Implications of benzodiazepines in drug related deaths Analyses of the french special mortality register data (DRAMES) Dr Michel Mallaret CEIP-Addictovigilance Grenoble France Lisboa, october 15th 2014
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) (The «French paradox») 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
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) ) Benzodiazepine Deaths and alprazolam (Florida, Johnson, 2014) Alprazolam Deaths and BZD and methadone Norway (Bernard et al.,2013) 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 depressionin 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 BHDtreated (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% 40 Prescription sheet forgeries in Europe : BDZ : differences between countries Belgique Espagne France 20 0 % de citations sur le nombre d'osiap Alprazolam Bromazepam Buprenorphine Clorazepate Diazepam Flunitrazepam Hydrocodone Lorazepam Methylphenidate Morphine Pentazocine Thebacon Zolpidem Zopiclone
French drug users and deaths 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 (capturerecapture) : 1 175 persons (Janssen, 2011)
DRD France Methodology 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 446 received cases 346 included cases Deaths with no other causes Nb of experts (toxicologists) 310 directly drug related deaths 36 drug related deaths with other causes
DRD France Interests 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 France DRAMES 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 France DRAMES 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?
Other causes of deaths (drowning, ) AND 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 drugs. n = 36 2 2 Oxazepam 2 2 Cathinones 1 1 Ketamine 1 1
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 24 19 28 Heroin+cocaine 16 11 8 Methadone 92 120 140 Buprenorphine 49 39 47 Methadone+Bup. 7 1
Methadone and DRD in France 88 deaths / 42 322 patients 2,0 deaths / 1000 patients [Met] median : 340 µg/l [30 2270] 160 140 120 100 80 60 40 20 0 121 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] cocktail majoritaire méthadone 2010 méthadone 2011 méthadone 2012 buprénorphine 2010 buprénorphine 2011 buprénorphine 2012
Buprenorphine and deaths in France 44 deaths / 103 014 patients 0.43 deaths / 1000 patients [Bup] médiane : 5,95 µg/l [0,3 154] 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]
No great differences between BZD associated deaths and patients following OMT BDZ in DRAMES 2011 and 2012 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 and addict outpatients in addiction center OPPIDUM 2011 BDZ, addicts and M.D. OPEMA 2012
DRD France DRAMES (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 350 300 310 : total fatalities 250 200 150 nbre cas Cas BZD % BZD/total Nb of cases with BZD 100 50 50% : % of BZD / total cases 0 2006 2007 2008 2009 2010 2011 2012
DRD France DRAMES (2006-2012) Methadone and benzodiazepines Increase of methadone prescription ( 1/1.000 inhabitants in next future) Participation of BZD in 50% of methadone cases Number of deaths 160 140 140 : Total methadone fatalities 120 100 80 60 Cas Méthadone Cas Méthadone + BZD % BZD+met/met Methadone + BZD 40 20 0 2006 2007 2008 2009 2010 2011 2012 50% : % of BZD in methadone cases
DRD France DRAMES (2006-2012) Buprenorphine and benzodiazepines Importance of buprenorphine prescription ( 2/1.000 inhabitants) Participation of BZD in 70% of buprenorphine cases Number of deaths 80 70% : % of BZD in buprenorphine cases 70 60 50 40 30 47 : total buprenorphine fatalities Cas Buprénorphine Cas Buprénorphine + BZD % BZD+bup/bup 20 10 0 2006 2007 2008 2009 2010 2011 2012 Buprenorphine + BZD
Conclusion Benzodiazepine 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