Dr Michel Mallaret

CEIP-Addictovigilance Grenoble France

Lisboa, october 15th 2014

Implications of benzodiazepines in drug related deaths

Analyses of the french special mortality register data (DRAMES)

Gaba modulators (agonists) and deaths

• Ethyl alcohol binge drinking and deaths

• Barbiturates : restriction of access �� deaths in case of abuse (or suicide)

• Benzodiazepines : initially supposed to be safe

– Less respiratory depression / barbiturates

– Less toxicity

– Pharmacodynamic tolerance in dependent patients

French context of benzodiazepine (BZD)

• French alcohol dependence (12.6 Litres consumed per capita in 2011)…

• Anxiolytics and hypnotics (BZD + Z..) easily available by M.D. prescription

• Abuse, misuse cases ; huge population with long term dependence

• Alternatives of BZD (more expensive) are not enough favoured

• Restriction of BZD access ? � Increase of alcohol consumption ?

• Even the association BZD – accidents, hypomnesia or potential risk of Alzheimer’s disease (Billioti de Gage et al.,2014) does not change prescription habits

(The « French paradox »)

BZD users prevalence in France

Anxiolytics (fig.1) and hypnotics (fig.2) use (DDD/1.000 hab) in Europe

EU and US warnings: benzodiazepines should be

avoided in Opioid Maintenance Treatment (OMT)

• Risk of respiratory depression, especially in case of misuse

• Risk of misuse

• Contribute to relapse ? (Brands et al., 2008)

• Development of psychological coping stategies is hindered (Soyka et al., 2010)

• Unsufficient dose of methadone or BHD ?

• Retention in generalised anxiety disorder is low : interest of BDZ ? (Liebrenz et al., 2010)

• Patients are often yet BZD dependent : reduction trial

�Benzodiazepines and ED visits, fatalities in the world

• BZD and ED visits(USA;DAWN (Gudin et al., 2014) )

• Deaths and alprazolam

(Florida, Johnson, 2014)

• Deaths andBZD and �methadoneNorway(Bernard et al.,2013)

Alprazolam

Benzodiazepine

Benzodiazepine

Experimental studies of benzodiazepines and interactions of benzodiazepine and buprenorphine

• Cross-tolerance in Rats may not occur between 2 agonists : risks of sedation (Vinkers et al, 2012) and respiratory depression in case of BDZ change :

• BZD+buprenorphine in Rats : protective bell-shaped dose response effect on respiration is eliminated (Nielsen and Taylor, 2005)

In Rats, only Diazepam, when associated with BHD, induces respiratory depression in BHD (acute or chronically) treated (Cohier et al., 2014)

• Acute IV Bup (30 mg/kg) + diazepam (30 mg/kg)

• Chronic Bup (14d.1mg/kg/day) ;

then acute Bup (10 mg/kg) + Diazepam (20 mg/kg)

Clinical evaluation of BZD and of interaction of benzodiazepine and OMT

Exemple of Alprazolam overdose :

more complications than other BZD?(Isbister et al., 2004)

BDZ and OMT :

In an US study (Schuman-Olivier et al., 2013), « few » BHD patients are BZD treated

•17% of 328 BHD treated patients have BZD prescription

•2,7% (n=9) : overdose related ED during first year of ttt

•No fatalities during ttt

Risk of fatalities if :

•Intravenous injection or snorting of opioid agonist (buprenorphine)

•Ongoing illicit use of full agonist opioids (Bell et al., 2009 ; Samhsha, 2011)

•Dropout from treatment (Clausen et al., 2008 ; Rosca et al., 2012)

Fatalities in OMT and benzodiazepine treated patients in France

• Overdose deaths in buprenorphine + BZD treated

patients (Reynaud et al., 1998)

• BZD misuse is common in French patients (OMT) :

31% of problematic use in past month in BHD-treated (Lavie et al., 2009)

Association of benzodiazepine and buprenorphine or methadone

in France

• In addiction Centers (CSAPA; OPPIDUM) : 24%

• Patients consulting G.P.’s (OPEMA) : 30%

• Systematic analysis in syringes : variable % of BDZ (1 à 45%)

% illicit purchase ; forgeries of

prescription of BDZ by users

Illicit purchase (OPPIDUM)

• Clonazepam : 36.6%

• Oxazepam : 22.1%

• Lorazepam : 21.9%

• Buprenorphine HD:13.5%

• Methadone : 5.9%

Prescription sheet forgeries in Europe :

BDZ : differences between countries0

20

40

Alpra

zolam

Bromaz

epam

Bupre

norp

hine

Clor

azep

ate

Diazep

amFlun

itraz

epam

Hydro

codo

neLo

raze

pam

Met

hylph

enid

ate

Mor

phine

Pent

azoc

ine

Thebac

onZolp

idem

Zopicl

one

% d

e c

itat

ion

s su

r le

no

mb

re d

'osi

ap

Belgique Espagne France

• French drug problematic users : 230 000 (Costes, 2009); more than 50% are buprenorphine or methadone users

• 160 000 persons use buprenorphine and methadone

(113 000) (47 000) in 2012

• Drug induced deaths in France in 2007 (capture-recapture) : 1 175 persons (Janssen, 2011)

French drug users and deaths

DRD FranceMethodology of D.R.A.M.E.S. data register

(Décès en Relation avec Abus de Médicaments Et Substances)

• Systematic complete toxicological analysis

and forensic study with autopsy

• Exclusion of suicide cases and car crash accidents

• Expertise of each case and imputability of each substance

• Cases of responsible drugs with no other cause of death

• Cases of partial participation of drug in death

(ex. : LSD and drowning)

Drug related deaths (DRAMES)in France

Deaths with no other causes

Nb of experts (toxicologists)

446 received cases

346 included cases

310 directly

drug related deaths

36 drug related

deaths with other

causes

DRD FranceInterests of DRAMES data register

• Systematic complete toxicological analysis

• Frequent forensic study with autopsy

(ex : myocardial infarction and high blood [THC])

• Analysis of drugs in tablets, syringes near the corpse

• Some informations about circumstances of death

• Imputability of each identified substance

• Other french registers : no toxicological analysis

- G.P. certificate (CépiDC)

- Police inquiry (OCRTIS : few cases)

DRD FranceDRAMES Biases and insufficiencies (1)

• Non exhaustive study (a priori, no bias in inclusion)

• No systematic inquiry by public prosecutor

• Not all analytical toxicologists are voluntary

(bias of increasing number)

• Do not participate : a few «départements» among the french 99 in which there is an important OMT or a low OMT

• Number of deaths/ treated patients is underestimated

DRD FranceDRAMES Biases and insufficiencies (2)

Disadvantages of anonymity

• Very few information about medical history

• Frequent unkown stage of addiction :

- few known cases of naive patients (hair analysis)

- Relapse (exit from jail) ?

- drop out patients from maintenance programs (OMT)?

• Unknown origin of licit drugs :

- black market ?

- prescription sheets forgeries ?

Substances Identified (n) Imputability (n)

Cannabis 28 19

Cocaine 7 7

Buprenorphine 5 5

Methadone 3 3

Morphine 3 3

Hydroxyzine 3 3

Ethanol 3 3

Amphetamines 2 2

Atropine scopolamine

2 2

Oxazepam 2 2

Cathinones 1 1

Ketamine 1 1

Other causes of deaths (drowning,…) AND drugs. n = 36

Drug Related deaths in France(D.R.A.M.E.S.)

No other found causes : 310 in 2012

Substances 2010 (254) 2011 (277) 2012 (310)

Heroin 68 42 39

Cocaine

Heroin+cocaine

24

16

19

11

28

8

Methadone 92 120 140

Buprenorphine

Methadone+Bup.

49

7

39

1

47

88 deaths / 42 322 patients2,0 deaths / 1000 patients[Met] median : 340 µg/L[30 – 2270]

0

20

40

60

80

100

120

140

160

mét

hado

ne 2

010

mét

hado

ne 2

011

mét

hado

ne 2

012

bupr

énor

phine

201

0

bupr

énor

phine

201

1

bupr

énor

phine

201

2 cocktail

majoritaire

Methadone and DRD in France121 deaths / 45 445 patients

2,7 deaths / 1000 patients[Met] median : 382 µg/L [12 – 4000]

140 deaths / 46 387 patients 3,0 deaths / 1000 patients [Met] médiane : 377 µg/L [61 – 3113]

44 deaths / 103 014 patients 0.43 deaths / 1000 patients[Bup] médiane : 5,95 µg/L [0,3 – 154]

Buprenorphine and deaths in France

40 deaths / 111 000 0.36 décès / 1000 patients[Bup] médiane : 3,2 µg/L [0,34 – 709,8]

47 deaths / 112 965 0.42 décès / 1000 patients[Bup] médiane : 4,0 µg/L [0,2 – 112]

2011 (n=280) 2012 (n=310)

Diazepam 35 (12,5%) 48 (15,5%)

Nordiazepam 44 (15,7%) 61 (19,7%)

Oxazepam 37 (13,2%) 57 (18,4%)

Bromazepam 26 (9,3%) 29 (9,4%)

Clonazepam 20 (7,1%) 9 (2,9%)

Zopiclone 19 (6,8%) 12 (3,9%)

Alprazolam 13 (4,6%) 12 (3,9%)

Zolpidem 6 (2,1%) 4 (1,3%)

Clobazam 4 3

BDZ in DRAMES 2011 and 2012

BDZ and addict outpatientsin addiction center OPPIDUM 2011

BDZ, addicts and M.D.OPEMA 2012

No great differences between BZD associated deaths and patients following OMT

DRD FranceDRAMES (2006-2012)

Participation of responsible benzodiazepines

• Participation of benzodiazepines in 50% of total cases

• In very few cases (2 in 2011 ; 2 in 2013), BDZ are the only responsible substances

Number of deaths

310 : total fatalities

Nb of cases with BZD

0

50

100

150

200

250

300

350

2006 2007 2008 2009 2010 2011 2012

nbre cas

Cas BZD

% BZD/total

50% : % of BZD / total cases

DRD FranceDRAMES (2006-2012)

Methadone and benzodiazepines• Increase of methadone prescription (≈ 1/1.000 inhabitants in next

future)

• Participation of BZD in 50% of methadone cases

0

20

40

60

80

100

120

140

160

2006 2007 2008 2009 2010 2011 2012

Cas Méthadone

Cas Méthadone + BZD

% BZD+met/met

Number of deaths

50% : % of BZD in methadonecases

140 : Total methadone fatalities

Methadone + BZD

DRD FranceDRAMES (2006-2012)

Buprenorphine and benzodiazepines• Importance of buprenorphine prescription (≈2/1.000 inhabitants)

• Participation of BZD in 70% of buprenorphine cases

Number of deaths 70% : % of BZD in buprenorphinecases

Buprenorphine + BZD0

10

20

30

40

50

60

70

80

2006 2007 2008 2009 2010 2011 2012

Cas Buprénorphine

Cas Buprénorphine + BZD

% BZD+bup/bup

47 : total buprenorphine fatalities

ConclusionBenzodiazepine implication in drug related deaths

Analyses of the french special mortality register data (DRAMES)

• Literature shows the participation of BDZ in DRD

• BZD use, misuse, abuse and dependence is frequent in drug addicts

• Alternatives of BDZ are needed

• French mortality register DRAMES, despite its insufficiencies, shows :

- high frequency (50%) of association of BDZ with drugs

- similar ‘’ (50%) ‘’ ‘’ ‘’ ‘’ methadone

- higher frequency (70%) ‘’ ‘’ ‘’ ‘’ buprenorphine

• Prevention of BDZ use in this population is needed