# DRAMES and DTA databases: Complementary tools to monitor drug-related deaths in France

Bruno Revol, Théo Willeman, Marc Manceau, Véronique Dumestre-Toulet, Jean-Michel Gaulier, Alexandra Boucher, Célian Bertin, Hélène Eysseric-Guérin, Nathalie Fouilhé Sam-Laï

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## To cite this version:

Bruno Revol, Théo Willeman, Marc Manceau, Véronique Dumestre-Toulet, Jean-Michel Gaulier, et al.. DRAMES and DTA databases: Complementary tools to monitor drug-related deaths in France. Thérapie, 2024, Therapie, 80 (2), pp.197-204. 10.1016/j.therap.2024.10.059. hal-04871054

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ADDICTOVIGILANCE

# DRAMES and DTA databases: Complementary tools to monitor drug-related deaths in France

Bruno Revol<sup>a,b,*</sup>, Théo Willeman<sup>c,d</sup>, Marc Manceau<sup>e</sup>, Véronique Dumestre-Toulet<sup>f</sup>, Jean-Michel Gaulier<sup>g</sup>, Alexandra Boucher<sup>h</sup>, Célian Bertin<sup>i</sup>, Hélène Eysseric-Guérin<sup>c,j</sup>, Nathalie Fouilhé Sam-Laï<sup>a</sup>, for the Compagnie nationale des biologistes et analystes experts (CNBAE), the French Addictovigilance Network (FAN)

Received 15 july 2024; accepted 11 october 2024

Available online 23 October 2024

## KEYWORDS

Addictovigilance ;
Amphetamine-type
stimulants ;
Analgesics ;

## Summary

Introduction. — The DRAMES (décès en relation avec l'abus de médicaments et de substances) registry is a French database of drug-related deaths (medications or illicit drugs) among drug users. The DTA (décès toxiques par antalgiques) registry is a French database of analgesic-

<footnote><sup>a</sup> Addictovigilance Dept, Grenoble-Alpes University Hospital, 38000 Grenoble, France</footnote>

<footnote><sup>b</sup> Inserm U1300, HP2 Lab, Grenoble-Alpes University, 38000 Grenoble, France</footnote>

<footnote><sup>c</sup> Pharmacology Pharmacogenetics and Toxicology Lab, Grenoble-Alpes University Hospital, 38000 Grenoble, France</footnote>

<footnote><sup>d</sup> Clinical Forensic Medicine Dept, Grenoble-Alpes University Hospital, 38000 Grenoble, France</footnote>

<footnote><sup>e</sup> Inserm CIC1406, Clinical Research Centre, Grenoble-Alpes University Hospital, 38000 Grenoble, France</footnote>

<footnote><sup>f</sup> ToxGen Lab, 33000 Bordeaux, France</footnote>

<footnote><sup>g</sup> Toxicology Dept, Lille University Hospital, 59000 Lille, France</footnote>

<footnote><sup>h</sup> Addictovigilance Dept, Lyon University Hospital, 69000 Lyon, France</footnote>

<footnote><sup>i</sup> Addictovigilance Dept, Clermont-Ferrand University Hospital, 63000 Clermont-Ferrand, France</footnote>

<footnote><sup>j</sup> Forensics Lab, Grenoble-Alpes University, 38000 Grenoble, France</footnote>

<footnote>* Corresponding author. CEIP-Addictovigilance, CHU Grenoble-Alpes, Pavillon E, CS 10217, 38043 Grenoble, France.
E-mail address: brevol@chu-grenoble.fr (B. Revol).</footnote>
Buprenorphine ;
Cannabis ;
Cocaine ;
Drug-related deaths ;
Heroin ;
Methadone ;
New psychoactive
substances ;
Opioids

related deaths among people without a history of drug abuse. Both registries are based on the
collection of data on deaths for which forensic toxicology experts have performed analyses.

*Material and methods.* — In the present study, we included drug- and analgesic-related deaths occurring from January 2013 to December 2022 in France. Subject demographic characteristics and medical history, forensic autopsy findings and toxicology reports were evaluated.

*Results.* — Among drug users (DRAMES registry), opioids used alone or in combination were the main contributor to drug-related deaths in France, as they are in most countries. However, licit methadone was the leading cause of opioid-related deaths (ahead of heroin) during the study period. The main trend was the dramatic increase in cocaine-related mortality. Among medical users of analgesics (DTA registry), tramadol was the leading cause of deaths throughout this period.

*Conclusion.* — A large-scale naloxone distribution program is urgently needed in France to prevent opioid overdoses, including among licit methadone users. However, our data do not support the hypothesis of an opioid crisis in France, although close monitoring is still required, particularly for oxycodone.

© 2024 The Author(s). Published by Elsevier Masson SAS on behalf of Société française de pharmacologie et de thérapeutique. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Abbreviations

ANSM French National Agency for the Safety of Medicines and Health Products

ATS amphetamine-type stimulants

CNBAE *Compagnie nationale des biologistes et analystes*
*experts*

COVID-19 coronavirus disease 2019

DRAMES *décès en relation avec l'abus de médicaments et de substances*

DTA *décès toxiques par antalgiques*

EUDA European Union Drugs Agency

FAN French Addictovigilance Network

LOESS locally estimated scatterplot smoothing

NPS new psychoactive substances

UNODC United Nations Office on Drugs and Crime

SNDS French National Health Data System

Introduction

Worldwide, deaths related to the use of drugs were estimated at about 500,000 in 2019, according to the recent World Drug Report from the United Nations Office on Drugs and Crime (UNODC) [1].

However, there is considerable regional variation, highlighted by the opioid epidemic currently raging in the United States, which has become the leading cause of accidental death in that country [2]. There is extensive debate as to whether Europe is facing a comparable opioid crisis [3], with some countries such as the United Kingdom reporting a significantly higher opioid-related mortality than others [4].

In France, the DRAMES (*décès en relation avec l'abus de médicaments et de substances*) registry is a database of drug-related deaths that aims to identify the psychoactive substances involved (medications or illicit drugs), assess their dangerousness, and estimate the trends in the number of these deaths among drug users. The DTA (*décès toxiques*

*par antalgiques*) registry is a database of analgesic-related deaths, among people without a history of drug abuse.

Both registries were created in response to a ‘‘French paradox’’ of the early 21st century: non-fatal drug-related events were better documented than drug-related deaths. This inadequacy was partly due to the fact that clinical, forensic and toxicological data were not aggregated. The DRAMES and DTA registries are therefore based on the voluntary reporting of data on deaths for which toxicology experts (throughout France, including the overseas territories) have performed analyses. Post-mortem toxicological analyses are performed as part of the search for the cause of death, at the request of the judicial authorities. These databases are part of the original pharmaco-epidemiological tools implemented by the French Addictovigilance Network (FAN) and developed in partnership with the CNBAE (*Compagnie nationale des biologistes et analystes experts*). The DRAMES registry was created in 2003 by the Marseille Addictovigilance Centre, and has been managed by the Grenoble Addictovigilance Centre since 2011. The DTA registry was added in 2013, following the withdrawal of dextropropoxyphene in France, because of the risk of transfer to other analgesics, especially tramadol.

The purpose of this study is to present the trends in the drugs implicated in fatal poisoning among drug-users and among people using analgesics for medical purposes in France over a 10-year period, from 2013 to 2022.

Methods

Data collection

Data were collected using a form completed by the forensic toxicologist containing the following items: demographic characteristics; medical and substance abuse history; circumstances in which the body was found; autopsy and pathological findings; identification of the substances found in analyses of biological specimens and quantities in the
blood or in other matrices if blood specimen was not avail-
able; and probable cause of death. These data made it
possible to classify each case as either directly substance-
related cause of death (toxic cause alone, usually overdose;
and toxic cause with related pathology) or indirectly
substance-related (e.g., falling from a high place while
under the influence of cocaine). Indirectly drug-related
deaths were not included in this report.

DRAMES: inclusion and exclusion criteria

The DRAMES registry includes deaths that meet the Euro-
pean Union Drugs Agency (EUDA) definition of drug-related
deaths. Specifically, cases were included when the under-
lying cause of death was drug-induced psychosis, drug
dependence, non-dependent drug abuse, accidental or self-
inflicted poisoning, and poisoning with undetermined intent.
Cases were included when the death was associated with
specific drugs or drug classes: cannabis, cocaine, hallucino-
gens, opioids, stimulants, or abuse of any other psychoactive
substance assessed as being responsible for the death.

The following records were excluded from the study sam-
ple: deaths by suicide (e.g., when the suicide was addressed
in writing and/or the means was by hanging); deaths caused
by a third party (homicide); deaths associated with acciden-
tal intoxication in children (excluding drug dependence);
deaths due solely to intoxication with licit and prescribed
drugs, without a documented history of substance abuse
(e.g., death associated with antidepressants); cases in which
another cause, not related to a psychoactive substance,
was found; cases with insufficient documentation (e.g., no
known cause of death); cases without drug testing (in the
absence of blood, analyses of other matrices such as bile
or muscle are needed); deaths associated with vehicular
crashes (drivers or passengers).

DTA: inclusion and exclusion criteria

The DTA registry includes deaths due to a standard list of psychoactive analgesics: buprenorphine, codeine, dextropropoxyphene (although it was withdrawn from the French market in 2011), dihydrocodeine, fentanyl, gabapentin, hydromorphone, ketamine (used off-label for pain), morphine, nalbuphine, nefopam, methadone (licensed in France for pain from August 2020), oxycodone, pethidine, pregabalin and tramadol.

The following records were excluded: deaths due to drug
intoxication by users with a documented history of substance
abuse; cases in which another cause not related to an anal-
gesic was found; cases with insufficient documentation; and
cases without any drug testing.

Imputability

For each case evaluated, each substance present in the
blood was subject to an imputability analysis regarding the
death, scored from high (level 1) to low (level 4).

To differentiate the substances identified in the blood
from the substance(s) involved in the death, therapeutic,
toxic and lethal blood concentrations [5–7] were used to
grade substance as follows: lethal concentration = level 1;
toxic concentration = level 1 or 2 depending on other sub-

stances present; therapeutic concentration = level 1, 2, 3 or 4 depending on other substances present; sub-therapeutic concentration = no score assigned. In the present study, only level 1 substances were considered as the cause of death. Depending on the number of substances involved, the score was subdivided into: 1.0 corresponding to only one drug present; 1.1 corresponding to one predominant drug (including active metabolites); 1.2 corresponding to 2 co-dominant drugs present; 1.3 corresponding to 3 or more co-dominant drugs present.

According to the grading scheme, several drugs could be
considered as the cause of death. The imputability of the
drug(s) in each case was independently assessed by two tox-
icology experts. In case of disagreement, the advice of a
third expert was sought.

Statistical analysis

All analyses were conducted with R, version 3.6.3 (R
Foundation for Statistical Computing), and its tidyverse
meta-package, including the ggplot2 package for plotting.
Smoothed curves correspond to LOESS (locally estimated
scatterplot smoothing) curves obtained using ggplot2.

Ethics

Because DRAMES and DTA registries used only routinely col-
lected, deidentified data, they did not require any ethics
committee approval, and informed consent was waived, in
accordance with French regulations for mandatory reporting
by health care professionals (article R5132-102 of the Public
Health Code).

Results

From January 2013 to December 2022, 4,503 cases were included in DRAMES (mean [SD] age, 38.2 [10.6] years) and 1,036 in DTA (mean [SD] age 48.3 [15.6] years). The over-dose mortality rate was highest among men in the DRAMES registry (sex ratio, 4.4:1), while it was slightly higher among women in DTA (sex ratio, 0.89:1). Subject characteristics are presented in Table 1.

Over the course of the survey period, the participation
of toxicology experts increased, covering more than 80% of
the national territory for DRAMES and almost half (48 French
departments out of 101) for DTA in 2022 (Fig. 1).

The trends in drugs responsible or co-responsible for
death among drug users are shown in Fig. 2 (DRAMES reg-
istry). Methadone, a legal substitution product, remained
the leading cause of death over the entire period, reach-
ing 40.3% in 2022. The relative incidence of heroin-related
deaths increased from 20.0% in 2013 to 28.5% in 2022.
Interestingly, the curves for methadone and heroin mir-
ror each other over the entire period. However, the main
trend was the dramatic increase in cocaine-related mortal-
ity, from 8.8% in 2013 to 31.8% in 2022. In contrast, the
relative incidence of buprenorphine-related deaths, other
licit opioid-related deaths and cannabis-related deaths
decreased from 15.8%, 11.6% and 10.9% in 2013 to 7.1%,
8.3% and 7.2% in 2022, respectively. The relative increases in
numbers of deaths related to amphetamine-type stimulants
<table><caption>Table 1 Number of subjects included and demographic characteristics, DRAMES and DTA registries, France, 2013–2022.</caption><thead><tr><td>Characteristics</td><td>DRAMES</td><td>DTA</td></tr></thead><tbody><tr><td>Participants, no. (%)</td><td>4503</td><td>1036</td></tr><tr><td>A single (1.0) or a predominant drug (1.1) involved</td><td>3106</td><td>626</td></tr><tr><td>Two or more co-dominant drugs (1.2 or 1.3) involved</td><td>1397</td><td>410</td></tr><tr><td>Age, mean [SD], y.</td><td>38.2 [10.6]</td><td>48.3 [15.6]</td></tr><tr><td>Sex ratio (male:female)</td><td>4.4:1</td><td>0.89:1</td></tr></tbody></table>

<figure><img src="image_4.png" /><figcaption>Figure 1. French counties* covered by DRAMES (A) and DTA (B) registries in 2022. *France is divided into 101 counties (called departments).</figcaption></figure>

(ATS) (9.1%) or new psychoactive substances (NPS) (3.8%) observed in 2015, have not been confirmed since that time. In 2022, a licit nonopioid drug (primarily a hypnotic, anxiolytic, antidepressant, or antipsychotic) was associated in only 8.3% of cases.

The trends in analgesics responsible or co-responsible for death among medical users are shown in Fig. 3 (DTA registry). Over the whole period, tramadol remained the leading cause of death, ahead of morphine. A relative increase in oxycodone-related mortality was observed (up to 1 in 5 cases in 2022) compared to a progressive decrease in tramadol, morphine and codeine-related deaths. The incidence of deaths due to other analgesics (buprenorphine, dihydrocodeine, fentanyl, gabapentin, ketamine, methadone, nefopam, pregabalin) remains low and stable over the period. Pregabalin and gabapentin were the only non-opioid analgesics regularly responsible for deaths, reaching a maximum of 3.5% in 2019 and 3.0% in 2014, respectively.

Discussion

In France, as in most countries, opioids are by far the drug class most frequently associated with drug-related or analgesic-related mortality. Globally, two-thirds of direct

drug-related deaths are due to opioids, and opioid use disorders accounted for 71% of the 18 million healthy years of life lost due to drug use disorders in 2019 [1].

In the United States, following a year-on-year trend of increase, there were more than 80,000 opioid overdose deaths in 2021. Most of them were attributed to synthetic opioids (primarily fentanyl) [1]. Fentanyl was also found in 86% of the samples from people who had died as a result of opioid overdose in the first half of 2021 in Canada [1]. However, the French situation seems different because no increase in other licit opioid-related deaths (a category including fentanyl) was observed in the DRAMES registry over the period 2013-2022. In addition, no increase in fentanyl-related deaths and only a progressive increase in oxycodone-related deaths were observed in the DTA registry. Taken together, our data do not support the hypothesis of an opioid crisis in France. In contrast, licit methadone has been the main cause of opioid-related deaths for many years in the DRAMES registry, ahead of heroin. Monitoring methadone use remains a public health challenge, particularly highlighted during the coronavirus disease 2019 (COVID-19) restrictions, with an increase in methadone misuse and its consequences [8,9]. Compared with methadone, our study confirms the relative safety of
<figure><img src="image_5.png" /><figcaption>**Figure 2.** Trends in drug-related deaths involving a single drug (1.0) or a predominant drug (1.1) or multiple co-dominant drugs (1.2 and 1.3) among drug users (DRAMES), France, 2013–2022. *ATS includes amphetamine, DOC, MDMA, methamphetamine, PMMA. *NPS includes alpha-PVP, butylone, carfentanil, deschloroetizolam, diclazepam, ethylphenidate, MDPHP, MDPV, mephedrone (4-MMC), methoxetamine (MXE), methylene, MPA, MXP, ocfentanil, U-47700, 25I-NBOMe, 3-CMC, 3-FPHEN, 3-HO-PCP, 3-MeO-PCP, 3-MMC, 4-CMC, 4-FMA, 4-FMPH, 4-MEC, 4-MPD, 5-APB, 5-APDB, 5-MAPB, 5-MeO-DALT. *Other illicit includes butane, GBL, GHB, ketamine, LSD, mitragynine, nitrous oxide, poppers. *Other licit includes alimemazine, alprazolam, amisulpride, amitriptyline, baclofen, bromazepam, citalopram, clobazam, clonazepam, clomipramine, clozapine, cyamemazine, diazepam, diphenhydramine, doxylamine, duloxetine, ether, fluoxetine, gabapentin, hydroxyzine, levomepromazine, lidocaine, loxapine, maprotiline, mephenesin, meprobamate, methylphenidate, mianserine, mirtazapine, nefopam, nordiazepam, olanzapine, oxazepam, paroxetine, phenobarbital, pregabalin, promethazine, propranolol, propofol, phenytoin, quetiapine, sertraline, tiapride, tropatepine, valproic acid, venlafaxine, zolpidem, zopiclone, zuclopenthixol. *Other licit opioids includes alfentanil, codeine, dextromethorphan, dihydrocodeine, fentanyl, hydrocodone, morphine, oxycodone, pholcodine, remifentanil, tramadol.</figcaption></figure>

buprenorphine in terms of death from overdose [10] and supports the "French model" of opioid use disorder treatment, mainly with buprenorphine prescribed by general practitioners [11].

Although the situation currently seems less problematic than in North America [12], the off-label use of fentanyl is frequent in France (oral transmucosal fentanyl formulations prescribed for noncancer pain) and the risk of primary fentanyl dependence is well described [13,14]. Oxycodone prescriptions have increased steadily since 2007 [15], and a large increase in the number of individuals with "doctor-shopping" behavior for oxycodone (a proxy for potential misuse or abuse) was also observed between 2010 and 2016 [16]. Early signals of abuse or diversion have also been reported in recent years for extended-release oral morphine [17,18], including when used off-label as an alternative to conventional opioid substitution treatments [19]. The problematic use of codeine increased between 2007 and 2016, either in a predominantly female population initially using it for pain relief [20], or among teenagers and young adults for recreational purposes in the form of the cocktail "Purple Drank" (or "Lean") [21]. In such cases, the use of falsified prescriptions to obtain codeine is well known [22]. Consequently, opioids should be monitored closely

and a large-scale naloxone distribution program is urgently needed in France.

Worldwide, the other opioid crisis — the non-medical use of tramadol — continues to affect countries in parts of North, West and Central Africa, in the Near and Middle East and in South-West Asia. Seizures in the above-mentioned regions suggest that the tramadol used is often a falsified product [1], whereas it comes from the legal supply chain in France. However, the DTA registry shows that tramadol has been the leading cause of fatal poisoning for many years, among people with no history of addiction. For patients with initial medical use, symptoms of withdrawal, craving and desirable opioid and/or stimulant effects play a leading role for ongoing tramadol use and for development of a severe primary substance use disorder [23]. In addition, prescribers often consider tramadol as having a low potential for substance use disorder. As a result, the maximum prescription period for analgesics containing tramadol was reduced from 12 months to 3 months in 2020 in France, and packs of only 10 or 15 tablets are marketed from 2024 to limit the risk of misuse, dependence and overdose-related deaths.

After opioids, the second leading cause of drug-related deaths in France were stimulant drugs, including cocaine, ATS, cathinones, and some other NPS [24]. The present study
<figure><img src="image_6.png" /><figcaption>**Figure 3.** Trends in analgesic-related deaths involving a single drug (1.0) or a predominant drug (1.1) or multiple co-dominant drugs (1.2 and 1.3) among medical users (DTA), France, 2013–2022. *Others include buprenorphine, dextropropoxyphene, ketamine, methadone, nefopam.</figcaption></figure>

highlights the dramatic increase in cocaine-related mortal-
ity, which could be described as a "cocaine crisis". Our
observations are in line with previous French studies that
reported an increase in cocaine-related deaths since 2014
[25], an increase in cocaine-related hospitalisations from
2010 to 2019 [26], or an increase in cocaine use among preg-
nant women between 2005 to 2018 [27]. This very important
trend has been confirmed elsewhere in Europe, notably in
the United Kingdom with an increase in cocaine-related
deaths that began in 2010 and accounted for one-quarter
of drug-related deaths in 2019 [28]. According to our study
findings, cocaine is now involved in more deaths than heroin
in France.

Pregabalin and gabapentin are the only non-opioid anal-
gesics regularly responsible for deaths over the period in the
DTA registry, which is consistent with their abuse potential
[29] and the related harms already reported in France (hos-
pitalisations, requests for addictological support or deaths)
[30].

Other non-opioid analgesics are rarely implicated in
deaths among medical users, although their abuse potential
has been demonstrated (e.g., ketamine [31,32] or nefopam
[33]).

Our registries have several limitations, particularly given
the voluntary participation of toxicology experts; there-
fore, data collection and description of drug-related and
analgesic-related deaths throughout France is not exhaus-
tive. In addition, only the judicial authorities can order
toxicologic investigations. Despite this, the results are suf-
ficiently reproducible from one year to another for certain
trends to be revealed. A challenge remains in comparing

DRAMES and DTA results with international data. Forensic
studies using similar methods are rare, geographically lim-
ited [34] or restricted to a single substance [35]. However,
health authorities in several countries require these data to
make and assess regulatory decisions [36–38]. Using a fatal
toxicity index (i.e. the absolute number of fatal poisonings
caused by a particular drug divided by its consumption [39])
could make it possible to compare drugs with each other or
from one country to another. Finally, the DRAMES and DTA
registries should be connected to other national databases,
such as the French National Health Data System (SNDS), in
order to trace the health trajectories of victims and improve
prevention, harm reduction or treatment programs.

Funding/support

This work was supported by the French National Agency for
the Safety of Medicines and Health Products (ANSM).

Role of the funder/sponsor

The sponsor had no role in the design of the study, its exe-
cution, analyses, interpretation of the data, or decision to
submit results.

Data sharing statement

Individual patient data that support the findings of
this study are available from the corresponding author,
upon reasonable request. Annual reports are avail-
able online on the ANSM website: https://ansm.sante.
fr/page/resultats-denquetes-pharmcodependance-
addictovigilance.

Acknowledgments

We sincerely thank all the investigators of the *Compagnie
nationale des biologistes et analystes experts* (CNBAE), lab-
oratoires de police scientifique de Lille, Marseille, Paris,
Toulouse, Institut de recherche criminelle de la gendarmerie
nationale (IRCGN) and of the French Addictovigilance Net-
work (FAN) for their help in setting up this survey (see the
list of non-author collaborators in *Supplementary material*).

Disclosure of interest

The authors declare that they have no competing interest.

Appendix A. Supplementary data

Supplementary data associated with this article can be
found, in the online version, at https://doi.org/10.1016/j.
therap.2024.10.059.

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