Lothian Drug Trends Relative to Scotland Drug-Related Deaths

Lothian drug trends relative to Scotland drug-related deaths

Scottish Drug Forum Conference 10th October 2018

Dr Paul Cawood Clinical Biochemistry Royal Infirmary of Edinburgh Scotland leads Europe in Drug-Related deaths. Drug-related deaths Scotland trend 1000 934 868 900 2016 had a 23% 800 706 increase over 2015. 700 614 574 584 600 2017 had an 8% 455 500 increase over 2016 382 400 291 300 244 There were regional 200 differences in 2016 with: 100 0 Ayrshire +99% Forth Valley +61% 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 180 Lanarkshire +55% 160 Lothian +28% 160 DRD per million 15-65 yrs (2016) 140 Glasgow/Clyde +16% 120 103 100 100 76 80 71 2017: 60 59 58 Tayside +52% 60 43 40 26 22 22 21 19 16 15 14 Fife +47% 20 10 9 9 8 7 7 6 6 4 4 2 0

Grampian +25% EU UK Italy

Glasgow/Clyde +9% Spain Latvia France Turkey Poland Ireland Austria Croatia Finland Estonia Norway belgium Bulgaria Slovakia Slovenia Hungary Portugal Scotland Romania Sweeden Denmark Germany Lithuania

Lothian +8% Rep Czech Netherlands

Ref: Drug-related deaths Scotland in 2016/2017: National statistics for Scotland Gabapentinoids (opioid boosters) were implicated in 26% of DRDs in 300 Gabapentinoid trend in DRD

2016. 250

200 121 Gabapentin increased by 51% in 2016 71 but decreased in 2017. 150 pregabalin Pregabalin increased by 69% in 2016 42 gabapentin and a further 70% in 2017. 100 36 154 144 50 12 102 67 5 51 24 0 2012 2013 2014 2015 2016 2017 Street benzodiazepines increased from 63 cases in 2015 to 294 in 2016 700 Benzodiazepine trend in DRD 26 and 446 in 2017. 600 99 500 13 Etizolam and Diclazepam were the 75 diclazepam 400 24 main findings in 2016. 21 alprazolam 300 Etizolam and Alprazolam were the delorazepam 300 main findings in 2017 225 etizolam 200 diazepam 43 Correlates with increased DRD in 100 37 205 122 154 Ayrshire, Lanarkshire and Glasgow / 106 85 0 Clyde in 2016, and the East of 2013 2014 2015 2016 2017 Scotland in 2017. 867 Scotland drug-related-deaths 250 200 800 706 650 +23% 2015v16 200 Grampian -2% 2015v16 Highland -18% 2015v16 600 493 426 150 100 2015 400 100 69 68 35 29 21 272 13 12 8 6 3 191 2016 48 50 43 41 50 0 200 63 13 7 DRD Op/meth benzo new benzos 0 0 DRD Op/meth benzo new benzos 250 DRD Op/meth benzo new benzos 200 200 Tayside -2% 2015v16 150 Forth Valley +61% 2015v16 100 100 63 62 49 54 50 36 38 37 8 19 50 31 21 25 8 3 7 0 0 DRD Op/meth benzo new benzos DRD Op/meth benzo new benzos 250 257 GGC +16% 2015v16 200 221 195 150 200 154 Fife +2% 2015v16 138 127 100 44 45 100 50 34 33 29 42 11 3 7 17 0 0 DRD Op/meth benzo new benzos DRD Op/meth benzo new benzos

200 200 Lothian +28% 2015v16 Ayr & Arran +98% 2015v16 128 100 92 85 100 66 100 71 47 43 38 43 38 19 2 12 5 8 0 0 DRD Op/meth benzo new benzos DRD Op/meth benzo new benzos 300 Dumfries & Galloway +55% 2015v16 200 Lanarkshire +55% 2015v16 200 200 113 85 100 Borders -23% 2015v16 100 73 100 46 50 43 11 17 8 7 0 1 0 1 8 4 13 10 8 7 1 3 1 0 0 0 0 DRD Op/meth benzo new benzos DRD Op/meth benzo new benzos DRD Op/meth benzo new benzos 934 1000 867 200 Scotland 2015-2017 250 Highland +10% 706 800 709 200 Grampian +25% 650 100 552 2015 150 35 29 32 21 29 19 600 493 13 12 8 6 3 9 85 426 100 69 68 75 0 347 2016 48 50 58 400 272 43 41 DRD Op/meth benzo new benzos 50 13 191 2017 7 10 200 63 0 DRD Op/meth benzo new benzos 250 0 200 Forth Valley -28% DRD Op/meth benzo new benzos 150 250 200 Tayside +52% 100 50 31 36 21 37 35 25 22 50 8 3 7 13 150 94 83 0 100 63 62 54 65 49 36 38 33 DRD Op/meth benzo new benzos 50 8 19 0 300 280 Glasgow & Clyde +9% DRD Op/meth benzo new benzos 257 242 250 221 195 180 200 164 250 154 138 150 127 200 150 100 Fife +47% 42 100 66 62 45 50 17 44 34 33 29 39 50 11 3 7 11 0 0 DRD Op/meth benzo new benzos DRD Op/meth benzo new benzos

250 250 Lothian +8% 200 Ayrshire & Arran -28% 200 150 137 85 150 128 113 100 61 71 100 92 43 53 43 38 36 38 33 100 66 66 50 5 8 47 50 19 24 0 2 12 DRD Op/meth benzo new benzos 0 DRD Op/meth benzo new benzos

250 250 200 Lanarkshire – 10% 200 200 150 113 Dumfries & Galloway +29% Borders +30% 73 102 85 87 150 100 46 50 51 43 46 100 100 22 22 50 8 11 17 8 7 6 2 50 13 4 0 1 0 1 13 10 8 7 11 1 3 7 0 1 2 0 0 0 DRD Op/meth benzo new benzos DRD Op/meth benzo new benzos DRD Op/meth benzo new benzos 1000 934 Scotland DRD drug trends 2012-2017

900 867

800

706 700

613 600 581 2012 552 2013

500 473 470 2014 439 426 2015 2016 400 362 345 347 2017

300 272 237 221 196 205 200 176 160 154 123

100 63 31 36

0 DRD Heroin Methadone Cocaine benzo diazepam Benzo other What is killing drug users in Scotland?

• Opiates/methadone are implicated in most DRD, but poly drug use is likely to be a major contributing factor.

• Heroin implicated in 55% of DRD in 2016 falling to 50% in 2017.

• Methadone implicated in 42% of DRD in 2016 increasing to 47% in 2017.

• Gabapentinoids implicated in 26% of DRD in 2016 increasing to 28% in 2017. Switch from gabapentin to more potent pregabalin in 2017.

• Benzodiazepines implicated in 59% of DRD in 2017 with large increase in more potent street benzodiazepines but with regional variations.

• Etizolam and Xanax implicated in 43% of DRD in 2017.

• Trend of increase in cocaine: implicated in 14.2% DRD in 2016 and 18.9% in 2017. Benefits of specific drug analysis by tandem MS v immunoassay

• Cost effective: £12 per sample

24 drugs analysed to confirmation standards on every sample:

• Opiates: morphine, codeine, 6MAM, DHC, Oxycodone • Methadone, buprenorphine, tramadol • Amphetamine, MDMA, Methamphetamine • Cocaine + benzoyl ecgonine • Gabapentin + Pregabalin • Benzos: Diazepam Nordiazepam temazepam oxazepam nitrazepam • Street benzo: etizolam, diclazepam, delorazepam, alprazolam.

• No false positive and more sensitive than immunoassay.

Liquid Chromatography - Tandem Mass Spectrometer Detector TANDEM MS Detector Lothian have an established, cost effective Tandem MS method for drugs of abuse

• Lothian service covers both urine and oral fluid.

• 50µL sample 6 min. per sample

• ISO 15189 accredited proven method

• >40,000 urine; >40,000 oral fluid to date

• Electronic ordering and reporting

• Cannabis only available in urine by immunoassay screening Chromatogram of 24 drugs

Diclazepam Diazepam Oral fluid chromatogram analysed on Delorazepam Waters Xevo Tandem MS in 5.2 minutes Temazepam Nordiazepam Etizolam Alprazolam

Urine also includes EDDP, Methadone

Norbuprenorphine and Oxazepam 7-amino-clonazepam Nitrazepam Buprenorphine

Cocaine Tramadol Benzoyl ecgonine

MDMA Methamphetamine

Amphetamine 6 mono-acetyl morphine

Oxycodone

Pregabalin

Gabapentin Codeine Dihydrocodeine Morphine Drug identification: 1) Retention times match Internal Standard 2) Peaks are same shape. Calibration curve 3) Ratio of quantifying : qualifying match calibrators.

Quantifying ion Calibrators 5µg/L 10µg/L 30µg/L Quality 100µg/L Control 300µg/L Qualifying ion 10µg/L 1000µg/L 20µg/L 50µg/L 100µg/L 300µg/L 400µg/L

Internal Standard Source of oral fluid drug thresholds

Threshold oral Threshold oral Drug Threshold oral fluid Threshold oral fluid fluid fluid EWDTS DRiving Under Influence of Drugs European Workplace Drug Testing DRUID EWDTS screen confirmation RIE Morphine 20 40 40 20 Codeine 20 40 40 20 6MAM 20 4 4 10 DHC 20 40 40 20 AMP 50 40 30 30 Met AMP 50 40 30 30 MDMA 50 40 30 30 Cocaine 10 30 8 10 BEC 10 30 8 10 Methadone 20 50 20 20 EDDP 50 20 NA Diazepam 5 10 10 1 Nordiazepam 1 10 10 1 Temazepam 1 10 10 5 Oxazepam 1 10 10 5 Nitrazepam 1 10 10 5 Clonazepam 1 10 10 NA Gabapentin/Pregab 40 Tramadol 40 Buprenorphine 5 5 1 Norbuprenorphine 5 5 NA Drug thresholds and duration of detectability

Drug Threshold Threshold Duration of detectability urine µg/L Oral fl µg/L Amphetamine MDMA 300 30 48 hrs urine Methamphetamine 24 hrs oral fluid Diazepam Nordiazepam 5 1 long-acting 7+ day urine Other Benzodiazepines 5-20 1-5 <7 days Oral fluid Cannabinoids 50 N/A 2-28 days urine – varies with usage Cocaine metabolite 300 10 48 -72 hrs urine Cocaine N/A 10 1-5 days oral fluid Methadone 300 20 7 days urine EDDP 100 N/A <7 days Oral fluid Opiates 50 20 48 hrs urine 6-MAM 50 10 1-5 days oral fluid Buprenorphine N/A 1 <12-48 hrs Oral fluid Norbuprenorphine 10 N/A 4-6 days urine Gabapentinoids 300 40 48 hrs urine Tramadol 300 40 <48 hrs Oral fluid Heroin (Diacetyl Morphine + Acetyl Codeine) - metabolised too quickly to detect in urine

6-MonoAcetyl Morphine 327.4 Conjugates

Morphine 285.3 Codeine 299.4

Hydrocodone 299.4

Dihydrocodeine 301.4

Conjugates Benzodiazepine metabolism

Chlordiazepoxide (librium) T½ 6-28 h Diazepam (valium) T½ 20-70 h

Nordiazepam T½ 39-96h Nitrazepam T½ 20-30 h Oxazepam* T½ 5-15 h Clonazepam T½ 18-50 h Temazepam* T½ 8-20 h

Flunitrazepam T½ 10-40 h Conjugation 7-Amino metabolites

Urinary Excretion Active drug Drugs implicated in Drug-related deaths in Lothian 2015-2017

160 Lothian DRD - drug trends

• DRD continue to increase 140 137 128 • Heroin peaked in 2016 • Methadone increase 120 • Cocaine increase 100 • Benzos increase 100 • Diazepam increase 2015 • Street benzos increase 80 2016 66 63 62 2017 60 54 51 49 43 42 38 40 35 37

24 19 20 15 17 12 8 2 0 DRD Heroin Methadone cocaine Benzo diazepam other benzo 60 Heroin: 48.9% - 32.4% = 34% drop

50 Cocaine: 15.7%-33.3% = 112% increase

30 6-MAM Cocaine 20

30 Cocaine only 6MAM+Cocaine

20 6MAM only

0 Methadone and buprenorphine in oral fluid % positive

Buprenorphine 40 methadone

16 17 18 16 17 16 17 18 16 16 17 17 18 16 17 16 17 18 16 16 17 17 16 16 16 17 17 17 18 ------Jul Jul Jan Jan Jan Jun Jun Oct Oct Apr Apr Apr Feb Sep Feb Sep Feb Dec Dec Aug Aug Nov Nov Mar Mar Mar May May May Gabapentinoid trend analysis in Lothian Jan 2016 to Sep 2018

30 Gabapentinoid trend in Lothian % positive 16 14 25 12 20 10

15 8 Pregabalin Gabapentin 10 Gabapentin 6 Pregabalin 4 5 2 0

16 17 18 16 17 18 16 17 18 16 17 16 16 17 17 18 18 ------16 17 18 16 17 18 16 17 16 17 18 ------Jul Jul Jul Jan Jan Jan Jul Jul Jul Sep Sep Sep Nov Nov Jan Jan Jan Mar Mar Mar Oct Oct Apr Apr Apr May May May

Gabapentin/pregabalin consistently present in 20-25% of all samples – almost always with opioid: 92% of these take methadone or buprenorphine. Pregabalin increasing, gabapentin falling. A survey of substance misusers in Lothian in 2012: 22% admitted abusing gabapentinoids to potentiate the high obtained from methadone and to increase the level of intoxication. Ref: Baird CRW, Fox P, Colvin LA. Gabapentinoid abuse in order to potentiate the effects of methadone: a survey among substance misusers. Eur Addict Res; 2014; 20:115-118 60 Benzos -14% Xanax +6-9% Etizolam +6-8% 50

Lothian trend in benzodiazepines: 40 Diazepam; nordiazepam; temazepam; 30 ETIZOLAM XANAX oxazepam and nitrazepam 20 BENZO

16 17 18 16 17 18 16 17 18 16 17 18 16 17 16 17 18 ------Jul Jul Jul Jan Jan Jan Sep Sep Sep Nov Nov Mar Mar Mar May May May

12 Lothian trend in street benzos: Xanax v Etizolam trend % March - Sept 2018 10 Diclazepam 22/10925 = 0.20% 8 Delorazepam 28/10925 = 0.26% 6 Xanax Etizolam 4

0 Mar-18 Apr-18 May-18 Jun-18 Jul-18 Aug-18 Sep-18 Glasgow urine samples for amphetamine confirmations: April – Sept 2018 Total Etizolam Diclazepam Delorazepam Alprazolam Total 146 51 2 8 0 61 34.9% 1.40% 5.50% 41.80% Novel “street” Benzodiazepines properties

Etizolam (thienotrizolodiazepine): • is rapidly absorbed and levels peak in 1-2 hours. • Half-life is around 3-4 hours with duration of detectability around 48 hrs • 10 times more potent than diazepam.

Diclazepam: • metabolises to delorazepam and then to lorazepam. • is a longer acting benzo with a half life 42 hours and duration of detectability 7 days.

Delorazepam: • also an active metabolite of diclazepam, metabolised to lorazepam • is rapidly absorbed and peak levels within 1-2 hours. • half life of 80-115 hours and duration of detectability is around 7 days. • like diclazepam is 10 times more potent than diazepam.

Alprazolam (Xanax): • Rarely prescribed in the UK – almost always due to street Xanax. • Short-acting: rapidly absorbed and levels peak 1-2 hours the dose. • Half-life is 6-27 hours and duration of detectability is 2-3 days. • is around 6 times more potent than diazepam. Dihydrocodeine / codeine / oxycodone / tramadol in oral fluid % positive

Oxycodone 10 Tramadol Codeine 8 Dihydrocodeine

16 17 18 16 17 16 17 18 16 16 17 17 18 16 17 16 17 18 16 17 16 17 16 16 16 17 17 17 18 ------Jul Jul Jan Jan Jan Jun Jun Oct Oct Apr Apr Apr Feb Sep Feb Sep Feb Dec Dec Aug Aug Nov Nov Mar Mar Mar May May May Amphetamines / MDMA in oral fluid % positive

3 MDMA - ecstasy Amphetamine

16 17 16 17 16 16 17 17 18 16 17 18 16 17 16 17 18 16 16 17 17 18 16 17 18 16 17 16 17 ------Jul Jul Jan Jan Jan Jun Jun Oct Oct Apr Apr Apr Feb Sep Feb Sep Feb Dec Dec Aug Aug Nov Nov Mar Mar Mar May May May

Methamphetamine – 1 positive in 40,000 samples over 3 years Present in 14 samples (>30µg/L) as contaminant of street amphetamine Possible candidates for inclusion in drugs of abuse panel

Not prescribed 2011 2012 2013 2014 2015 2016 2017 % DRD 2015/16

Total number of DRDs 584 581 527 614 706 868 934

Drug / substance name ANTI-DEPRESSANTS 38% AMITRIPTYLINE 28 32 47 30 41 45 36 FLUOXETINE 3 7 5 8 8 12 12 MIRTAZAPINE 10 18 20 19 35 35 59 SERTRALINE 3 4 4 8 8 12 12

ANTI-PSYCHOTICS 50% OLANZAPINE 5 12 3 3 10 8 9 QUETIAPINE 6 7 4 6 12 5 11

BENZODIAZEPINES FLUBROMAZEPAM . . . . 2 2 8 LORAZEPAM . 1 1 . 6 11 8 PHENAZEPAM 13 19 34 6 6 6 30

OTHER DRUGS CITALOPRAM 11 10 7 9 12 7 5 FENTANYL 4 7 4 4 3 7 15 PROMETHAZINE 1 2 3 7 5 2 6 ZOPICLONE 4 9 15 9 20 22 29 82% Current service in rest of Scotland

• Other HB offer only urine testing by immunoassay • Confirmation testing by Gas Chromatography Mass Spectrometry:- slow, labour intensive and expensive – not available for benzos • Oral fluid by commercial company using immunoassay - unconfirmed drug results. • Identification of gabapentinoids or street benzodiazepines not available

Business case for NHS oral fluid service by tandem MS for Scotland • Outline business case approved by Diagnostic Steering Group – to proceed to full business case • National v Regional options • Reduce costs? • Improve service • Need for accurate workload • Clinical Buy-in? Predicted drug workload - Scotland

Health Board Population Drug users OF tests predicted Urine Total Scotland 5,348,600 61,500 (100%) 110,000 Grampian 584,220 4,600 (7%) 8,300 ?? Highland 320,730 2,000 (3%) 3,600 ?? Orkney 21,580 30 50 0 50 Shetland 23,220 340 600 0 600 Tayside 413,800 4,600 (7%) 8,300 ?? Western isles 27,250 110 200 0 200 NORTH 1,390,800 (25%) 11,680 (19%) 21,050 (90/day) Borders 114,000 710 (1%) 1,300 800 2,100 Fife 367,250 2,900 (5%) 5,200 2,900 8,100 Lothian 858,120 9,800 (16%) 17,500 (1.8 tests/yr/user) 4,500 22,000 EAST 1,339,370 (25%) 13,410 (22%) 24,000 (100/day) 8,200 32,200 Ayrshire & Arran 371,140 4,100 (7%) 7,400 ?? Dumfries & Galloway 148,900 1,300 (2%) 2,300 ?? Forth Valley 300,400 3,100 (5%) 5,600 0 5,600 Lanarkshire 653,300 6,900 (11%) 12,400 ?? Glasgow & Clyde 1,142,390 20,900 (34%) 37,600 20,000 57,600 WEST 2,616,390 (49%) 36,300 (59%) 65,300 (270/day)