opioids is being observed 3,5. 5

10 1.2 Classical recreational drugs Currently, the most concerning drug problem in the world 1 and particularly in Europe is still represented by the classical recreational drugs of abuse, which are considered illegal in most parts of the world. The UK, considered to have the highest rates of recorded illegal drug misuse in the western world, has comparatively high rates of heroin and crack cocaine use 9. Generally, the most commonly used drugs in Europe are cannabis, followed by cocaine, 3,4- methylenedioxymethamphetamine (MDMA), and amphetamines 7,10. However, levels of lifetime use differ considerably between countries 7,10. Substances that are considered harmful are strictly regulated according to a worldwide accepted classification system 11 that takes into account the harms and risks of taking each drug 9. According to recent studies among the population of young adults, the use of prescription drugs (eg. methylphenidate and modafinil) and recreational illicit drugs like cocaine and amphetamines are also used to improve performance while studying 12,13. However, the initiation of the use of these substances is reportedly to induce euphoria, a feeling of reward and of a state of well-being 2. Considering the global growth of recreational drug use 1,3,4,5, identifying and responding to localised patterns of stimulant use and related harms should be given greater priority 10. According to the 2017 Global Drug Report, the magnitude of the harm caused by drug use is underlined by the estimated 28 million years of healthy life (DALYs) lost worldwide in 2015 as a result of premature death and disability caused by drug use 3,4,5. Of those years lost, 17 million were attributable solely to drug use disorders across all drug types 3,4,5. The 2017 European Drug report highlights some potentially worrying changes in the market for illicit 14 recreational drugs, substances that continue to be associated with a high level of morbidity and mortality in Europe 14,15. We note an overall increase in opioid-related overdose deaths as well as increasing reports of problems linked with opioid substitution medications and new synthetic opioids 4. Only a few countries have monitoring systems in place that allow an analysis of trends on a national scale in acute drug intoxications. From these registrations, it was found that acute heroin emergencies have increased in the United Kingdom 4,16, but continued to decline in the Czech Republic and Denmark 4, where methadone emergencies are increasing 4. In Lithuania, opioid-related emergencies almost doubled between 2013 and In Spain, cocaine is involved in about half of the reported drug-related emergencies, and the trend is stabilising after a decline, while cannabis emergencies are continuing to increase 4,14. Slovenia also reports an upward trend in cannabis emergencies 4,15. In the Netherlands, half of the cases presenting at first aid stations at festivals (51 %) involved 6

11 MDMA and the proportion is decreasing. Methamphetamine-related emergency cases, recorded by sentinel centres in the Czech Republic, increased by more than 50 % between 2014 and In Belgium, 10.1% of young adults used cannabis in 2016, however there is no data regarding high-risk opioid, MDMA, amphetamines or cocaine use in the same age-group (15-34 years) according to the 2017 Country Drug Report 17. Recent findings from wastewater analysis match seizure and survey data 4,10, all highlighting regional differences in stimulant consumption patterns across Europe 10. Two Belgian cities (Brussels and Antwerp) participated in the Europe-wide annual wastewater campaigns 18 undertaken by the Sewage Analysis Core Group Europe (SCORE). This study provides data on drug use at a community level, based on the levels of illicit drugs and their metabolites in sources of wastewater. The 2016 data indicate an increase in the levels of MDMA between 2011 and Levels of methamphetamine residues were very low. The levels of cocaine were higher in Antwerp than in Brussels, and the concentration of cocaine metabolites increased at the weekends in both cities 4,17. These findings and particularly the lack of data on recreational drug related toxicity and use/abuse in Belgium has been the main reason of our centre at the University Hospital of Ghent to join the Euro-DEN network. Although the Euro-DEN network project (presented in detail further on in this paper) was focussing on novel psychoactive substances and the effect of these recreational drugs, our centre aimed at widening this objective to get a view on global recreational drug use around the Ghent area (including NPS, classical (illicit) and prescription drug misuse). There were hardly any reports, researches or data collections earlier regarding drug use and abuse in Belgium outside the Euro-DEN centres. Although the VAD (Vlaamse expertisecenrum voor Alcohol en andere Drugs - Flemish Expertise Centre for Alcohol and other Drugs) is continuously analysing and updating the general Belgian status about drug use and abuse, there is still scarce national information available for healthcare professionals about use of many of the classical illegal recreational drugs. There is somewhat more detailed information available about cannabis and cocaine 19 use in the country but only general knowledge about the rest of the classical recreational drugs (heroin, MDMA, amphetamines etc.). Since the amendment of the law in 2003, a distinction has been made for adults between cannabis and other illicit drugs 20. Cannabis remains an illegal drug but adults are legally 7

12 allowed to possess up to 3g of cannabis or one cultivated plant (not both at the same time) for personal use only. Any other classical recreational drug use (cocaine, heroine, MDMA, amphetamines etc.) remains illegal in Belgium. As a consequence, anybody caught in possession of these drugs will be legally prosecuted according to the Belgian law. 1.3 Novel psychoactive substances Novel psychoactive substances (NPS) have been defined by the United Nations as new narcotic or psychotropic drugs that are not controlled by the United Nations 1961 Single Convention on Narcotic Drugs or by Psychotropic Substances Conventions 21, 22. In September 2017, the Belgian legislation reinforced the law regarding novel psychoactive drugs, following several other countries. In the amendment of the new Royal Decree, a number of groups of psychoactive substances (amphetamine, cathinone, tryptamine, piperazine, synthetic cannabinoids and fentanyl) are brought under the drug law based on their basic chemical structure 23,20. The Royal Decree amends the legislative framework for gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) 23. These substances are converted into gamma-hydroxy-butyric acid (GHB or the so-called liquid XTC), a psychotropic substance, susceptible to abuse by individuals and with a potential danger to the health of the user after ingestion. As a result, customs, police and judiciary have a legal basis to determine infringements, take and prosecute offenses regarding all substances containing the substances above. The number of detected novel psychoactive substances (NPS) in Europe has reached a historic peak in the last years 24. The NPS market proves to be very dynamic and is characterized by the emergence of large numbers of new substances belonging to diverse chemical groups. Between 2009 and 2016, 106 countries and territories reported the emergence of 739 different NPS to the United Nations Office on Drugs and Crime (UNODC) 5. These reports obviate a significant change in the use of recreational drugs in the last 5-10 years with increasing availability and use of a range of different NPS 25, 26. By the end of 2016, the EMCDDA was monitoring more than 620 new psychoactive substances that have appeared on Europe s drug market. Although these recreational substances are becoming illegal to use in more and more countries, not all of them are covered by international drug control convention 27 and make up a broad range of drugs such as synthetic cannabinoids, 8

13 stimulants, opioids and benzodiazepines 4 (Figure 1). Currently, new substances are identified in Europe at a rate of one or more per week 14. Figure 1: The number of new substances detected each year: of the 620 new substances currently monitored, 423 (70 %) were detected on the drug market in 2015; this compares with 365 in 2014 and 299 in 2013 (illustrating how complex this market has become) 4 NPS availability and supply is highly complex and volatile. New products are continually introduced and a global network of suppliers, distributors and vendors ensures a constantly adjusting market space. Technological advances have lowered, if not eliminated, barriers to diffusion of NPS knowledge and properties. 28 Although NPS are marketed in numerous different ways and forms 29, many of them stay on the market for a very short period of time before they disappear without a trace. Based on the known inconsistencies in packaging both from an ingredient and drug concentration perspective, according to a study recently performed in the UK 30, it is likely that many users are not aware of the type and dose of drugs being used; and subsequently are at risk of 9

14 adverse health effects 30. Also, the vast majority of the patients treated for recreational drug toxicity and suspected to have used novel psychoactive substances have also taken classical drugs 31. As the number of different NPS is ever increasing, even extensive laboratory screenings fail to keep up, and some substances will go undetected 28. A number of countries have included NPS in their general population surveys 25, although different methods and survey questions limit comparisons between countries. Gold standard evidence (such as animal studies or human clinical trials) regarding the pharmacokinetics and pharmacodynamics of the novel psychoactive substances, interaction with other substances, toxicity, treatment etc. is rarely available 8,21. This is a problem both for healthcare professionals and users. These substances are often labelled as not for human consumption in order to evade legal restrictions and therefore do not include information to the intended user on their potential unwanted effects 8. Additionally, marketing as legal highs 24,32 or herbal highs may suggest to users that these compounds are less likely to be associated with the same acute toxicity as that seen with the use of established recreational drugs 8. Therefore, an accurate description of the pattern(s) of acute toxicity following human use of these NPS, signs, symptoms and drug interactions is needed; not only for the healthcare professionals dealing and treating these patients, but also to the authorities, who could then ensure an appropriate control of these substances. Although the market and the substances are changing constantly, there are a number of potential data sources that can provide useful information on the acute toxicity associated with their use 33. These sources are as follows: (1) user reports on Internet discussion fora; (2) subpopulation level surveys of self-reported harms/unwanted effects (3) regional or national poisons information service accesses for support on presentations to healthcare facilities relating to acute toxicity; (4) case reports/series based on self-reported use or analytically confirmed use; and (5) human volunteer studies assessing potential acute toxicological effects 8,33. These data sources all have their own limitations, particularly the ones based on a selfreported use. National and international population level surveys, such as the British Crime Survey, European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) annual report and the UNODC annual World Drug Report collect detailed data on the prevalence of use of illicit 10

15 and established recreational drugs, but they have very limited data on the use of novel psychoactive substances 8. Similarly, the national hospital admission datasets (such as for example the UK Hospital Emergency Statistics), which are based on international coding systems, like the ICD 10 (International Classification of Diseases Version 10) are not detailed enough to identify presentations related to novel psychoactive substance-related acute toxicity 8,34,35. The yearly European Drug Reports highlight changes in the market of illicit opioids, synthetic opioids and other illicit classical drugs but they still provide limited information on the evolution of new psychoactive substances. Furthermore, we are aware of different local and national reports all over in Europe regarding intoxications and occasionally death reports due to new psychoactive substances. For example in Belgium, healthcare professionals are continuously informed through The Belgian Early Warning System on Drugs (BEWSD), the drug monitoring system of the Scientific Institute for Public Health (Sciensano), regarding potentially dangerous or deathly drugs which appear on the market. For example, in September 2017 healthcare professionals were informed about a death case of a young adult due to U (a novel NPS opioid, at that moment still legal in Belgium) and 3-MeO-PCP (a hallucinogenic dissociative substance that is illegal in Belgium) 36. The only overarching European report has been the one from EMCDDA. However, there is a still need of a cumulative force in Europe with good communication and proactive teamwork between countries to identify the pattern of the NPS s as the number of them available in the illegal market was increasing. By using data triangulation from a number of different sources 8,33, an overall picture of the pattern of toxicity associated with an individual novel psychoactive substance was developed, which then reduces the impact of the limitations of any individual data source 8,33. Before the data triangulation for novel psychoactive substances was adopted, the drug monitoring body in Europe was reporting data mainly on classical drugs of abuse, but with limited emphasis on clinical presentation in the ED regarding classical drugs. Given the substantial development of the market 29 of different new (or novel) psychoactive substances and the fact of having scarce information regarding illicit drug use and abuse (including NPS s) presenting in the ED, the EU Drugs Strategy stated that new approaches to improve the knowledge of drug-related adverse consequences and assess the risks associated with drugs in general, and NPS in particular, were required 25. One of the 11

16 components of the EU Drug Strategy was to ensure a reduction in health harms 37,38 caused by drugs in Europe 25. Following these requirements, The European Drug Emergencies Network (Euro-DEN) was founded in This project was initially funded by the European Commission DG Justice DPIP. The Euro-DEN was a European Commission-funded project that aimed to improve the knowledge of acute drug toxicity of both classical recreational drugs and NPS 39. To set a baseline for this project, a study was performed to establish which data were already being collected and reported in Europe on ED presentations with acute toxicity related to NPS and classical drugs of abuse 40. The study involved a literature review together with a survey of the EMCDDA National REITOX Focal Points 41. ( Réseau Européen d Information sur les Drogues et les Toxicomanies ). REITOX links national drug information systems and is the main way in which the EMCDDA exchanges data and methodological information on drugs and drug addiction in Europe 41. REITOX directly contributes to the EMCDDA s core task of collecting and reporting consistent, harmonised and standardised information on the drug phenomenon across Europe 41. The report of the study at the baseline of the Euro-DEN network showed that data on a number of drugs related indicators were collected at the national level, and reported to and collated by the EMCDDA and the UNODC. These two institutes collate national data on key indicators such as drug-related deaths and attitudinal data related to drug use and report these in an annual report and other publications. However, this included limited data on acute toxicity with recreational drugs and NPS as not a single robust source of information existed regarding this matter The Euro-DEN and the Euro-DEN Plus network As the systematic collection of data on ED presentations of toxicity related to NPS and classical drugs in Europe was scarce and the collection of data was highly variable between the different countries, the Euro-DEN project was founded with the aim of closing some of these gaps 40. The Euro-DEN and the Euro-DEN Plus project is now supported by the EMCDDA, and it involves the collection of data on ED presentations with acute drug toxicity from more and more centres in Europe. The Euro DEN Steering Group developed a minimum dataset to enable capture of the key demographic, clinical and outcome variables in presentations with 12

17 acute recreational drug and NPS toxicity to the ED 25, which will be used in this study to document local patterns and feed into the Euro-DEN network. The objective of the original activity was to develop a representative minimum dataset to be able to identify, monitor and respond to new trends and patterns of adverse consequences related to the use of drugs and NPS The Euro-DEN network The Euro-DEN was established in October 2013 to collect data on presentations to ED across Europe with acute recreational drug toxicity 39. Initially there was a network of 16 volunteering sentinel centres in 10 European countries, collecting data between October 2013 and September 2014: Estonia (Tallinn, Parnu), France (Paris), Germany (Munich), Germany (Munich), Ireland (Dublin and Drogheda), Norway (two centres in Oslo), Poland (Gdansk), Spain (Barcelona, Palma de Mallorca), Switzerland (Basel) and United Kingdom (UK) (York and two centres in London) 39,42. The 16 sentinel centres had a specialist clinical and research interest in acute recreational drug toxicity and collected data using the Euro DEN minimum dataset on all acute drug toxicity presentations to their ED over a 12 month period (October 2013 September 2014) 25, Euro-DEN Plus Network Given the usefulness and necessity of a cumulative data collection and data analyses (based on the Euro-DEN Network), more centres were recruited to increase the value and representativeness of this European data. The project aims at providing more detailed information on the harms associated with the use of both established drugs and new psychoactive substances. The EMCDDA supports the continuation of the network s activities. This is how the initial Euro-DEN network expanded under the name of Euro-DEN Plus to 31 centres in 21 countries (Figure 2). The methodology for data collection, utilisation of a minimum dataset for data collection and the inclusion criteria for cases in the Euro-DEN Plus project have been previously described in the Euro-DEN project 25,39. 13

18 Figure 2 - Location of Euro-DEN Plus centres 4 before the approval of the Ghent University ED Although not yet shown on the map above, our centre, the ED of the University Hospital of Ghent, successfully joined this wide networking system in 2017 with the purpose of reinforcing the network and to target areas where specific drug-related harms are continuing to raise concerns. With a special interest in toxicology, the ED of Ghent University Hospital became one of the two centres in Belgium collecting data on acute toxicity of recreational drug use. 2 Methods and materials 2.1 Definition and purpose of the study research The objective of this thesis is to provide an overview of the patients presenting with acute recreational drug toxicity to the ED of the University Hospital of Ghent following the standard operating procedure of the Euro-DEN Plus network. It aims to describe the prevalence of patients presenting with recreational drug intoxication in the ED. This includes epidemiology of ED presentations related to recreational drug use, clinical features at the time of presentation, treatment and analytical confirmation of the used substances when clinically indicated. 14

19 Furthermore, it looks into the insurance status of the patients, which is influenced by several socio-economic factors. This status determines how patients or insurance companies fulfil repayments of treatments using the Belgian insurance coding system. The University Hospital of Ghent, being one of the only two centres in Belgium collecting data regarding recreational drug intoxication, also aims to highlight local characteristics of patients presenting with recreational drug toxicity. 2.2 Methods We conducted a prospective, descriptive, comparative study at our University Hospital to identify cases involving the self-reported use (misuse) of classical recreational drugs and/or new psychoactive substances with or without alcohol, over a 12-month period between January 2017 and December The results were compared with the Euro-DEN Plus project results across Europe performed between January 2017 and December A second objective was to analyse the insurance status of the patients according to the Belgian insurance coding system, as a proxy for socio-economic status. 2.3 Case definition For the purpose of data collection in accordance with the Euro DEN Plus project, the following case definition was used: An individual who presents to participating acute care facilities with symptoms and/or signs consistent with acute recreational drug toxicity and/or directly related to recreational drug use. Patients with a primary diagnosis of isolated ethanol intoxication will be excluded (although those who co ingest ethanol and present with recreational drug toxicity will be included) 4,25, Definition of a recreational drug A recreational drug was defined as a psychoactive compound that was taken for the purpose of recreational activities rather than for medical or work purposes or as part of (deliberate) self-harm 4,25,39. The following type of drugs, substances were included in this project: 15

20 - classical recreational drugs - new (novel) psychoactive substances (NPS) - plants, fungi, spices or herbal/alternative medicines - use of prescription and over the counter (OTC) medicines for recreational purposes - use of industrial and/or domestic products (i.e. solvents, propellants etc.) for recreational purposes. 25 The identification of the recreational drug(s) associated with the presentation was based on one or a combination of the following: - the patient s self - reported use; - information retrieved from witnesses; - the opinion of the physician assessing the patient; - and/or the toxicologist reviewing data entry/case records Identification and recruitment of patients The standard operating procedure (SOP) was written by the lead centre in London to assist the data collection process. In addition to the inclusion/exclusion criteria each data field and the pre determined responses were defined in the SOP. This SOP has been used and respected by our centre during data collection. We recruited our patients via a systematic search within the electronic patient s files. In order to be able to identify the patients, doctors who had initially seen the patients had to specifically indicate acute recreational drug use/toxicity in a newly added section within the patient s electronic file. The automated search used this section to identify potential patients. From this selection, relevant patients were included in the study through a manual screening procedure. A second patient recruitment procedure was performed within the context of another local research project on patterns and costs of all intoxications presenting to the ED in , based on systematic searches within the electronic patient files and billing information. Both of the databases were compared and additionally identified patients were added to the registration. 16

21 2.4.1 Inclusion criteria 25 Any case in which a patient had symptoms and/or signs consistent with acute recreational drug toxicity and/or directly related to acute recreational drug use was included in the data collection. This included patients who presented to the ED because of concerns about an acute episode of drug use or who had been unwell prior to attendance to the ED (e.g. seizures in a nightclub) even if they had no clinical signs at the time of examination. The clinical symptoms the patients described or that they were witnessed to have experienced were recorded Case exclusion criteria 25 A patient who attended the ED with any of the following presentations was excluded from the data collection: - Lone alcohol ingestion or intoxication, including cases involving spiked drinks (i.e. drinks to which it is alleged a substance has been maliciously added) where patients had no symptoms of acute recreational drug toxicity. - Symptoms and signs consistent with an alternate medical diagnosis and not related to acute recreational drug toxicity. - Injury related to trauma, unless the trauma was directly related to drug use e.g. as a result of hallucinations. - Drug or ethanol withdrawal. - Secondary complications of chronic drug use (e.g. infected injection sites, viral infection (HIV/HBV/HCV), endocarditis) and no evidence of acute recreational drug toxicity. - Secondary complications of previous acute drug use complications (e.g. previous stroke secondary to hypertensive intracranial haemorrhage, presentation with aspiration pneumonia). - An individual transferred through the ED for care to other areas of the participating centres (e.g. intensive care, surgery etc.) and not for a primary ED evaluation. 17

22 2.5 Data collection The data collection in our centre was performed between January 2017 and December We collected the minimum dataset in agreement with the Euro-DEN Plus project on each patient presenting to the ED of the University Hospital of Ghent, which met the inclusion criteria. Data were collected according to the pre - formatted Excel spreadsheets circulated bi - monthly by the lead centre in London. To ensure consistency most cells had a dropdown menu from which specific answers were selected (see appendix 1). Free text entry was used for the agent s name, the additional clinical observations and the laboratory analysis; there was also a free text field for any additional comments about the case Demographic and outcome details The demographic data of the study collected the date and time of presentation of the patient. The time of discharge and length of stay was separately recorded. We included the gender and age of the patients presenting with recreational drug use. The means of transport to the hospital were also recorded (brought in by ambulance, friends, self presented etc.). The outcome and the place of discharge of the patients were recorded separately. Whether the patient died in the hospital or not has also been individually recorded. The declared type of drug consumption was recorded, as well as whether this has been consumed in combination or not with alcohol Clinical features and initial vital signs This includes collection of the clinical features and vital signs at the time of presentation. The recorded vital signs were body temperature, conscious level, heart rate, blood pressure, respiratory rate and measurement of the lactate. 18

23 Clinical features: Vomiting Headache Hallucination Psychosis Cerebellar features Chest pain Arrhythmias Hyperthermia Anxiety Agitation/aggression Seizures Palpitations Hyper/hypotension Lowest conscious level Treatment The treatment received before and/or in the hospital, the type of sedation - if applicable -, administered antidotes and the analytical test results were recorded separately Analytical drug screening methods As a screening tool for drugs of abuse in the serum/plasma or urine, our centre uses an automated immunoassay test. Most of the analyses are performed with the Indiko Plus Clinical and Specialty Chemistry System (Thermo Fisher Company) 44. Different measurement types are used depending on the substance. The CEDIA (Cloned Enzyme-Donor Immunoassay Technology) method is used to identify amphetamines, methamphetamines, cocaine, cannabis, benzodiazepine, LSD, opioids and methadone (not routinely screened) in the plasma/serum. GHB is screened via enzymatic spectrophotometric measurement instead of the CEDIA technique. At the University Hospital of Ghent the Architect c8000 (Abbott Diagnostics) test is also used for screening for amphetamines, cannabis and cannabinoids, cocaine, methadone and opioids in the urine. These are tests based on absorbance measurements, not on immunoassays. When a screening assay is positive, the results are confirmed with an independent technique (eg GC-MS, HPLC-UV, LC-MS). On specific retrospective highlight from the ED consultant or treating physician further tests are done to detect NPS, with advanced analytical techniques, including multi-component liquid chromatography tandem mass spectrometry (LC-MS/MS) and high-resolution MS. Additional activity-based screening (a powerful and better alternative for regular antibody- 19

24 based screening assays) was done on clinical indication when LC-MS/MS and high-resolution MS yielded no result Ethical approval Contrary to the other Euro-DEN centres, the ethical committee required our centre to obtain informed consent for all eligible patients via opting-out. A copy of this informed consent (in Dutch) is shown in Appendix 2. All data was anonymised before analysis and data transfer to the Euro-DEN project. 2.7 The Belgian healthcare system: the insurance status and compensation eligibility of patients The Belgian healthcare system provides high coverage for patients but one needs to have state or private health insurance (i.e. a healthcare fund or the Auxiliary Illness and Disability Insurance Fund 46 ) to access it and claim Belgian healthcare refunds either as a policyholder or a dependant. 47,48 This system is divided into state and private sectors, with fees payable in both, funded by a combination of Belgian social security contributions and health insurance funds. After joining one of the organisations, one will be able to receive various allowances, for example: refunds for consultations with a doctor, fixed allowances for hospitalisation, the payment of allowances in the event of being unable to work or pregnancy/maternity. The payment of medical services usually requires the patient to pay for each individual consultation or treatment upon presentation of their eid card, before submitting a claim to the relevant insurance company in order to reclaim part of the cost. In most instances, up to percent of the cost can be claimed back through the Belgian health insurance, with the patient responsible for covering the rest of the fee. However, for some patients circumstances may be different and they will be paying less 48. One must join a health insurance fund when: - is over 25 years of age - is under 25 years of age and working - is under 25 years of age, unemployed and receiving benefits 20

25 Although the health system and the healthcare compensations are very well defined in Belgium, there are still people with low income who could be living in poverty. Poverty is described as: - a lack of resources - social exclusion - an accumulation of exclusions 49 The definition of the poverty level in Belgium is changing each year, and the limit is adjusted yearly according to the family s situation. In % of the Belgian population was considered at risk group for monetary poverty. This concerns people who live in a household with a total income of less than 1,139 per month ( netto income per year) for a single person 50. These people benefit from a higher health insurance compensation. According to the 2017 EU-SILC (European Union Statistics on Income and Living Conditions) statistics % of the general population of Ghent had the benefit of this increased compensation. In 2017, there were year-olds who received a higher compensation from the health insurance funds in Ghent, which constitutes of 20.7% of the 0-24 year-olds in the municipality 51. In the group of 25 to 64 year-olds, 14.5% (21.020) received higher compensation in the municipality 51. A total of (27.2%) people aged 65 and over benefited from the same welfare 51. The international treaties ratified by Belgium have generated an abundance of insurability codes starting with CG1 followed by CG2. These codes indicate the reason of cover in Belgium as well as the country of origin of the patient. The number of possible combinations of CG1 and CG2 is very high. The values of CG1 and CG2 define the insurance status of an individual, hence they determine the reimbursement of medical care. The care provider can invoice correctly on the basis of the value of these codes. The CG1 / CG2 codes contain three figures, the third of which relates to obtaining a preferential treatment: 0 = no right to an increased allowance, 1 = entitlement to an increased allowance. 52 This study looked into the insurance status and increased reimbursement eligibility of the recruited patients and compared it with the general population statistics of Ghent and the province of East-Flanders. 21

26 3 Results 3.1 Number of presentations reported In 2017, the first year of data collection at Ghent University Hospital, there were 152 reported cases with recreational drug toxicity during the 12-month data collection period (114 patients via the prospective registry and 38 patients via the additional selection process). The total number of patients presenting in the ED of the University Hospital of Ghent in the same year was This makes an average presentation of patients with recreational drug use of 0.45%. Furthermore, the number of presentations varied monthly as shown in Table 1. Month Total no. of patients in ED No. of cases in the study % of patients January % February % March % April % May % June % July % August % September % October % November % December % Total % 0.39% mean median Table 1: The number of cases reported in 2017 at Ghent University Hospital per month 3.2 Demographics The age and gender breakdown of the patients presenting with recreational drug toxicity is shown in Figure 3. There were no patients with unknown age within the 152 included patients. The age of all patients was identified relying on a valid identity card. The majority of the presenting patients were male (73.03%, 111/152). The age ranged between 14 and 85 years old. The median age in males was 26 years (IQR= 22-34), and 29 22

27 years in females (IQR= 23-37). The youngest patient (14 years) was a first-time cannabis user, male patient, while the oldest patient was an 85 years old female benzodiazepine user with recreational purposes. Figure 3 - Presentations by age and gender UZGhent (University Hospital Ghent) 3.3 Time and date of presentations Two separate figures (Figure 4 and Figure 5) show the time and the day of the week on which patients have presented in ED with acute recreational drug toxicity. The peak time of presentation is between 04:00 and 06:00 o clock. The fewest presentations were recorded between 10:00 and 14:00 o clock, with 62% (94) of the patients presenting between 20:00 and 08:00 o clock. Most presentations occurred on Saturdays (19.1%, 29/152) and least on Wednesdays (9.9%, 15/152). A slight peak is noticed on Thursdays (14.5%, 22/152). The highest number of presentations was recorded in March (15.1%, 23/152), the lowest in December (3.9%, 6/152). 23

28 Figure 4 - Time of presentations Figure 5 - Presentations by day of the week 3.4 Drugs of abuse reported Overall, there were 40 different substances reported by patients presenting with acute toxicity of recreational drug use, this excludes the agents that patients couldn t name (e.g. white powder, some pills ). The most frequent agents are shown in Figure 6. 24

29 Figure 6 - Most common reported drugs The group of other contains all the drugs that patients have taken with recreational purposes but according to the international classification are not classified as recreational drugs (e.g. TCA s, antibiotics, testosterone). Out of the 40 different agents, the most frequently reported ones by patients in our centre were cannabis (18.9%, 50 occurrences out of 265 documented agents, as some patients have taken more than one substance) and cocaine (18.5%, 49 occurrences). Cannabis, cocaine and MDMA together represent 51.7% of the total occurrences of substances reported by patients. Other than cannabis, cocaine and MDMA, patients reported to have taken amphetamines (7.9%), GHB (7.9%), benzodiazepines, methadone, heroin, ketamine, LSD, caffeine, PCP, magic mushrooms, morphine, norketamine, procaine, 2C-B and other or unknown drugs. According to our data, there were very few patients (2/152) presenting with NPS use in Ghent University Hospital. The mean number of drugs used by a single patient was 1.74 (SD 1,0), with 52.6% (80/152) patients using a single drug, 30.9% (47/152) using two different drugs, 8.6% (13/152) using three agents and 7.9% (12/152) using more than three drugs at the same time. 25

30 In this registry, 53.3% (81/152) of the patients co-ingested alcohol with the use of recreational drugs, 46.1% (70/152) denied alcohol use and in 0.7% (1/152) of the cases this information was not recorded. 3.5 Toxicology screening A laboratory toxicology screening was carried out in 72.3% (110/152) of the cases in our centre, 27% (41/152) of the cases have not been tested and 0.7% (1/152) of the cases have no records of being tested (Figure 7). Despite presence of clinical features of intoxication and reported ingestion of recreational drugs, no analytical screening was done in a number of patients. Out of the 110 patients in which toxicological screening was performed, 89.1% (98/110) had an analytical (blood or urine) toxicology screening which confirmed the self - reported agent. The remaining 10.9% of the tested patients reported to be taking a certain substance, but the analytical results were positive for a different substance. Figure 7 - Analytical confirmation 3.6 Clinical features and recorded observations The vital parameters at the time of presentation (or the first time that the parameters have been recorded after presenting in ED) of the patients are summarized in table 2 below. 26

31 Vital parameter Number of presentations recorded (%) Number of presentations with observations > predefined upper limit Number of presentations with observations < predefined lower limit definition N (% total) definition N (% total) Level of consciousness at presentation 152 (100.0%) Not applicable GCS<8/'coma' 10 (6.6%) Heart rate at presentation 144 (94.7%) >120 bpm 19 (13.2%) <60 bpm 8 (5.6%) Blood pressure at presentation 143 (94.1%) systolic >= 180 mmhg 0 (0.0%) systolic <= 90 mmhg 5 (3.5%) Respiration rate at presentation 29 (19.1%) Not applicable <12 per min 7 (24.1%) Temperature at presentation 116 (76.3%) >=39 C 0 (0.0%) Not applicable Lactate mmol/l 68 (44.7%) >1 mmol/l 56 (82.4%) Not applicable Table 2: Recorded observations at the time of presentation and lactate levels Lactate was measured in 44.7% of the patients (68/152) during ED admission, of which 82.4% had an elevated lactate level (56/68) with a range between 1.05 mmol/l (9.45 mg/dl) and mmol/l ( mg/dl) (normal range: mmol/l for this study, or 4.5-9mg/dL). Figure 8 shows a more detailed range of lactate within the group of the tested patients. 76.8% (43/56) of the patients had a lactate level ranging between 1-3 mmol/l (9-27mg/dL), 17.9% (10/56) between 3-10 mmol/l (27-90 mg/dl) and 5.4% (3/56) patients had a lactate above 10 mmol/l (>90mg/dL). Figure 8 - Range of lactate (mmol/l) 27

32 The presence of 15 pre defined clinical features (occurring at any stage before/during the hospital stay) are presented in Figure 9. Figure 9 - Clinical features The most frequently observed clinical feature in patients with recreational drug use was agitation or aggression seen in 32.9% (50/152), closely followed by anxiety (26.3%; 40/152) and palpitations (23%; 35/152). 3.7 Treatment Ninety-four (61.8%) patients were brought to the ED by ambulance or by the ambulance and MUG team (Medische Urgentie Groep; the Belgian Mobile Intensive Care Unit - MICU). In only 1 case, the means of transport was not recorded. Out of all patients presenting in the ED, 72.4% (110/152) received treatment. Figure 10 shows the most frequently received treatments in keeping with the standard circulated spreadsheet. 28

33 Figure 10 - Most frequently received treatment The most frequently used treatment was sedation in 29.6% (45/152) of the cases, 24.3% of this being given in the hospital. Another regularly administered treatment was naloxone in 3.3% (5/152) of the cases, followed by other antidotes in 3.3% (5/152) and flumazenil in 1.3% (2/152) of the cases. Out of the total cohort 3.9% (6/152) of the recruited population required endotracheal intubation. Benzodiazepines are the drugs of choice used for sedation in the pre-hospital setting and in the hospital in our centre, other type of sedatives have not been recorded. Nevertheless, if the patient needed to be intubated, other sedatives have most probably been used but these drugs were not specifically recorded in our database. Other antidotes and treatments (administered drugs/medication) that have been given are presented in table 3. Although not specifically recorded in our database, IV fluids are commonly administered in patients presenting with intoxication in this department. 29

34 Name of antidote (Co)Ingested drug and/or clinical features No. N-acetyl cysteine Paracetamol co-ingestion 1 Activated charcoal Intoxication with unknown substances 1 NaHCO3 Steroids Mixed recreational drug intoxication with cocaine, methamphetamines and benzodiazepines with severe metabolic acidosis Allergic reaction: - mild reaction, only received steroids moderate reaction, received antihistamines and steroids 1 MgSO4 Methamphetamine overdose with prolonged QTc 1 Atropine Severe bradycardia after mix use of amphetamines, procaine and opioids 1 Table 3: Other antidotes and/or treatments received by patients 3.8 Outcomes The majority of patients (89/152, 58.6%) were medically safe to be discharged from the hospital as shown in Figure 11. Figure 11 Outcomes 30

35 Twenty-five per cent (38/152) of the patients have been admitted to the psychiatry ward and 7.8% (12/152) were admitted to the critical care unit. Out of the 12 patients admitted to ITU, nine were male, six have been intubated, of which three in-hospital and three in the prehospital setting. One patient out of these 12 patients who were admitted to critical care has eventually died. The median length of stay in the hospital was 9 hours and 33 minutes (IQR= 3 hours 46 min 19 hours 10 min), with the shortest stay of 9 minutes in the ED and the longest admission spanning over 13 days 10 hours and 39 minutes. Figure 12 shows the average length of stay of the patients in the hospital. The majority of the patients (73.7%) have left the hospital within 18 hours of admission. According to our data there is a slight peak around 16 hours stay in the hospital. Figure 12 - Length of stay in hours Ghent 3.9 Fatalities Two patients out of 152 (1.3%) have died in the hospital. Both patients were male. The first patient was a young 28-year old patient of foreign origin with an important language barrier (no knowledge of English, French, Dutch or German) who had also presented in the department the day before, but then denied any drug use. After an extensive evaluation by a multidisciplinary medical team, the patient was discharged, only to then be brought back by 31

36 his friends in cardiac arrest in less than 12 hours. His blood sample tests were positive for methadone and GHB. The second patient was a 54-year old man who reportedly (by friends) overdosed on amphetamines and opioids (most probably heroin); his analytical tests were positive for amphetamines, opioids and procaine. He was brought in after a witnessed cardiac arrest, was successfully resuscitated and admitted to ICU with severe lactic acidosis and ST-segment depression. This patient died after 17 hours and 38 minutes at the critical care unit. The presumed cause of death was acute cardiac failure with cardiogenic shock The patient s insurance status and reimbursement entitlement Regarding the insurance status and compensation entitlement of the patients, 94.8% (144/152) of our whole cohort has had a valid health insurance, with 61.2% (92/144) not being entitled to high compensation (they were not from an underprivileged milieu). Of the recruited patients, 33.6% (51/144) were entitled to a high compensation reimbursement. Eight (5.3%) patients had no records of a valid health insurance (Figure 13). Figure 13 - Compensation status of presentations with recreational drug use in UZGhent Source: Studiedienst Vlaamse Regering - portaal lokale statistieken Provincies in Cijfers 32

37 4 Discussion with comparison of Ghent University Hospital and the global Euro-DEN Plus centres cohorts This study, being part of the Euro-DEN Plus project, provides a unique insight into the acute harms associated with recreational drugs and NPS in the region of Ghent. Before joining Euro-DEN project, there was no systematic data collection of attendances to the hospital ED related to the recreational use of drugs and new psychoactive substances in Ghent. This represents a significant gap in the understanding of the public health impact of drug/nps use in Ghent and by extension in Belgium. By using a relatively simple data collection tool following the Euro DEN project spreadsheets we tried to demonstrate that a comprehensive picture on the harms associated with drugs and NPS can be collated. 25 This includes demographic information, data on the drugs/nps responsible for toxicity, clinical pattern of toxicity, outcome (length of hospital stay, admission to critical care, mortality) and management of recreational drug/nps presentations. Moreover, we were able to look into the insurance and compensation status of the patients presenting with recreational drug toxicity. We used the insurance status as an indicator of 'social deprivation' with the purpose of investigating the prevalence of the latter within the group of patients who present with recreational drug use. This is a first step towards future research, which could investigate the possibility of a correlation between the financial milieu that patients originate from. 4.1 Number of presenting patients There were 7914 total presentations across Europe at 30 different sentinels. The largest number of patients was recorded in Oslo AEOC (1593/ ), followed by London STH (1040/ ), Dublin (586/no total number of patients recorded), Antwerp (500/36.281). Ghent University Hospital occupies the 17 th place within the 30 sentinels, with 152/33740 presentations (0, 45%) (Figure 14). The total number of recorded patients contributed with 1.9% to the total patient population of the Euro-DEN project in

38 Figure 14 - Number of presentations per centre We note that smaller centres like Prague in the Czech Republic or Sofia in Bulgaria show a higher percentage of recreational drug users, very closely followed by Antwerp. Figure 15 shows the percentage of presentations per centre across Europe excluding Dublin, Paris, Helsinki, Gdansk, Riga and Tbilisi, from which the total number of patients presenting in ED per year was unavailable, so a percentage of presentations related to recreational drug use could not be calculated. Figure 15 - Percentage of recreational drug users per ED attendances

39 In the Czech Republic, high-risk drug use is mainly linked to the use of home made methamphetamine, known locally as pervitin, which is usually injected. 53 It is estimated that in this particular country there are primary methamphetamine users, while approximately people are mainly heroin or other opioid users. 53 This could be one of the reasons of the high prevalence of recreational drug use in Prague/Czech Republic. Although the number of presenting patients in different departments are not necessarily representative for a certain city or country, one could assume that the proportion of drug users around the mentioned sentinels is higher. Analysing the total amount of presentations per country (some countries contain more than one sentinel centre), we estimate that the Czech Republic and Bulgaria have the highest percentage of recreational drug use related presentations, with over 3% of total presentations. The other cumulative percentages per country are displayed in Figure 16. Figure 16 - Percentage of drug users in ED presentations per country excluding the sentinels were a total no. of patients was unavailable Within the global Euro-DEN data, the percentage of the recruited population in Belgium is on the 6 th place, in which Ghent University Hospital recruited less patients in comparison with the Antwerp sentinel centre. The relatively low number of presentations could be related to the geographical location of the hospital: on one hand, Ghent University Hospital is situated at the periphery of the student s night life region and not in the centre of the city of Ghent, whereas the centre in Antwerp is a central urban hospital. On the other hand, this might be 35

40 explained by incomplete patient selection: being a new project some data/cases might have not been recorded by the treating physicians. In order to minimise this bias, we completed our database with data from a parallel study resulting in another 33% of recruited patients. In comparison, the sentinel centre in central Antwerp recruited 500 patients on a total of patients per year (1.3%). This higher percentage may be due to a higher prevalence of recreational drug use toxicity, bearing in mind that the recruitment process may also be a reason for this higher percentage. Although there are fewer patients recruited at the University Hospital of Ghent in the last months of the year, we believe that all efforts have been done to exclude the recruitment bias. 4.2 Demographics According to literature, people are most likely to begin experimenting and abusing drugs including tobacco, alcohol, illegal and prescription drugs during adolescence and young adulthood 54,55,56,57,58. Men are more likely to use or experiment with drugs and recreational substances than women 59,60. Young adulthood is defined as a person ranging from its late teens or early twenties to its thirties, which could be an explanation of our cohort alignment with the theory above by the fact that most frequent recreational drug users presenting in the ED were male and young adults between the ages of years, partly overlapping with young adulthood. The mean age of our cohort is slightly younger than the Euro-DEN cohort, though with similar standard deviation (SD = Ghent vs. SD = Euro-DEN). By performing a t- test for independent data collection with an alpha value of 0.01, it seemed that the difference is significant (with a p-value of < 0.01). 4.3 Time of presentation Although there is a difference between the peak time of presentation between the global cohort from Europe (peak time between 20:00-02:00 o clock) and Ghent (peak time: 04:00-06:00 o clock), more than 50% of the patients present in the night-time all over Europe, including Ghent. 36

41 Looking into the number of presentations per day of the week, there is an increase of presentations on Saturdays and Sundays in both cohorts. This is in keeping with data from recent publications 25, according to which people are experimenting more with recreational drugs in the weekend than during the week. In this cohort, we notice a slight peak on Thursday, which could be suggestive of the fact that more students might be using recreational drugs on Thursdays, this being the night-out evening in the student milieu. Nevertheless, there is no evidence linking the night-out evening with increased recreational drug use and toxicity. 4.4 Patterns of drugs associated with presentations (reported substances) The mean number of drugs per presentation across Europe was 1.48 (SD 0.77) in comparison to 1.74 (SD 1.00) in Ghent. In total 65.4% of presentations across Europe and 52.6% in Ghent involved only a single drug. There are numerous substances used with recreational purposes in Ghent, however not all of these substances are part of the illicit drug groups. Some patients use a combination of substances, mixing illicit drugs with prescription drugs or other recreational agents. For example, we recorded patients using benzodiazepines in combination with high amounts of cannabis or benzodiazepines with cocaine. The most common drugs reported in the Euro-DEN cohort in comparison with the Ghent cohort are displayed in Figure 6. Our results are supporting the previous general findings of general drug use in Europe 4,61. Based on several reports 4,61,62, the most commonly used drug in Europe is cannabis 4, 7 by all age groups across Europe. Moreover, the availability of cannabis is even higher in Belgium since the amendment made to the law 20 regarding use and possession of cannabis. On the other hand, for the 2017 wastewater monitoring campaign, raw 24-hour composite samples were collected during a single week in March. 18 These samples were analysed for the urinary biomarkers (i.e. measurable characteristics) of the parent drug (i.e. primary substance) for amphetamine, methamphetamine and MDMA. 18 In addition, the samples were analysed for the main urinary metabolites of cocaine and cannabis, which are benzoylecgonine (BE) and THC-COOH (11-nor-9-carboxydelta9-tetrahydrocannabinol) 18,63. This report was focused on illicit stimulants and no results for cannabis were reported. 18,63 37

42 According to this study, the highest mass load of BE was found in Belgium (Antwerp), Spain and the United Kingdom 10,18. The lowest load was observed in the eastern European cities, however with a concerning continuous up-rise of the use of this illicit drug 10,18. These findings align with the high number of cocaine intoxication that is reported across Europe, including a high percentage in cocaine toxicity in our cohort. The next two most frequently reported agents in Ghent were MDMA and amphetamines. These substances are the most available illicit stimulant drugs in Europe 4,10. All of these drugs (cocaine, amphetamines, methamphetamines, MDMA) are illegal and as regularly seized in Europe (see Figure 17). Figure 17 - Most frequent seized drugs across Europe In the global context, Europe is an important market for stimulant drugs, supplied with both domestically produced drugs and drugs tracked from other world regions. South America, West Asia and North Africa are important source areas for illicit drugs entering Europe, while China is a source country for new psychoactive substances. 5 There is a noticeable difference in the use of MDMA. In Ghent, 8.7% of the patients have reported to have used MDMA (third most reported drug within our patient s population) 38

43 while in the European cohort there is only a 4.98% of MDMA use reported (6 th reported drug) (see Figure 6). This sector of the illicit drug market has significantly grown in complexity in Europe 4. Recent reports highlighted increases in the availability and use of high-dose MDMA tablets 4. Although seizures of non-scheduled MDMA pre-precursors remained steady at around kilograms, while safrole (pre-precursor of MDMA) seizures were negligible, PMK (piperonyl methyl ketone) seizures resumed, with the Netherlands reporting 622 kilograms in 2015 compared to zero in These numbers are highly likely further increasing. Having no closed borders between Belgium and The Netherlands, this may yield a high MDMA availability and hence high MDMA use in Ghent. Furthermore, until recently, facilities in the Netherlands and Belgium have represented the only major MDMA production hub, with products trafficked by crime groups primarily to Europe and North American markets. 64 The production market continues to increase in the Netherlands and Belgium, with clandestine laboratories becoming larger and more professional, but they are no longer the solely MDMA producers. 64 In recent years production has reportedly been taking place in other countries, including both Canada and China. 64 Another significant difference between the reported classical recreational drugs used in Ghent and Europe is composed by the use of heroin. While in Europe, according to the 2017 Euro- DEN database, 12.12% of the patients have reported to be using heroin (3 rd most commonly reported drug), in Ghent this number is much lower with 2.6% of the total presentations (9 th most commonly reported substance). This might be due the other recreational drugs like cocaine and cannabis being more readily available in Ghent 65. Heroin enters Europe along four main tracking routes 4. The two most important are the Balkan route and the southern route. The first of these runs through Turkey, into Balkan countries (Bulgaria, Romania or Greece) and on to central, southern and western Europe. An offshoot of the Balkan route involving Syria and Iraq has also emerged. The southern route, where shipments from Iran and Pakistan enter Europe by air or sea, either directly or transiting through African countries, has gained importance in recent years. Other routes include the northern route and a route through the southern Caucasus and across the Black Sea. 4 Benzodiazepines were the most prevalent group of prescription drugs in the overall Euro DEN dataset, including Ghent. 39

44 Some of the benzodiazepines, e.g. diazepam, clonazepam and alprazolam were seen across the majority of centres, although there was variability in the number per centre. Others, such as bromazepam and oxazepam, were only seen in a minority of centres. Further work is required to understand the reasons for these patterns, including comparison with prescribing data to be able to inform appropriate geographically targeted prevention activity. The second most common prescription drugs recorded in Europe were opioids, with a relatively high occurrence of methadone (2.7%), other prescribed opioids (2.0%) and buprenorphine (1.0%). To our knowledge, buprenorphine is not frequently prescribed and used in the Ghent region and specifically in UZ Ghent. We recorded no occurrence of toxicity due to recreational buprenorphine use in our centre. NPS use and/or toxicity was less frequently reported across Europe. The most frequently reported NPS group was represented by the synthetic cannabinoids, constituting 2.81% of all reported drugs and 51.7% of the total NPS (Figure 18). Figure 18 - Ten most common NPS in Europe Considering that our centre has only recorded 2 patients with NPS toxicity, this may be due to minimal use of these NPS, although there may be reduced recognition and testing of this group of drugs across Belgium/Ghent, as physicians may not be familiar with these products. 40