Drug prevention and treatment

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Drug prevention and treatment

• Part I
• Pleven October 2004

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Structure of the presentation

• Introduction to addiction problems
• Tolerance
• Dependence
• Addiction
• Drugs (overview)
• Opiates XTC
• Opiates
• From neurobiology to clinical management
• Treatment
• Relapse prevention (AAA)

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Addictions
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Introduction

• Tolerance
• Dependence
• Addiction
• Craving
• relapse

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Tolerance and dependence not pathological
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Adaptations

• Tolerance
• innate
• aquired
• Pharmacokinetic
• Pharmacodynamic
• behavioral
• Cross sensitisation
• Behavioral sensitisation (inverse tolerance)

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Adaptations (2)

• Dependence
• Withdrawal syndrom
• Loss of control
• addiction

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Drugs overview

• Opiates - XTC

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Opioïdes

• Opioïdes (opiacés)
• Héroïn
• Morphine
• Methadone
• Codeine

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Ecstasy

• MDMA
• Produits apparentés
• DMMA
• PMA
• TMA
• DDPR
• 2 CB
• MDMA adjuvants ecstasy

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Ecstasy

• Stimulant
• Hallucinogen
• Conséquence possible
• toxicity
• Hepathic saturation
• Intoxication
• Acute hepathitis

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cannabis

• Cannabis sativa
• 400 composants
• 60 cannabinoids
• Delta 9 THC
• Delta 8 THC
• Synthetic Cannabinoids

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A reality Polydrug abuse
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Why polydrug use

• Tolerance
• Personnality
• Sensation seeking
• Synergic actions (learning)
• genetic (sensitivity)

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Opiates
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Nicotine or caffeine withdrawal ?

• Pause

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Evaluation

• Drogues
• Others drugs (alcohol, medications, )
• Medical problems
• Psychiatric problems
• Psychological context
• Familial context
• Social context
• Interventions, existing network

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Opiacés et opioides

• Natural (opium)
• Synthetic (methadone)
• Semi-synthetic (heroin)

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Opiates - Objectives

• Opiate detoxification
• Harm reduction
• substitution
• MASS
• Controlled heroin deliverance

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Polydrug use

• Complete detoxification
• long term programm
• Step by step

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Others therapeutic objectives

• Medical problems
• (HIV, hépatitis C,)
• Psychiatric comorbidities
• Psychological revalidation
• Social revalidation
• Familial reconstruction - restructuration

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GPs

• Methadone prescription maintenance, withdrawal
• Medical problems
• The center of the patients life

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Substitution objectives

• Stop illegal drugs
• Harm reduction
• Psycho-social revalidation, quality of life
• long term to stop opiate

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Substitution

• General principles
• evaluation
• Global strategy
• Family , psychology,
• Long term

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Méthadone (1)

• Indications
• Opiates Substitution (héroïn, codéin,)
• Stabilisation
• Withdrawal
• Heroin ? methadone ? detoxification

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Méthadone (2)

• opiate receptors agonist
• Effects
• Euphoria (possibilité dabus)
• Sedation
• Analgésia
• decrease gastro-intestinal motility,
• Nausea,
• Cough relieving

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Méthadone (3)

• Surdosage
• Sedation -gt coma
• Respiratory depression
• Hypothermia
• Hypotension
• Hypoglycémia
• Surdosage treatment
• Antagonist naloxone (Narcan) IV, 1 amp de
  0.4mgr (2 hours ok !)
• Watch for 24 - 36 hours
• Multiple intoxications !!!

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Méthadone (4)

• Per os
• t1/2 15 heures
• Plasmatic peak 2 - 6 hours,
• Slow increase, efects from 12 to 24 hours
• Hepatic degradation, renal elimination, cross the
  placenta barrier , through breast milk

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Méthadone side effetcs

• sedation, euphoria, incoordination
• Constipation
• Sweating
• Memory problems
• Libido modifications

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Methadone substitution

• Opiate dependance
• No emergency !!!
• Avoid abuses specific pharmacy, weekly or dayly
  intake.

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Methadone substitution results

• Retention rate 50 à 80
• effetcs
• Nothing lt 3 mois
• Quality of life between 6 and 24 mois
• In general
• 1/3 OK
• 1/3 abstinence and relapses
• 1/3 no effetcs

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Opiate detoxification

• From neurobiology to clinical practice

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Chemical sedation psychiatry

• 1944 Sargant Slater
• We must be prepared to give the patient what he
  needs when it is clear that he needs it, and not
  be dissuaded by illusory dangers. Especially is
  this the case when psychotherapy and
  environmental readjustment have failed to produce
  substantial benefits

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Rapid antagonis induction (RAI)

• General principles
• History
• Actuality
• Clinical applications worldwide
• First application in Belgium - 1998 (Brugmann
  Hospital - Brussels)
• Development of pre-clinical models

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Addicted Rats

• Staircase regimen
• 10 to 100 mg/kg in 3 days
• 3 times/day at 9-12-17
• Third day at 17 experiment (detox)
• Chloral hydrate
• Midazolam
• ketamine

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design
nalox
nalox
saline

2 hours
nalox
nalox
Chloral Hydrate
2 hours
nalox
nalox
Chloral hydrate
4 hours
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Chloral hydrate
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Conclusions (1)

• Do not suppress withdrawal
• Temporary overshadowing
• Signs can reappear even being potentiated
• Different effects on central and peripheral
  systems
• Residual effect of anesthetic agent ?

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 Design
nalox
nalox
saline
nalox

nalox
nalox
Midazolam
nalox
nalox
nalox
Ketamine
nalox
2 hours
4 hours
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midazolam or ketamine
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Conclusions (2)

• Interference in withdrawal expression
• Each anesthetic interfere specifically
• Residual effect or complex pharmacological
  interactions ?
• If residual effect decreased doses decreased
  residual effects

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midazolam or ketamine (dose 75)
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Conclusions (3)

• Dosage reduction 75
• Interference of withdrawal signs
• Anesthetic-specific and dose dependent
• Not compatible with residual effect
• Pharmacological basis ?

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Hypothesis

• Interactions with endogenous opiates
• Naloxone ? increase endorphines
• Endogenous opiates more competitive
• Increase dosage to block exo/endo opiates
• Anesthetic agents ? interactions with opiates
  receptors
• GABA agonists
• NMDA antagonists

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Hypothesis 2

• Interference with excitatory amino acids
• Noradrenergic storm
• Internal mechanism (cellular adaptations)
• K channels decreased activity
• External mechanism
• Excitatory input
• Glutamate from nucleus paragigantocellularis
• Anesthetics agents and glutamate
• GABA agonist and NMDA antagonist decrease
  glutamate liberation

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Addicted rats and relapse

• Morphine in water
• 8 days
• 0,1-- 0,2 -- 0,3 -- 0,4 -- 0,5- 0,5 0,5 0,5
• Detoxification procedures
• ? free choice paradigm
• Water vs. water morphine (0,5 mg/ml)
• Why forced conditioning before free choice
  paradigm.

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Relapse evaluation
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Design
Free choice paradigm opiate vs water 30 days
Control Naloxone Midazolam naloxone Ketamine
naloxone
detoxification
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Detoxification procedure and relapse rate
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Naltrexone and relapselate vs early induction
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Conclusions

• Procedure do not interfere with relapse rate
• Naltrexone interfere with relapse rate
• Early induction better than late induction
• Opiate receptor blockade
• Inverse agonist ?

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Final analysis

• Anesthetic agents useful in interference of
  withdrawal signs
• Pharmacological exponations
• Narcosis obviously not required
• Whatever the procedure naltrexone is the key
  issue for post-detoxification
• Early induction is associated with better outcome

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References

• Streel al. (2000) Life Sci. 67 2883-2887
• Streel al. (2001) Life Sci. 70 517-522
• Streel al. (2001) Add. Biol. 6 385
• Streel Verbanck (2003) Add. Biol. 8 123-128

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limitations

• The purpose is to detoxify human not rats
• Anonym reviewer

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Withdrawal in humans after RAI
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The problem is not to stop, but not to start
again

• Relapse prevention

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Biology and psychology

• Biology
• Craving
• Risk of relapse
• If drug intake ? reinstatement of biological
  dependence

• Psychology
• Craving
• Need to learn how to stay abstinent
• Detoxification procedure is to fast

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Learning the language of abstinence

• Antagonist assisted abstinence
• (AAA)

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Learning foreign language analogy

• To learn English
• England ? immersion method
• Fast and Effective
• Once you learn the new language you can switch
  from one to another
• To learn new habits without drugs
• Immersion ?
• A place without drugs ?
• Sooner or later the patients will have to face
  drug reality
• A place where drug has no effect
• This place does not exist !
• Create such a place

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A place where drug has no effect pharmacology

• The opiate receptor
• G-protein coupled
• Agonists and antagonists
• opiate receptor blockade
• Opiate receptor antagonists
• Naltrexone
• Nalmefene
• Per os
• Implants

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A place where drug has no effects Psychology

• Learn English in England
• Need to communicate
• Want to communicate
• You cant ? Learn
• Opiate receptor blockade
• Need to take drugs
• Want to take drugs
• Drugs have no effects
• Have to learn

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Antagonist assisted abstinence

• Combination of pharmacology and counseling

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Antagonist assisted abstinence

• Pharmacology
• Receptor blockade
• Test the blockade
• Technical relapse
• No drug effect

• Psychology
• Maintenance stage
• Develop new habits

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Pharmacology reinforce the effectiveness of
psychological follow-up
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Antagonist assisted abstinence

• Naltrexone
• Per os (50 mg/Day)
• Implants
• 3 6 months
• Avoid early relapses
• Increase psychotherapy effectiveness

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Last but not least

• A short note on opiate management in children

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Opiate withdrawal in children
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Paediatric Intensive Care UnitH.U.D.E.R.F

• Medico-surgical unit
• 15 beds
• Neonates and childrenlt18 years
• Cardiac surgery 40

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Sufentanil

• 1000 x more powerful than morphine
• Fast action delay 3-4 minutes
• Short action time 30 minutes-1 hour
• Less cardiovascular effects ( cardiac surgery)

Sufenta
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Tolerance and Withdrawal

• Tolerance decrease in a drugs effect over
  time or need to
  increase dose to achieve the same effect
• Withdrawal physical signs and symptoms
  occuring when a sedative or
  analgesic agent is stopped in a patient
  physically tolerant
• Physical dependence need to continue a sedative
  or analgesic agent to prevent withdrawal

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Sedation in cardiac surgery

• Continuous IV opioids Sufentanil
• Continuous IV benzodiazepine Midazolam
• Prolonged infusions 48 hours to 21 days

WITHDRAWAL
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• How to recognise a child with withdrawal syndrome
  ?
• How to differentiate withdrawal from pain ?

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Activation of sympathetic system
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Gastro-intestinal manifestations
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Central Nervous System
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Paediatric Scoring Systems of Withdrawal

• Describe and quantify the patients symptoms
• Assess the need of treatment

lt 3 months FINNEGAN
? 3 months PAEDIATRIC ABSTINENCE SCORE
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Neonatal Abstinence Score
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Validation of a paediatric abstinence score

• DESIGN Prospective clinical trial
• PATIENTS 28 patients aged 3 months to 15 years
  (average 13 months)
• Continuous infusion of sufentanil gt 5
  day (2 patients excluded unrelated
  medical complications)
• METHODS Sufentanil interrupted abruptly if
  infusion lasted lt 216 hours and tapered
  if infusion lasted gt 216 hours (9 days)
• Withdrawal scoring system
  based medical literature
• Nursing team observations
  every 3 hours during the first day and
  every 6 hours over the following 48 hours
• Medical team clinical
  observations concomitantly and
  indenpendtly, withdrawal treatment with
  oral methadone

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Validation of a paediatric abstinence score

• RESULTS
• Underlying conditions cardiac surgery 22
  
  severe
  pneumonia 3
  
  near-drowning 1
• Incidence of withdrawal 21 patients (71)
• Cumulative dose of sufentanil mean 260 ?g/kg
  (63-1244)
• Lenght of sufentanil infusion mean 247 hours
  ( 120-495)
• Associated sedative or analgesic drugs
  midalozam infusion (25/26)
  clonidine (5/26)
  ketamine (1/26)
  paracetamol
  (26/26)

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Validation of a paediatric abstinence score
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Validation of a paediatric abstinence score
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Treatment of withdrawal
GOAL OF THE THERAPY patient not agitated
or distressed, sleeping between feeding not
too much sedated, but with signs of mild
withdrawal

• METHADONE
• starting dose 0.1 mg/kg every 6 hours
• increasing dose 0.05 mg/kg/dose

• NURSING
• reduction of the stimuli
• swaddling
• presence of the parents

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CONCLUSION

• Opioïd withdrawal is a real problem in PICU
• Paediatric abstinence score is an
• appropriate tool to identify withdrawal
  (validation)
• Methadone is an effective treatment for
  children