1. RCP Cardiff November 2015 “Why don’t they just stop using?” The psychopharmacology of (opiate) addiction Jan Melichar BSc MB BS MD FRCPsych Medical Director, DMT Ltd & Medical Director, DHI Consultant Psychopharmacologist, Glen Hospital, Bristol Consultant, Complex Pain Service, Southmead Hospital Consultant Psychiatrist, Somerset Drug Service Until 1/2015: HEFCE “New Blood” Clinical Senior Lecturer in Psychopharmacology, University of Bristol Consultant in Substance Misuse, Inpatient and Outpatient Specialist NHS Drug & Alcohol Service, Bristol Thanks to Fergus Law, Anne Lingford Hughes, David Nutt, Nathan Wallbank and others for some of the slides

2. Another way of looking at it: When I grow up I’m going to be an addict I want help (Methadone & Recovery ™ Agenda)

3. Social dominance in monkeys: dopamine D 2 receptors and cocaine self-administration. Morgan, et al 2002 Nature Neuroscience, 5 ( 2), 169 - 174.

4. Di Chiara et al., Neuroscience, 1999.,Fiorino and Phillips, J. Neuroscience, 1997. Natural Rewards Elevate Dopamine Levels 0 50 100 150 200 060120180 Time (min) % of Basal DA Output NAc shell Empty Food Sex Box Feeding 100 150 200 DA Concentration (% Baseline) Sample Number 12345678 Female Present

5. Amphetamine Cocaine Time After Drug Morphine 0 100 150 200 250 0123 hr Time After Drug % of Basal Release Accumbens Caudate Nicotine Di Chiara and Imperato, PNAS, 1988 Effects of Drugs on Dopamine Release

6. Tobacco, 32% Heroin, 23% Cocaine HCl, 16%-17% Alcohol, 15% Stimulants other than cocaine, 11% Cannabis, 9% Anxiolytic, sedative, & hypnotic drugs, 9% Analgesic drugs, 9% Psychedelic drugs, 5% Inhalant drugs, 5% Estimated proportion of drug users who have become drug dependent % of Users who become Dependent, 1992-98. Crack-cocaine, Estimated 20% Reproduced with permission of JC Anthony; Data from Anthony et al., 1994; Chen & Anthony, 2004)

7. National Epidemiologic Survey on Alcohol and Related Conditions, 2003. Age 0.0% 0.2% 0.4% 0.6% 0.8% 1.0% 1.2% 1.4% 1.6% 1.8% 5 5 10 15 21 25 30 35 40 45 50 55 60 65 % in each age group who develop first-time dependence CANNABIS ALCOHOL TOBACCO Addiction Is A Developmental Disease that starts in adolescence and childhood Age at tobacco, alcohol, and cannabis dependence per DSM IV

8. Why take drugs ? Pleasure Escapism Euphoria Rush ‘feel normal’ Anxiolytic Overcome withdrawal Loss of control positive reward or reinforcement negative reinforcement ‘urge’, compulsion } } }

9. Addiction syndrome (remarkably similar between drugs of abuse) Salience Mood modification Tolerance Similarity of relapse rates between drugs Refining of mode of delivery to increase rate of drug delivery to the brain Withdrawal Conflict Relapse

10. Environmental Cues & Conditioned Responses Positive and negative affective states associated with drug taking can become linked with stimuli in the drug taking environment This association between drug and external stimuli called conditioning Environmental stimuli can act as powerful reinforcement for taking drug Important in relapse

11. Adapted from Volkow et al., Neuropharmacology, 2004. Drive OFC Saliency NAc Memory Amygdala Control PFC/ACG Non-Addicted Brain NO GO Addicted Brain Drive Memory Control GO! Saliency “Why don’t they just stop using?” Because Addiction Changes Brain Circuits

12. Biological adaptations + environmental stimuli = Very difficult to stop taking drugs.

13. Another way of looking at it: When I grow up I’m going to be an addict I want help (Methadone & Recovery ™ Agenda)

14. Pharmacokinetics of Opiates Time Effect “normal” HeroinMethadone Buprenorphine 4mg Buprenorphine 8mg

15. Buprenorphine occupies the mu opioid receptor. Zubieta et al 2000

16. Substitution : urinalysis +ve for opiates Methadone –full  agonist –t1/2 = ~23.5 hrs –start (< ~ 50 mg) –higher doses are more efficacious (>60mg) –titrate –oral / injectable –supervised consumption Diamorphine –well liked –short acting –higher street value Buprenorphine –partial  agonist –  antagonist –t1/2 = >24 hrs –dose ~8-16mg, sublingual –+ naloxone –can be abused (Temgesic) –less severe withdrawal, safer (respiratory depression), –less dysphoric, effects of on- top opiates blocked Dihydrocodeine –short acting –weaker

17. What does the patient actually think or believe is going on? And the doctor? Same opioid, different specialist, different doses! Buprenorphine Analgesia: 1.6mg in 24 hr, 3-4 hrly Dependence: 16-32mg OM

18. Perceived Progress in Addiction Treatment Land of Dependence Land of the (Drug) Free Mountain of Detoxification Relapse Client controlled by brain predisposition Client controls choices Drug UseAbstinence Early Peak Detox Late 1-2 weeks in all

19. The Long Hard Road to Abstinence Mountain of Effort Late AbstinenceDrug UseEarly Abstinence 4-7 years Detox 1-2 wks Mountain Molehill of Detoxification Land of Dependence Land of the (Drug) Free Client controlled by brain predisposition Client controls choices

20. Time(days) 1 2 3 4 5 6 7 Withdrawal Severity Heroin Methadone Buprenorphine Lofexidine Given Buprenorphine and Lofexidine

21. Engagement helps: Recovery of Self-esteem & Normalisation of Anxiety in Abstinent Addicts 1 2 3 4 5 6 7 Years of Recovery Mean Test Score Mean for normal people Anxiety Score Self-esteem score Christo 1994, Christo & Sutton 1994

22. Relapse Rates Are Similar for Drug Addiction & Other Chronic Illnesses Type I Diabetes Drug Addiction 0 10 20 30 40 50 60 70 80 90 100 Hypertension Asthma 40 to 60% 30 to 50% 50 to 70% Percent of Patients Who Relapse McLellan et al., JAMA, 2000.

23. “The good physician treats the disease, but the great physician treats the person.” William Osler William Osler

24. 24 Guidance, help and evidence Alas, from the era before “revolving door” Lansley’s mishmash and 40%+ cuts bap.org.uk

25. Help – what do I do? Opiates: They won’t die but they might leave & come back in a worse state. Methadone 5-10mg 2-4 hourly PO, omit if drowsy Max is 120mg (60-120) Roll up 24hr dose to make one single daily dose Community prescription or brief detox on discharge Alcohol: They might die if ignored Give Chlordiazepoxide – lots then less over 4-8 days. 10mg /10 units every 4-6 hrs e.g. 1 litre of 40% vodka = 40 units/day = 40mg Chlordiazepoxide QDS & 2-3 extra PRN doses for first 1-2 days. Then reduce Add Pabrinex as WKS kills. Other Drugs – in the main, supportive. Consider 2-3 days reducing Chlordiazepoxide regime

26. Population 56.1 million Trends in the prescribing of opioid analgesics by type Tramadol