. Euro-DEN Plus: 2013-2017 . 23,947 presentations

Classical Recreational Drugs and New Psychoactive Substances

Professor Paul I Dargan Guy’s and St Thomas’ NHS Foundation Trust and King’s College London London, UK

“Classical Drugs” Classification

Stimulants Depressants

MDMA (ecstasy) Opioids Amphetamine Benzodiazepines Cocaine GHB/GBL/1,4BD

Hallucinogenics

LSD Ketamine

1 Opioid Antagonist – Naloxone GHB and its Analogues GBL / 1,4BD . Competitive opioid antagonist – Onset 1-2 minutes, duration 30-90 minutes . Give in titrated 100 – 200 micrograms doses . Naloxone should be given IV – Can be given IM if no IV access . Aim to restore normal oxygenation/improve alertness . Infusion if long-acting preparation / features recur – Initial hourly dose of infusion is 2/3 of initial dose

. What additional test is important in everyone with opioid toxicity? Paracetamol concentration . Ingestion of all 3 causes similar clinical features

Effects of GHB / GBL Management of acute GHB/GBL toxicity

1-2mL . Mild-Moderate: – relaxation, appreciation for music & dancing, euphoria . Supportive care: ABC and monitoring – nausea, tremor, diarrhoea, agitation . Coma normally lasts 1-3 hours 3-4mL . Severe: . Airway reflexes generally well maintained – Increasing drowsiness …. coma, convulsions, respiratory depression, . Need for intubation: bradycardia – Not usually indicated if maintaining airway, no vomiting NB. Vomiting in 15-20%, convulsions in <10% . Think about dependence / risk of withdrawal in those with acute toxicity 3-6mL . Deaths: – Mostly pre-hospital, related to aspiration How many have seen a patient with this?

2 GHB Dependence/Withdrawal Acute Stimulant Toxicity

. GHB: GABA-B agonist, also upregulates dopamine . Agitation and aggression, psychosis . Very frequent use: 1-2 hourly including overnight . Sweating, dilated pupils, bruxism – short duration from last dose to withdrawal . Seizures . Severe acute withdrawal syndrome: marked psychosis and agitation . Hypertension, chest pain, arrhythmias . High-dose benzodiazepines: 100-200mg++ diazepam in first 24 hours – Baclofen (GABA-B) may have potential role . Hyperthermia – Barbiturates/propofol for resistant withdrawal – Rhabdomyolysis, acute renal failure, DIC . Stroke (haemorrhagic/thrombotic)

Acute Stimulant Toxicity Acute Stimulant Toxicity . Hyperpyrexia . Agitation / psychosis – T > 39-40ºC: medical emergency – Quiet, reassuring atmosphere . COOL RAPIDLY: comparative rates of cooling – Benzodiazepines – Packing in ice: 0.20ºC/min – Caution with anti-psychotics whilst sympathomimetic – Helicopter downdraft: 0.11ºC/min . Hypertension (systolic >200mmHg) – Spraying with water: 0.05ºC/min – Benzodiazepines – Endovascular cooling: 0.04ºC/min – IV nitrates (GTN) . Benzodiazepines – AVOID b –blockers – Paralysis – CYPROHEPTADINE 12mg PO/NG then 4mg 4hrly – (carvedilol), (chlorpromazine), ± dantrolene

3 Cocaine Associated Acute Coronary Syndrome Cocaine Induced Vasoconstriction

. Risk of ischaemia: 24-fold in first hour after use . Landmark study – May be delayed 4-6 hours – Intranasal cocaine (2 mg/kg) to patients . Studies in Eastern USA, Spain undergoing routine cardiac catheterisation – “Recent” cocaine use in 15-25% with ACS Cocaine Phentolamine Propranolol Mechanism of cocaine related myocardial ischaemia Coronary vascular resistance    Coronary artery diameter    . Most important = coronary artery vasoconstriction Coronary sinus blood flow    . Also: myocardial oxygen demand,  endothelin (vasoconstrictor), nitric oxide (vasodilator),  platelet activation and aggregation . Effects mediated through a adrenergic mechanism . Effects worsened by b blockade

Effect of Nitrates

. Benzodiazepines increase this nitrate related vasodilation . Oxygen + Aspirin – Also decrease stimulant effects . Benzodiazepines – Decrease stimulant effects; increase nitrate vasodilatation

JACC 1991;18:581 . IV GTN . b blockers are contra-indicated – Increase blood pressure, risk of seizures, animal mortality

4 Second Line Treatments What is a New Psychoactive Substance (NPS)? . Medical treatments – Calcium channel blockers (e.g. Verapamil) – Alpha-blockers (e.g. Phentolamine)

. Coronary Angiography – Primary angioplasty – Intra-luminal drugs (e.g. GTN) . Synthetic substances - Small structural modifications of existing drugs - Sufficient to take outside legal control, insufficient to significantly change pharmacology or desired effects

Evolution of NPS 730 NPS monitored by EMCDDA . Rapidly evolving field: knowledge amongst clinicians, analytical Over half are detected each year toxicologists, legislative authorities & others often lags behind changes – Pre 2005: GHB and GBL – 2006-2008: Piperazines (1-BZP, TFMPP) – 2008-2009: ‘Spice’ (synthetic cannabinoids) – 2008-2010: Cathinones (mephedrone …) – 2011-2014: Methoxetamine, arylcyclohexamines, pipradols, indanes, tryptamines, NBOMes, continued use of others … – 2015-2017: All of the above AND synthetic opioids/benzodiazepines

5 Manufacture and Importation . Most drugs are synthesized in China and bordering countries in South East Asia . Generally shipped labelled as other chemicals in “white powder” form: difficult to spot by customs . Final packaging prior to sale occurs locally – zip-locked bags of powder, or pressed into tablets / encapsulated . Sold to users through conventional street level dealers, headshops and the Internet

Europol, EMC DDA, ACMD

Expect the unexpected Crystals sold as MDMA (ecstasy) seized in UK (2017) NPS: Acute Toxicity Analysis identified the synthetic cannabinoids ADB-FUBICA and ADB-FUBINACA

Tablet sold as ecstasy: 15 ED presentations in Hungary Analysis identified the synthetic cannabinoid ADB-FUBINACA

5g herbal material bought on Internet 2017 Analysis identified NPS opioid U-47,700: 112.5 mg/g ~ 36 mg per joint > 30 U-47,700 related deaths in Europe

Fake oxycodone seized in Sweden 2017 © Swedish Police Analysis identified methoxyacetylfentanyl

6 2013-17: 23,947 presentations involving 36,232 drugs NPS Acute Toxicity: Under-recognition using self-report

NPS detected in 7.6% of 158 acute toxicity presentations with no clinical history of NPS use

Synthetic cannabinoids detected in 10% of 179 acute toxicity presentations Self-reported synthetic cannabinoid use in only ½ of these

“Classical” Recreational Drugs NPS

Stimulants Stimulants Depressants Piperazines Depressants Cathinones Opioids GBL / 1,4-butanediol Amphetamines Synthetic cocaine Benzodiazepines Novel opioids MDMA (ecstasy) Pipradrols GHB/GBL Novel benzodiazepines Cocaine Indanes Benzofurans NBOMes Hallucinogens Hallucinogens Glaucine Ketamine analogues LSD Tryptamines Psylocibin Synthetic cannabinoids Ketamine Salvia TFMPP

7 Cathinones Mephedrone Amphetamine b-keto derivatives of amphetamine Methylone MDMA (‘ecstasy’) (bk-MDMA)

Methedrone 4’-MMA Butylone MDEA MDPV Methylenedioxypyrov alerone MBDB

Catha edulis Methamphetamine (Khat) Methcathinone Mephedrone 4-methy lmethcathinone

8 Synthetic Cannabinoids . Sold as smoking mixtures, also pure powder and liquid for vaping . 1st Generation synthetic cannabinoids reported in Europe in 2008

. Relatively similar to THC chemically ~ 1-5x more potent than THC at CB-1 receptor . Classified in UK/Europe in 2010-12 – Led to emergence of 2nd/3rd generation compounds Potency associated with outbreaks of acute toxicity and deaths

rd 3 Generation Synthetic Cannabinoids Synthetic Cannabinoid Associated Coagulopathy . Particularly MDMB-CHMICA & the PINACA/FUMINACAs – Agitation, psychosis … drowsiness/coma – Metabolic acidosis – Vomiting, tachycardia, seizures – Less commonly ACS, rhabdomyolysis, AKI . Dozens of fatalities across Europe, North America, Russia, Japan . Toxicity contributed to by potency and more risky patterns of use in problematic drug users and other vulnerable populations

9 Synthetic Cannabinoid Associated Coagulopathy Novel benzodiazepines . 23 novel benzodiazepines in last 5yrs; 2.5 million tablets seized in 2017 . >150 patients presented to Illinois hospitals Mar/Apr 2018: bleeding and severe coagulopathy associated with synthetic cannabinoid use . Used to self-treat adverse effects of stimulants, insomnia, withdrawal . Generally longer T½ than prescription benzodiazepines ± slower onset . Detailed data on 34 patients of action – Mean presentation INR 15.8 . Reports of deaths from around Europe – 1 fatality: intracerebral bleed – Median 1 (IQR 1-3) day since SC use; daily use 47%, 1st use 12% – Vitamin K1 given orally (100%) and/or IV (68%) - FFP / other clotting products in 59%, blood transfusion in 15% – Super-warfarins involved: brodifacoum, difenacoum, bromadiolone

Novel Opioids Conclusions

. 49 novel opioids reported including 34 novel fentanils . Changing patterns of drugs available and being used – Often found with heroin/cocaine – Huge variety of new NPS – Novel administration routes: nasal sprays, eye droppers – BUT generally management is based on clinical features present – Very potent and longer T½ than heroin – Greater toxicity associated with more recent and potent NPS - Hundreds of fatalities and acute toxicity outbreaks . Acute toxicity of recreational drugs / NPS: three broad categories - Higher dose (titrated) naloxone, longer observation may be required - Stimulants … hyperpyrexia: benzos / ice cooling are the priority - Hallucinogens … rarely causes severe clinical features - Depressants … titrated naloxone for opioids … GHB withdrawal

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