Epidemiology & Pharmacological approaches in Substance Misuse

Dr Shivashankar, ST6 29 th October, 2009

Agenda

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Epidemiology

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Pharmacological approaches

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MCQs

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CASCs

Alcohol

 1 Unit = 10 ml or 8 g of absolute alcohol  Recommended max level= 21 for men & 14 for a women  The permissible limit of alcohol for driving is 80 mg per 100 ml of blood, here in UK.

Epidemiology:

 Increase in per capita alcohol consumption in UK by 31% over the last 20 years.

 22000 premature deaths per year and costs an estimated £20 billion (PM’s strategy unit, 2003)   In UK, prevalence of dependence – 5% (Farrell et al, 2001) In US, ECA study – 14% lifetime (Reiger et at, 1991)

Epidemiology:

 Age- heaviest

i

n late teens & early twenties - less with advancing age - peak for dependency b/n 30-44 yrs  Sex - M: F=3:1   More in divorced, separated or never married In unskilled manual occupations, publicans, travelling salesmen, journalists, dentists & doctors

Neurobiology:

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Agonist at neuroinhibitory GABA receptors

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Antagonist at Neuroexcitatory glutamate / NMDA

Brain-reward circuit

Amphetamine Cocaine Heroin Nicotine

Alcohol • • • • •

Functions reward (motivation) pleasure, euphoria motor function (fine tuning) compulsion perseveration

Heroine

Goals of treatment:

 Physical health  Psychological adjustment ( or Mental health)  Vocational adjustment  Social adjustment  Interpersonal adjustment  Legal status & Criminal activity  Polydrug use & dependence; Blood-borne virus risks, needle sharing and sexual behaviour

Stages of Change Model:

Pre-contemplation Contemplation Relapse Decision Action Maintenance

Prochaska, JO, DiClemente, CC (1992)

Stages of change in the modification of problem behaviors. Prog Behav Modif. 28:183-218.

Abstinence v/s Controlled drinking

 Traditionally one of the controversial topic  Controlled drinking may be an option for young, socially stable drinkers with short, less severe drinking histories  Abstinence should be the goal for people with heavy dependence or those with protracted alcohol problems.

Screening

Questionnaires:      CAGE AUDIT (Alcohol Use Disorders Identification Test) FAST (Fast Alcohol Screening Test) MAST (Michigan Alcoholism Screening Test) PAT (Paddington Alcohol Test) Chemical investigations:      AST ALT GGT MCV CDT

Characteristics of Tests

AST ALT GGT MCV CDT AUDIT Sensitivity 30-50% 30-50% 50-70% 25-52% 40-70% 70-92% Specificity 80-86% 80-86% 75-85% 85-95% 80-98% 93-98% Duration 1-2 months 1-2 months 1-2 months 1-3 months 1-3 weeks Past Year

Alcohol Withdrawal Syndrome:

 wide range of severity of withdrawal symptoms and in some cases withdrawal may be life-threatening 

Early withdrawal symptoms

-occur up to 12 hours after the last drink (sometimes within a few hours if the patient is severely alcohol dependent). - include restlessness, tremor, sweating, nausea, vomiting, loss of appetite, and insomnia, with tachycardia and systolic hypertension. -in moderate withdrawal, the signs are more marked and transient auditory hallucinations in clear consciousness may also occur.

Alcohol Withdrawal Syndrome:

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Withdrawal fits

-can occur at 12 to 48 hours, especially if there is a previous history of withdrawal fits or epilepsy. -Fits tend to be generalized and may occur in bouts. -30% of cases are followed by DTs.

Alcohol Withdrawal Syndrome:

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delirium tremens

-usually develops at 48 to 72 hours -patients consuming more than 30 units per day (a bottle of spirits per day or equivalent) are particularly at risk. -Clinical features include: marked tremor, confusion, disorientation, agitation, restlessness, fearfulness, visual and auditory hallucinations, delusions, autonomic disturbances; tachycardia, sweating, fever and dehydration -DTs often present insidiously with night time confusion and carry a mortality of 1-2%.

Community Vs in-patient detoxification:

Most patients can be managed in the community but in-patient detoxification is required if a patient:  is severely dependent on alcohol, therefore likely to have severe withdrawal symptoms;  has a current or past history of severe withdrawal symptoms such as delirium tremens (DTs) or epileptiform seizures;  suffers with a serious or life threatening medical or psychiatric condition;  is at risk of self harm or harming others;  is homeless, lacks social support or had previous unsuccessful community detox attempts

Detoxification

 Reducing doses of Benzodiazepines  Commonly used benzo is the Chlordiazepoxide (diazepam 5mg  chlordiazepoxide 15mg)  Longer acting benzos- risk of accumulation in elderly and with liver failure  Shorter acting benzos like lorazepam or oxazepam in patients with alcoholic liver disease

Dose of benzodiazepines

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Severity of dependence -clinical history -number of units per day -score of SADQ

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Severity of Withdrawals -CIWA

Severity of Alcohol Dependence Questionnaire (SADQ)

 is a self-administered, reliable questionnaire  The SADQ questions cover the following aspects of dependence syndrome -Physical withdrawal symptoms -Affective withdrawal symptoms -Relief drinking -Frequency of alcohol consumption -Speed of onset of withdrawal symptoms  The degree of severity of alcohol dependence can be classified as mild (upto 15), moderate (16-29), severe (30-40) and very severe (up to 40-60).

SEVERITY OF ALCOHOL DEPENDENCE QUESTIONAIRE (SADQ)

Please recall a typical period of heavy drinking in the last 6 months.

When was this? Month most appropriate response Year Please answer all the following questions about your drinking by circling your

During that period of heavy drinking

1. The day after drinking alcohol, I woke up feeling sweaty ALMOST NEVER SOMETIMES 2. The day after drinking alcohol, my hands shook first thing in the morning 3. The day after drinking alcohol, my whole body shook violently first thing in the morning if I didn’t have a drink.

4. The day after drinking alcohol, I woke up absolutely drenched in sweat.

5. The day after drinking alcohol, I dread waking up in the morning 6. The day after drinking alcohol, I was frightened of meeting people first thing in the morning OFTEN NEARLY ALWAYS 7. The day after drinking alcohol, I felt at the edge of despair when I awoke.

8. The day after drinking alcohol, I felt very frightened when I awoke.

9. The day after drinking alcohol, I liked to have an alcoholic drink in the morning 10. The day after drinking alcohol, I always gulped my first few alcoholic drinks down as quickly as possible.

SEVERITY OF ALCOHOL DEPENDENCE QUESTIONAIRE (SADQ) 11. The day after drinking alcohol, I drank more alcohol to get rid of the shakes 12. The day after drinking alcohol, I had a very strong craving for a drink when I awoke.

13. I drank more than a quarter of a bottle of spirits in a day (OR 1 bottle of wine OR 7 beers) 14. I drank more than half a bottle of spirits per day (OR 2 bottles of wine OR 15 beers) 15. I drank more than one bottle of spirits per day (OR 4 bottles of wine OR 30 beers) 16. I drank more than two bottles of spirits per day (OR 8 bottles of wine OR 60 beers)

Imagine the following situation:

1. You have been completely off drink for a few weeks 2. You then drink very heavily for two days How would you feel the morning after those two days of drinking?

17. I would start to sweat.

18. My hands would shake 19. My body would shake 20. I would be craving for a drink.

Measurement of withdrawals:

 can be measured by using Addiction Research Foundation Clinical Institute Withdrawal Assessment of Alcohol scale, revised. (CIWA-Ar)  a very sensitive instrument and helps in adjusting the dose of benzodiazepines  can be mild (<10), moderate (10-20) or severe (>20).

Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised, (CIWA-Ar)

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Nausea & Vomitting Tremor Paroxysmal sweats Anxiety Agitation Tactile disturbances Auditory disturbances Visual disturbances Headache Orientation

Treatment Regime

Daily Alcohol Consumption Severity of dependence Starting doses of Chlordiazepoxide 15 – 30 Units Moderate SADQ Score 15-30

15 - 30 mg q.d.s.

Day 1 (starting dose) Day 2 Day 3 Day 4 Day 5 Day 6 Day 7

15 qds 10 qds 10 tds 5 tds 5 bd 5 nocte 20 qds 15 qds 10 qds 10 tds 5 tds 5 bd 5 nocte

Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 30 - 40 Units Severe SADQ Score 30-40

30 - 40 mg q.d.s.

30 qds 25 qds 20 qds 15 qds 10 qds 10 tds 5 tds 40 qds 35 qds 30 qds 25 qds 20 qds 15 qds 10 qds 5 bd 5 nocte 10 tds 5 tds 5 bd 5 nocte

40 - 60 Units Very Severe SADQ Score 40-60

50 mg q.d.s

50qds 45 qds 40 qds 35 qds 30 qds 25 qds 20 qds 15 qds 10 qds 10 tds 5 tds 5 bd 5 nocte

A flexible regimen for moderate dependence:

Morning Lunch Tea Bedtime PRN Day 1 20mg 20mg 20mg 20mg 20mg up to x 4 in 24 hours If 3-4 PRNs used on Day 1 - remain on 20mg QDS for Day 2 with 2 PRN doses of 20mg available If 1-2 PRNs used on Day 1 - remain on 20mg QDS with no PRN If no PRNs used on Day 1 – proceed to Day 2 on protocol PRN is not usually required after initial 48 hour period.

Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 15mg 10mg 10mg 5mg 5mg 15mg 10mg 15mg 10mg 10mg 5 mg 15mg 10mg 10mg 5mg 5mg 5mg

Vitamin Supplementation

 Wernicke’s encephalopathy - due to thiamine deficiency - triad of nystagmus, ophthalmoplegia & ataxia - lessions around third ventricle and aqueduct, including dorsomedial thalamus, the mamillary bodies & hypothalamus  Korsakoff’s syndrome - persistent, prominent impairment of recent memory & hence new learning - immediate recall & procedural memory may be intact - confabulation can occur

 About 80% of alcoholic patients recovering from Wernicke’s encephalopathy develop Korsakoff’s syndrome.  Victor et al (1971) reported that 25% of patients with Korsakoff syndrome recovered, 50% showed improvement over time and 25% unchanged. While it is unlikely that any established patients completely recovering, it is probably correct to say that 75% show a variable degree of improvement, while 25% show no change.

Vitamin Supplements

 All heavy drinkers should receive vitamin supplements.  Severely dependent drinkers and those at a risk of Wernicke’s Encephalopathy will require parental preparations (e.g. Pabrinex High Potency).  Anaphylaxis is a rare but recognised complication.

Vitamin Supplements

 Incipient Wernicke’s encephalopathy : Two pairs high-potency thiamine injection three times daily for 3 days, followed by one pair once daily for 3-5 days depending on response.

 At-risk (significant weight loss, poor diet, signs of malnutrition) : One pair high-potency thiamine injection once daily for 3-5 days  Lower risk: Thiamine 100 mg orally, three times daily, plus vitamin B compound strong two tablets two times daily during detox  Continue Oral Thiamine 50 mg TDS for six months after detoxification or indefinitely in persons with chronic alcohol problems or low oral thiamine intake.

Others

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Carbamazepine loading in patients with untreated seizure or those with more than two seizures during previous withdrawal episodes

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Neuroleptics like Haloperidol in small doses can be used for severe behavioural disturbances.

Relapse Prevention

Disulfiram (Antabuse):  Inhibits aldehyde dehydrogenase  Leads accumulation of acetaldehyde, causing headache, flushing, palpitations, nausea & vomiting  Halitosis is common side effect.

 CI – in cardiac failure, coronary artery disease, HT, liver disease, pregnancy & breastfeeding  Can cause fatal acute hepatotoxicity in about 1 in 25000 patients.

Disulfiram

 Hughes & Cook (1997) reviewed 24 outcome studies for oral disulfiram & 14 for disulfiram implant -No good evidence for implant  Others (Fuller et al, 1986; Chick et al, 1992)- no overall difference in drinking outcome, but reduction in the number of drinking days  Better outcome if supervised.

Acamprosate

 A synthetic taurine analogue, acts on Glutamate & GABA system  Reduces craving  CI- severe renal & hepatic impairment  Modest treatment effect in a recent meta analysis (Boothby LA et al, 2005)

Naltrexone

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An opioid receptor antagonist

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Blocks endogenous opioid pathways stimulated by alcohol use

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Reduces the reinforcing effects

Project COMBINE

 Anton et al, 2006; Designed to evaluate the efficacy of two relapse prevention medications in combinations with behavioural treatment  1,383 abstinent patients with dependence  Naltrexone, acamprosate, N+A, placebo; all medical treatment with or without behavioural management. Ninth gp only with behavioural management.

 Naltrexone gp did better than others, no evidence of benefit from acomprosate

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B.

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MCQ1: One of your A&E colleague asks for you to suggest a screening test for problem alcohol use which can be quick but efficient.

What do you suggest?

AUDIT MAST FAST TWEAT T-ACE

MCQ1: One of your A&E colleague asks for you to suggest a screening test for problem alcohol use which can be quick but efficient.

What do you suggest?

A.

B.

C.

D.

E.

AUDIT MAST FAST TWEAT T-ACE Answer: c. FAST Fast alcohol Screening Test (Hodgson et al.,2002)

MCQ 2: Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised, (CIWA Ar) does not include the following

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B.

C.

D.

E.

Tremor Auditory disturbances Visual disturbances Seizure Orientation

MCQ 3: The chemical composition of Acomprosate is

A.

B.

C.

D.

E.

Calcium bisacetyl homotaurine Magnesium bisacetyl homotaurine Calcium acetyl homotaurine Magnesium acetyl homotaurine Calcium tetraacetyl homotaurine

MCQ 4: Project COMBINE (Anton et al, 2006) which was designed to evaluate the efficacy of two relapse prevention medications in combinations with behavioural treatment showed relative superiority with the following group

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B.

C.

D.

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Naltrexone Acomprosate Naltrexone + Acomprosate Placebo Combined behavioural intervention

MCQ 5: Severity of Alcohol Dependence Questionnaire (SADQ) doesnot include the following

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B.

C.

D.

E.

Physical withdrawal symptoms Affective withdrawal symptoms Relief drinking Use inspite of harmful consequences Frequency of alcohol consumption

CASC 1

You assessed Mrs Smith, a 38 year old lady and diagnosed her as suffering from alcohol dependence. She has previous history of DTs and altered LFTs.

Discuss the management options with her partner, Mr Smith. She has given consent to speak to him.

Break !

Opioids

 Natural (poppy, papaver somniferum morphine, heroin, codeine extracts) –  Synthetic – pethidine, methadone, buprenorphine, dipipanone  Endogenous opiates- enkephalins & endorphins  Acts through opioid receptors, morphine & heroin are quite selective for mu receptors  Smoked (chasing the dragon), snorting or injected (IV, IM / SC) (Skin popper)

Opioids

 Average opiate use in the previous year in adult population – 1% ( British household survey, Coulthard et al, 2002)  UK has one of the higher prevalence of problem opiate use in Europe – 6/1000 (Kraus et al, 2003)  Annual mortality for opiate dependent users – 1-2%, mostly from overdose

Effects:

  Euphoria & analgesia Sedation, emotional numbing, dream like state  Physiological - pupillary constriction - respiratory depression - decreased sympathetic outflow - nausea & vomiting - constipation - seizures can occur

Withdrawals

 Thought to reduce firing at NA neurones in the locus coeruleus, sudden cessation increased NA activity.

 Appears within 6-12 hrs, peaking at 48-72 hrs and subsiding by 7-10 days.

 Muscle & joint pains, dysphoria, insomnia, agitation, lacrimation, dilated pupils, yawning, shivering, diarrhoea, fatigue, sweating and gooseflesh (cold turkey)  Unpleasant but not life threatening

Pharmacological Treatment

 ODs: IV /+ IM naloxone ( opioid antagonist)  Detoxification v/s Maintenance - Clonidine & Lofexidine: alpha 2 agonists - Methadone: long acting mu agonist - Buprenorphine: partial mu agonist - Suboxone ( buprenorphine+ naloxone 4:1) -Ultra rapid detoxification: antagonists under GA -Injectable opioid treatment  Relapse prevention - Naltrexone: opioid antagonist.

NICE Guidelines, Jan 2007:

 Methadone and buprenorphine (oral formulations) are recommended as options for maintenance therapy in the management of opioid dependence.

 The decision about which drug to use should be made on a case by case basis. If both drugs are equally suitable, methadone should be prescribed as the first choice.

 Methadone and buprenorphine should be administered daily, under supervision, for at least the first 3 months. Both drugs should be given as part of a programme of supportive care.

Amphetamine

 Powder form, ‘speed’ ‘whizz’  Methamphetamine ‘ice’  Used orally (bombing), IV or snorting  Release of catecholamines, particularly dopamine, from presynaptic terminals  In UK, 22% of 16-29 yr olds have used at least once with further 2% in the last yr (Ramsay et al, 2001)

Effects

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Elevate mood, induce euphoria and feeling of wellbeing Over-talkativeness, overactivity, anorexia and insomnia Pupils dilate, pulse & BP increases Arrhythmia, severe HT, CVA & circulatory collapse Seizures & Coma Sometimes dysphoria, anxiety & panic

 Amphetamine induced psychosis and exacerbation of underlying psychotic illness  Withdrawals - ‘crash’: anxiety, tremulousness, dysphoric mood, lethargy, fatigue, nightmares (with rebound REM sleep), headache, sweating, cramps and insatiable hunger.

- depression  Treatment is mainly psychosocial, with some evidence for dexamphetamine substitute prescription.

Cocaine

 ‘charlie’, ‘coke,’ ‘snow,’ ‘crack’  In UK, lifetime use – 6% (Ramsay et al, 2001)  Effects & withdrawals similar to speed.

 Cardiac arrhythmias, MI, myocarditis , cardimyopathy, cerebral infarction & subarachnoid haemorrhage can occur  Treatment is mainly psychosocial

MDMA (Ecstasy)

 3,4 methylenedioxymethamphetamine  Stimulant with mild hallucinogenic properties  Increases release of DA and also 5-HT  Produces positive mood state with euphoria, sociability & heighted perceptions along with loss of appetite, tachycardia, bruxism, sweating  Deaths can occur with hyperthermia, cardiac arrhythmias, hypertensive crises & intracranial haemorrhage  Can cause 5-HT neuronal damage (McCann et al, 1998)

Hallucinogens

 Lysergic acid diethylamide (LSD)  Natural: magic mushrooms ( psilocybin psilocybe semilanceata ) containing  In UK, 29% aged 16-29 have used atleast once, with 5% in the previous month (Ramsay et al, 2001)  Act mostly as 5-HT 2A partial agonists  ‘Trip’: pleasant state of detachment, euphoria with distortions of perception , synaesthesia  General physiological arousal with increase in pulse, BP, dilated pupils

Hallucinogens

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‘Bad trip’: anxiety, mood disturbances, hallucinations with alterations in consciousness

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No withdrawal syndrome & dependence syndrome is uncertain.

Phencyclidine & Ketamine

 NMDA antagonists    Produce drunkenness, analgesia of toes & fingers and anaesthesia Agitation, altered consciousness, psychotic like symptoms, nystagmus, inc BP, ataxia, muscle rigidity, convulsions and absence of response to environment with eyes open.

Adrenergic crises with heart failure, CVA & malignant hyperthermia  Tolerance can occur, withdrawals are rare

Cannabis

 From cannabis sativa, ‘marijuana’, ‘grass’, ‘hashish’  Psychoactive component: delta-9-tetrahydrocannabinol  In UK, 27% used at least once with 6% current users (Ramsay et al, 2001)  Causes dry mouth, tachycardia, injected conjunctivae, distorted sense of time, perceptual abnormalities, panic, paranoia, impaired concentration & confusion  Irritate respiratory tract & potentially carcinogenic  No evidence of tolerance or dependence  Arseneault et al (2004) : cannabis use in adolescence increased the risk of developing schizophrenia about two fold; and removal of cannabis from society would prevent 8% of schizophrenia cases.

Khat

 ‘natural amphetamine’, from catha edulis plant  Possession & use are not illegal in UK  Active constituents, cathinone & cathine, are scheduled as class C drugs  Chewing of leaves, common in countries around red sea and eastern coast of Africa  Produces sympathomimetic & CNS stimulation similar to amphetamine  Dependence- debatable, psychological rather than physical.

 Short lived psychosis, mania and rarely depression

Nicotine

 In UK, 29% of adults smoke tobacco  Around half of all smokers die prematurely  Their overall life expectancy reduced by an average of 8 years.

 Single most common preventable cause of death in Britain, 120,000 death/ year (13 / hour)  1000 admissions/ day with smoking related illnesses, with estimated cost of £1500 million/ year for NHS; while UK treasury earns £8 billion in tax on tobacco sold in the UK.

Nicotine

 Each cigarette provides around a mg of nicotine.

 Less than 4% of smokers smoke less frequently than daily  Agonist at nicotinic Ach receptors  Causes dependence, activates reward circuit like other addictive drugs

Nicotine

 Smoking cessation is UK government’s one of the top 13 priorities     Smoking cessation programmes Bupropion: inhibits reuptake of DA & NA Varenicline: partial agonist of nicotinic receptor Nicotine replacement therapy

MCQ 1: What is the best time for detoxification in pregnancy?

Options:

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B.

C.

D.

E.

Never in pregnancy. First trimester Second trimester Third trimester Anytime in pregnancy

MCQ 2: You want to prescribe an alpha 2 agonist to control opioid withdrawals for one of your patients attending the drug and alcohol clinic. He has a tendency to get low blood pressure with various drugs. Select the most appropriate drug you choose .

Options:

A.

B.

C.

D.

E.

Buprenorphine Clonidine Lofexidine Methadone Naltrexone

MCQ 3: What is the recommended minimal period of supervised consumption for someone starting on methadone treatment for opiate dependence?

Options: A.

B.

C.

D.

E.

One month Two months Three months Four months Six months

MCQ 4: One of your patients in the ward wants quit smoking and seen a new drug varenicline in the internet. How does the new drug act?

A.

B.

C.

D.

E.

Options: Alpha2 beta4 nicotinic acetylcholine receptor partial agonist Alpha4 beta2 nicotinic acetylcholine receptor partial agonist Alpha4 beta2 nicotinic acetylcholine receptor antagonist Alpha2 beta4 nicotinic acetylcholine receptor antagonist Alpha2 beta4 nicotinic acetylcholine receptor agonist

     MCQ 5: Choose the structure that plays a dominant role in the reward pathway of the brain facilitating the reinforcing effects of drugs that cause dependence.

Options: Amygdala Frontal operculum Temporal pole Superior temporal gyrus Ventrotegmental area

Thank You!