New psychoactive substances Simon Thomas National Poisons Information Service (Newcastle) Newcastle upon Tyne Hospitals NHS Foundation Trust Medical Toxicology Centre, Newcastle University Deaths related to drug poisoning England and Wales: 2017 registrations
Clinical Pharmacology, Therapeutics and Prescribing 4 https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/bulle 2 2 tins/deathsrelatedtodrugpoisoninginenglandandwales/2017registrations NPS are usually closely related to established drugs of misuse
Methamphetamine Class A drug of misuse NPS are usually closely related to established drugs of misuse
Mephedrone Uncontrolled until 2010 Class / subclass Conventional examples NPS examples (receptors) Stimulants Amphetamines Ethylphenidate (DA, NA, 5HT) Cocaine 25I-NBOMe Benzofurans Stimulants/ Empathogens MDMA Mephedrone (5HT, DA, NA) Hallucinogens LSD 1P-LSD (Tryptamines/ergolines) Dimethyltryptamine Alpha-methyltryptamine (5HT2) Hallucinogens/Dissociatives Ketamine Methoxetamine (NMDA, Glu) Cannabinoids/CRAs Cannabis SCRAs (CB1, CB2) e.g. JWH-018, 5F-PB 22 Depressants - Benzodiazepines Diazepam Etizolam (GABA) Diclazepam Depressants - Opioids Heroin MT-45, U47,700 (Opioid) Morphine novel fentanyls NPS notified in the EU
Clinical Pharmacology, Therapeutics and Prescribing 4 ED presentations, drugs of misuse (EURO-DEN Plus)
* * * * * *
Clinical Pharmacology, Therapeutics and Prescribing 4 NPIS top 10 drugs of misuse, 2017/18
n % change n % change Telephone enquiries (2017/18) (from 2016/17) TOXBASE accesses (2017/18) (from 2016/17) 1 Cocaine (including crack) 256 57.1% Cocaine (including 11,971 4.1% crack) 2 MDMA (including 164 17.1% MDMA including 10,057 -2.2% ecstasy) ecstasy) 3 Cannabis 135 16.4% Heroin 4,810 -7.5% 4 Heroin 96 41.2% Cannabis 4,328 11.3% 5 Unknown drug of 86 -14.0% Amphetamine 4,108 3.2% misuse* 6 Diazepam 72 -5.3% Methylphenidate 3,945 1.1% 7 Codeine (incl co-codamol) 70 70.6% SCRAs (including 3,528 11.4% ‘spice’)* 8 Pregabalin 62 63.2% Ketamine 2,786 29.7% 9 Methadone 62 -7.5% GHB / sodium oxybate 2,694 3.9%
10 SCRAs (including ‘spice’)* 59 15.7% Branded products* 1,845 -10.5% 8 Psychoactive Substances Act 2016
• Applies to: • Any psychoactive substance if the substance is likely to be used for its psychoactive effects and regardless of its potential for harm • Exemptions • Substances already controlled by the Misuse of Drugs Act, nicotine, alcohol, caffeine and medicinal products • Offences • Production, supply, possession with intent to supply Time trends - NPIS data (SCRAs and branded products) 1200
1000 Toxbase accesses
800
600
400
200
0
Jul-12 Jul-15 Jul-18
60 Jul-09
Jan-10 Jan-13 Jan-16
Jun-08 Jun-11 Jun-14 Jun-17
Oct-09 Oct-12 Oct-15 Oct-18
Apr-12 Apr-15 Apr-18
Sep-08 Feb-11 Sep-11 Sep-14 Sep-17
Dec-08 Dec-11 Dec-14 Dec-17
Aug-10 Aug-13 Aug-16
Nov-10 Nov-13 Nov-16
Mar-09 Mar-14 Mar-17
May-10 May-13 May-16 50 Telephone enquiries
40 P < < P 0.001* 30 < P 0.001*
20
10
0
Jul-09 Jul-12 Jul-15 Jul-18
Jan-10 Jan-13 Jan-16
Jun-08 Jun-11 Jun-14 Jun-17
Oct-09 Oct-12 Oct-15 Oct-18
Apr-12 Apr-15 Apr-18
Sep-08 Feb-11 Sep-11 Sep-14 Sep-17
Dec-11 Dec-14 Dec-17
Clinical Pharmacology,Dec-08 Therapeutics and Prescribing 4
Aug-10 Aug-13 Aug-16
Nov-10 Nov-13 Nov-16
Mar-09 Mar-14 Mar-17
May-10 May-13 May-16 Deaths involving NPS (England and Wales)
140 120 114 123 100 80 82 61 60 63 40 55 31 20 0 Illicit drug overdose deaths with fentanyl detected, British Columbia , Canada (2012-16)
12 Fentanyls – opportunities for modification to structure IONA Study
Inclusion criteria • 16 years or older • Suspected exposure to • NPS [‘NPS cohort’] since Mar 2015 • non-pharmaceutical opioid [‘Opioid cohort’], since Jan 2017 • Presence of severe acute toxicity (specific criteria) • Patient consent (or consultee advice with subsequent retrospective Clinicalconsent) Pharmacology, Therapeutics and Prescribing 4 IONA - Methods
▪ Residual clinical samples (pre-consent) and new samples (blood, urine, post consent) provided with patient data (structured data collection sheet): • Age, sex, limited postcode • Results of investigations • Reported exposures • Treatments given • Clinical effects recorded • Outcome
▪ All identified by unique code (linked anonymised data)
▪ Analysis of samples by liquid chromatography-tandem mass spectrometry (No analysis for GHB/GBL, Δ-9-THC, organic nitrites or ethanol)
Clinical Pharmacology, Therapeutics and Prescribing 4 IONA Study Data analysed March 2015-January 2019
• Data presented for 542 participants with analytical data available • Separation into cohorts (update from abstract) • Predominantly males, high incidence of poly- drug exposure
Opioid NPS cohort cohort Detected drug group (n=461) (n=81) Nil 17 (3.7%) - NPS 267 (58%) 17 (21%) Conventional 384 (84%) 77 (95%) Both 207 (45%) 13 (16%) NPS alone 60 (13%) 4 (5%) Conventional alone 177 (39%) 63 (78%) Clinical Pharmacology, Therapeutics and Prescribing 4 Numbers of drugs identified in cases of severe toxicity
Clinical Pharmacology, Therapeutics and Prescribing 4 Most common NPS groups and SCRA
Clinical Pharmacology,Proportion Therapeutics of participants and with Prescribing at least one 4 positive sample SCRA = synthetic cannabinoid receptor agonist Non-opioid conventional (top 10)
ClinicalProportion Pharmacology, of participants Therapeutics andwith Prescribing at least one4 positive sample Opioids
Confirmation pending*
Confirmation pending*
ClinicalProportion Pharmacology, of Therapeutics participants and with Prescribing at least 4 one positive sample Time trends – Overall
(NPS cohort only)
P < < P 0.001* P < < P 0.001*
Trusts 5 10 12 19 20 23 25 Clinical Pharmacology,Proportion Therapeutics of participants and Prescribing with at 4 least one positive sample Classification of drugs of misuse by clinical effects
▪ Depressants ▪ Stimulants ▪ Hallucinogens ▪ (Volatile substances)
There is overlap between these groups Clinical Pharmacology, Therapeutics and Prescribing 4 22 22 Depressants
Chemical group Traditional Novel Opioids Heroin MT-45 Morphine AH-7921 Methadone Carfentanil Fentanyl Benzodiazepines/ Diazepam Etizolam Benzodiazepine- Temazepam Phenazepam like Alprazolam Diclazepam Zopiclone Flubromazepam Zolpidem Flunitrazolam
Barbiturates Phenobarbitone
GHB/related GHB GBL Clinical Pharmacology, Therapeutics1,4 Butanediol and Prescribing 4 23 23 Depressants – clinical effects
Non-specific More specific (found with all) Opioids Benzodiazepines GHB / related General Hypothermia Needle tracks Urinary incontinence Piloerection Drooling Neurological Sedation, confusion, Miosis Retrograde Headache, amnesia, coma, ataxia, reduced amnesia seizures, tremor, muscle tone/reflexes myoclonus CVS Hypotension Bradycardia (relative), Bradyarrhythmia Pulmonary oedema Respiratory Respiratory depression/failure, Aspiration pneumonia Abdominal Nausea/vomiting, Nausea/vomiting, Ileus Muscle Rhabdomyolysis
Antidote Naloxone Flumazenil -
Specific clinical effects of type Clinical Pharmacology, TherapeuticsEffects and commonPrescribing to 4 all depressants 24 Stimulants Chemical group Traditional Novel Cocaine Cocaine Dimethocaine Flourotropococaine Amphetamines Amphetamine 5-fluoroamphetamine MDMA, Methylamphetamine PMA, PMMA, Cathinones Khat Mephedrone, Methylone, MDPV, α-PVP
Piperazines 1-Benzylpiperazine Triflouromethylphenylpiperazine (TFMPP)
Benzofurans/difurans 5-APB, Bromodragonfly Aminoindans 5,6-Methylenedioxy-2-aminoindane (MDAI) D-Series DOB, DOM 2C-series 2C-B, 2C-E NBOMe compounds 25I-NBOMe Piperidines Methylphenidate Desoxypipradrol, Diphenylprolinol Ethylphenidate ClinicalThiophenes Pharmacology, Therapeutics and Prescribing 4 Methiopropamine 25 25 Phenethylamine-related stimulants and hallucinogens - pharmacology
▪ Reuptake inhibition (and reverse transportation) of Dopamine
• Dopamine Ratios dependent on drug and location in brain • Norepinephrine • Serotonin Norepinephrine Also ▪ Sodium channel blockade (cocaine) ▪ Interaction with NMDA and glutamate/NMDA receptors (cocaine) Serotonin ▪ 5HT2 agonist (MDMA) Clinical Pharmacology, Therapeutics and Prescribing 4 26 MDMA 26 Stimulant toxidrome
General Euphoria, Sweating Hyperthermia Anorexia Neurological Mydriasis Agitation/psychosis Confusion Trismus Seizures CVS Tachycardia Hypertension, Arrhythmias Muscle Tremor Rhabdomyolysis, Laboratory Hyponatraemia Metabolic acidosis 27 Sympathomimetic stimulants – acute complications of use
▪ Seizures (especially cocaine) ▪ Metabolic acidosis ▪ Hyponatraemia (especially MDMA) ▪ Myocardial ischaemia/infarction (especially cocaine) ▪ Arrhythmias (especially cocaine) ▪ Circulatory collapse, pulmonary oedema (especially cocaine) ▪ Stroke (especially amphetamines) • Cerebral haemorrhage • Cerebral infarction ▪ Hyperpyrexia, rhabdomyolysis, malignant encephalopathy, DIC, multi-organ failure (especially MDMA)
Clinical Pharmacology, Therapeutics and Prescribing 4 28 28 Hallucinogens
Chemical group Traditional Novel Cannabinoids Cannabis SCRA (e.g. JWH-018, AM2201, STS-135, BB-22, 5F-PB-22, 5F-ADB, AMB-FUBINACA)
Arylcyclohexamines Ketamine Methoxetamine (‘dissociatives’) PCP 2-FDCK Ergolines/Tryptamines LSD AMT DMT 4-hydroxy,N,N- dimethyltryptamine (Psilocin)
Clinical Pharmacology, Therapeutics and Prescribing 4 29 29 Hallucinogens – clinical effects
Non-specific SCRAs Arylcyclohexamines Tryptamines /dissociatives /ergolines General Dry mouth Hyperthermia Hyperthermia
Neurological Agitation, confusion, Hypertonia Sedation Mydriasis behavioural Myoclonus Blurred vision Myoclonus disturbances, Sedation Ataxia hallucinations, Ataxia psychosis, seizures CVS Tachycardia Bradycardia Hypertension Hypertension Chest pain ECG changes Respiratory Dyspnoea, Respiratory T2 Respiratory depression failure Abdominal Nausea/vomiting Laboratory Hypokalaemia Creatine kinase Renal dysfunction increased Metabolic acidosis Long term Chronic cystitis No info No info Clinicalcomplications Pharmacology, Therapeutics and Prescribing 4 30 Serotonin syndrome - features ▪ Cognitive-behavioural changes • agitation, confusion, hallucinations, coma, ▪ Neuromuscular dysfunction • tremor, teeth grinding, myoclonus, hyperreflexia ▪ Autonomic dysfunction • tachycardia, fever, hyper or hypotension, flushing, diarrhoea ▪ Others • Vomiting, seizures, hyperpyrexia, rhabdomyolysis, renal failure, coagulopathies
Clinical Pharmacology, Therapeutics and Prescribing 4 31 NPS – Management considerations
▪ You may not know what specific substance you are dealing with ▪ Multiple substance use is very common ▪ Specific treatments are limited to naloxone (opioids) and flumazenil (BDP) ▪ Provide general supportive care and treat the clinical effects you encounter Clinical Pharmacology, Therapeutics and Prescribing 4 Antidotes
▪ Use according to clinical assessment • Suspected opioid – naloxone • Suspected BDP – consider flumazenil but risk of seizures if co-used stimulants (and you/the patient may not know about these)
Clinical Pharmacology, Therapeutics and Prescribing 4 Treatment – naloxone dosing (adult)
High dose Low dose Community Acute severe overdose (TOXBASE) Palliative care or high risk of withdrawal Bystander use (Prenoxad®)
• Initial dose 400 mcg IV • Dilute 2mL of an 800 microgram/2mL • 0.4 mL (400 mcg) IM • No response after 60 seconds -further formulation of naloxone with 8mL of • Repeat every 2-3 mins (every 2 mins 800 mcg water for injection or sodium Thischloride highduring CPR)dose until content of syringe • Still no response after another 60 • Initial dose 100-200 mcg IV (=2mg in 2 ml) is used seconds –further 800 mcg • Further doses of 100 mcg everyregimen 2 mins is suitable for • Still no response – further 2 mg. until satisfactory respiration • Large doses (4 mg) may be required in a OR seriously poisoned patient. • Give the resultant solution bynon slow -pharmaceutical • Aim for reversal of respiratory intravenous injection 80mcg at a time depression, not full reversal of consciousness. fentanyl poisoning
34 Managing complications
Clinical effect Responsible agents Management
Agitation, psychosis, Stimulants, Benzodiazepines aggression hallucinogens Bradycardia Opioids, GHB, SCRA Atropine
Convulsions Stimulants, Benzodiazepines hallucinogens Metabolic acidosis Stimulants, Sodium bicarbonate hallucinogens Narrow complex tachycardia Stimulants, No treatment or short acting beta-blocker hallucinogens (extreme cases)
Clinical Pharmacology, Therapeutics and Prescribing 4 Managing complications Clinical effect Responsible Management agents
Hyperthermia Stimulants, Mist and fan, ice packs, ice baths, invasive cooling, hallucinogens benzodiazepine, dantrolene (muscular hyperactivity)
Hypertension Stimulants, Benzodiazepines, then nitrates. CCBs, nitroprusside or hallucinogens phentolamine may be considered
Hypotension ALL Intravenous fluids Rhabdomyolysis Opioids, IV Fluids. Urinary alkalinisation Stimulants, hallucinogens Serotonin syndrome Stimulants, Cyproheptadine, (chlorpromazine, diazepam) hallucinogens Clinical Pharmacology, Therapeutics and Prescribing 4 Reporting Illicit Drug Reactions (RIDR)
• RIDR is a national system for reporting new and unusual adverse illicit drug reactions • Aims to reduce the length of time between drug-related health harms emerging and developing effective treatment responses. • Professionals can submit reports by registering with the RIDR website • Information requested includes symptoms, suspect substance(s), frequency of use, dose and date of presentation.
REPORT TREAT ✓ Report the new and unusual ✓ Get an up-to-date headline summary of the latest clinical adverse illicit drug reactions that messages and intelligence on new psychoactive substances you encounter quickly online: (NPS) and other drug health harms: report-illicit-drug- ✓ report-illicit-drug-reaction.phe.gov.uk/latest-information/ reaction.phe.gov.uk/
Clinical Pharmacology, Therapeutics and Prescribing 4 Summary
▪ Misused drugs (novel or otherwise) can be broadly classified into depressants, stimulants, hallucinogens and volatiles, although there is overlap between these groups
▪ In the last decade many new agents (NPS) have emerged. These are almost always related to established drugs of misuse and have similar clinical effects.
▪ Severe drug toxicity presenting to hospital is commonly associated with multiple drug exposures.
▪ Management of toxicity associated with drug misuse is generally supportive, with treatment of complications as appropriate
▪ Antidotes are available for opioids and benzodiazepines. Conventional doses are appropriate for new varieties
▪ Please report novel or unusual episodes of illicit drug poisoning via RIDR 38