new psychoactive substances · 2019. 8. 26. · new psychoactive substances simon thomas ......

New psychoactive substancesSimon Thomas

National Poisons Information Service (Newcastle)Newcastle upon Tyne Hospitals NHS Foundation Trust

Medical Toxicology Centre, Newcastle University

Clinical Pharmacology, Therapeutics and Prescribing 4

Deaths related to drug poisoningEngland and Wales: 2017 registrations

22https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/bulletins/deathsrelatedtodrugpoisoninginenglandandwales/2017registrations

http://nuth-vintranet1/cms/Home.aspx

NPS are usually closely related to established drugs of misuse

MethamphetamineClass A drug of misuse

http://nuth-vintranet1/cms/Home.aspx//upload.wikimedia.org/wikipedia/commons/4/4d/Racemic_methamphetamine.svg

NPS are usually closely related to established drugs of misuse

MephedroneUncontrolled until 2010

http://nuth-vintranet1/cms/Home.aspx//upload.wikimedia.org/wikipedia/commons/b/b9/4-Methylmethcathinone.svg//upload.wikimedia.org/wikipedia/commons/4/4d/Racemic_methamphetamine.svg//upload.wikimedia.org/wikipedia/commons/b/b9/4-Methylmethcathinone.svg//upload.wikimedia.org/wikipedia/commons/4/4d/Racemic_methamphetamine.svg

Class / subclass

(receptors)

Conventional examples NPS examples

Stimulants

(DA, NA, 5HT)

Amphetamines

Cocaine

Ethylphenidate

25I-NBOMe

Benzofurans

Stimulants/ Empathogens

(5HT, DA, NA)

MDMA Mephedrone

Hallucinogens

(Tryptamines/ergolines)

(5HT2)

LSD

Dimethyltryptamine

1P-LSD

Alpha-methyltryptamine

Hallucinogens/Dissociatives

(NMDA, Glu)

Ketamine Methoxetamine

Cannabinoids/CRAs

(CB1, CB2)

Cannabis SCRAs

e.g. JWH-018, 5F-PB 22

Depressants - Benzodiazepines

(GABA)

Diazepam Etizolam

Diclazepam

Depressants - Opioids

(Opioid)

Heroin

Morphine

MT-45, U47,700

novel fentanyls



NPS notified in the EU



ED presentations, drugs of misuse (EURO-DEN Plus)

* * * * * *


NPIS top 10 drugs of misuse, 2017/18

Telephone enquiriesn % change

TOXBASE accessesn % change

(2017/18) (from 2016/17) (2017/18) (from 2016/17)

1 Cocaine (including crack) 256 57.1% Cocaine (including crack)

11,971 4.1%

2 MDMA (including ecstasy)

164 17.1% MDMA including ecstasy)

10,057 -2.2%

3 Cannabis 135 16.4% Heroin 4,810 -7.5%

4 Heroin 96 41.2% Cannabis 4,328 11.3%

5 Unknown drug of misuse*

86 -14.0% Amphetamine 4,108 3.2%

6 Diazepam 72 -5.3% Methylphenidate 3,945 1.1%

7 Codeine (incl co-codamol) 70 70.6% SCRAs (including ‘spice’)*

3,528 11.4%

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


• 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

Psychoactive Substances Act 2016



Time trends - NPIS data (SCRAs and branded products)

P <

0.0

01

*

P <

0.0

01

*

0

200

400

600

800

1000

1200Ju

n-0

8

Sep

-08

Dec

-08

Mar

-09

Jul-

09

Oct

-09

Jan

-10

May

-10

Au

g-1

0

No

v-1

0

Feb

-11

Jun

-11

Sep

-11

Dec

-11

Ap

r-1

2

Jul-

12

Oct

-12

Jan

-13

May

-13

Au

g-1

3

No

v-1

3

Mar

-14

Jun

-14

Sep

-14

Dec

-14

Ap

r-1

5

Jul-

15

Oct

-15

Jan

-16

May

-16

Au

g-1

6

No

v-1

6

Mar

-17

Jun

-17

Sep

-17

Dec

-17

Ap

r-1

8

Jul-

18

Oct

-18

Toxbase accesses

0

10

20

30

40

50

60

Jun

-08

Sep

-08

Dec

-08

Mar

-09

Jul-

09

Oct

-09

Jan

-10

May

-10

Au

g-1

0

No

v-1

0

Feb

-11

Jun

-11

Sep

-11

Dec

-11

Ap

r-1

2

Jul-

12

Oct

-12

Jan

-13

May

-13

Au

g-1

3

No

v-1

3

Mar

-14

Jun

-14

Sep

-14

Dec

-14

Ap

r-1

5

Jul-

15

Oct

-15

Jan

-16

May

-16

Au

g-1

6

No

v-1

6

Mar

-17

Jun

-17

Sep

-17

Dec

-17

Ap

r-1

8

Jul-

18

Oct

-18

Telephone enquiries


Deaths involving NPS (England and Wales)

3155

63

82

114 123

61

0

20

40

60

80

100

120

140


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 consent)



IONA - Methods▪ Residual clinical samples (pre-consent) and new samples (blood, urine, post consent) provided

with patient data (structured data collection sheet):

▪ 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)

• Age, sex, limited postcode• Reported exposures• Clinical effects recorded

• Results of investigations• Treatments given• Outcome



IONA StudyData 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

Detected drug groupNPS cohort

(n=461)

Opioid cohort(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%)



Numbers of drugs identified in cases of severe toxicity



Most common NPS groups and SCRA

Proportion of participants with at least one positive sampleSCRA = synthetic cannabinoid receptor agonist



Non-opioid conventional (top 10)

Proportion of participants with at least one positive sample



Opioids

Proportion of participants with at least one positive sample

Confirmation pending*

Confirmation pending*



Time trends – Overall(NPS cohort only)

P <

0.0

01

*

P <

0.0

01

*

Proportion of participants with at least one positive sampleTrusts 5 10 12 19 20 23 25



Classification of drugs of misuse by clinical effects

▪ Depressants

▪ Stimulants

▪ Hallucinogens

▪ (Volatile substances)

2222

There is overlap between these groups



DepressantsChemical group Traditional NovelOpioids Heroin

MorphineMethadoneFentanyl

MT-45AH-7921Carfentanil

Benzodiazepines/ Benzodiazepine-like

DiazepamTemazepamAlprazolamZopicloneZolpidem

EtizolamPhenazepamDiclazepamFlubromazepamFlunitrazolam

Barbiturates Phenobarbitone

GHB/related GHBGBL1,4 Butanediol 2323



Depressants – clinical effectsNon-specific(found with all)

More specific

Opioids Benzodiazepines GHB / related

General Hypothermia Needle tracksPiloerection

Urinary incontinenceDrooling

Neurological Sedation, confusion, coma, ataxia, reduced muscle tone/reflexes

Miosis Retrograde amnesia

Headache, amnesia, seizures, tremor, myoclonus

CVS Hypotension Bradycardia (relative), Pulmonary oedema

Bradyarrhythmia

Respiratory Respiratory depression/failure, Aspiration pneumonia

Abdominal Nausea/vomiting, Ileus

Nausea/vomiting,

Muscle Rhabdomyolysis

Antidote Naloxone Flumazenil -

Specific clinical effects of typeEffects common to all depressants

24



StimulantsChemical group Traditional Novel

Cocaine Cocaine DimethocaineFlourotropococaine

Amphetamines AmphetamineMDMA, MethylamphetaminePMA, PMMA,

5-fluoroamphetamine

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, DOM2C-series 2C-B, 2C-ENBOMe compounds 25I-NBOMePiperidines Methylphenidate Desoxypipradrol, Diphenylprolinol

EthylphenidateThiophenes Methiopropamine

2525



Phenethylamine-related stimulants and hallucinogens - pharmacology

▪ Reuptake inhibition (and reverse transportation) of

• Dopamine

• Norepinephrine

• Serotonin

Also

▪ Sodium channel blockade (cocaine)

▪ Interaction with NMDA and glutamate/NMDA receptors (cocaine)

▪ 5HT2 agonist (MDMA)

Ratios dependent on drug and location in brain

Dopamine

Norepinephrine

Serotonin

26MDMA26

http://nuth-vintranet1/cms/Home.aspxhttp://en.wikipedia.org/wiki/File:Dopamine2.svghttp://en.wikipedia.org/wiki/File:Norepinephrine_structure_with_descriptor.svghttp://en.wikipedia.org/wiki/File:Serotonin-2D-skeletal.pnghttps://en.wikipedia.org/wiki/File:MDMA_(simple).svg

Stimulant toxidromeGeneral 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)

2828



Hallucinogens

Chemical group Traditional NovelCannabinoids Cannabis SCRA (e.g. JWH-018, AM2201,

STS-135, BB-22, 5F-PB-22, 5F-ADB, AMB-FUBINACA)

Arylcyclohexamines(‘dissociatives’)

KetaminePCP

Methoxetamine2-FDCK

Ergolines/Tryptamines LSDDMT4-hydroxy,N,N-dimethyltryptamine (Psilocin)

AMT

2929



Hallucinogens – clinical effectsNon-specific SCRAs Arylcyclohexamines

/dissociatives

Tryptamines

/ergolines

General Dry mouth Hyperthermia Hyperthermia

Neurological Agitation, confusion,

behavioural

disturbances,

hallucinations,

psychosis, seizures

Hypertonia

Myoclonus

Sedation

Ataxia

Sedation

Blurred vision

Ataxia

Mydriasis

Myoclonus

CVS Tachycardia Bradycardia

Chest pain

ECG changes

Hypertension Hypertension

Respiratory Dyspnoea,

T2 Respiratory

failure

Respiratory

depression

Abdominal Nausea/vomiting

Laboratory Hypokalaemia

Renal dysfunction

Metabolic acidosis

Creatine kinase

increased

Long term

complicationsNo info

Chronic cystitisNo info

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

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



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)


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• No response after 60 seconds -further

800 mcg• Still no response after another 60

seconds –further 800 mcg• Still no response – further 2 mg. • Large doses (4 mg) may be required in a

seriously poisoned patient. • Aim for reversal of respiratory

depression, not full reversal of consciousness.

• Dilute 2mL of an 800 microgram/2mL formulation of naloxone with 8mL of water for injection or sodium chloride

• Initial dose 100-200 mcg IV• Further doses of 100 mcg every 2 mins

until satisfactory respirationOR• Give the resultant solution by slow

intravenous injection 80mcg at a time

• 0.4 mL (400 mcg) IM• Repeat every 2-3 mins (every 2 mins

during CPR) until content of syringe (=2mg in 2 ml) is used

34

This high dose regimen is suitable for non-pharmaceutical fentanyl poisoning



Managing complicationsClinical effect Responsible agents Management

Agitation, psychosis, aggression

Stimulants, hallucinogens

Benzodiazepines

Bradycardia Opioids, GHB, SCRA Atropine

Convulsions Stimulants, hallucinogens

Benzodiazepines

Metabolic acidosis Stimulants, hallucinogens

Sodium bicarbonate

Narrow complex tachycardia Stimulants, hallucinogens

No treatment or short acting beta-blocker (extreme cases)



Clinical effect Responsible agents

Management

Hyperthermia Stimulants, hallucinogens

Mist and fan, ice packs, ice baths, invasive cooling, benzodiazepine, dantrolene (muscular hyperactivity)

Hypertension Stimulants, hallucinogens

Benzodiazepines, then nitrates. CCBs, nitroprusside or phentolamine may be considered

Hypotension ALL Intravenous fluids

Rhabdomyolysis Opioids,Stimulants, hallucinogens

IV Fluids. Urinary alkalinisation

Serotonin syndrome Stimulants, hallucinogens

Cyproheptadine, (chlorpromazine, diazepam)

Managing complications



Reporting Illicit Drug Reactions (RIDR)

REPORT TREAT

✓ Report the new and unusual adverse illicit drug reactions that you encounter quickly online: report-illicit-drug-reaction.phe.gov.uk/

✓ Get an up-to-date headline summary of the latest clinical messages and intelligence on new psychoactive substances (NPS) and other drug health harms:

✓ report-illicit-drug-reaction.phe.gov.uk/latest-information/

• 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.


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

new psychoactive substances · 2019. 8. 26. · new psychoactive substances simon thomas ......

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