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Pharmacology of Opioids, Assessment and Management of Opioid Dependence : 

Pharmacology of Opioids, Assessment and Management of Opioid Dependence © 2009 University of Sydney Opioids Part 2

Treating James …. : 

Treating James …. James is a 29 yr man with >10 yr Hx heroin & other drug use Presents to ED with abscess in arm, pyrexia, heart murmur Injects heroin 2-3 times a day for past 15 months Works part time. ‘Deals to friends’ to support habit. Girlfriend started using heroin 2 years ago. She is 5 months pregnant & now infrequently uses heroin. In treatment 4 times before … Relapsed within days after each of 3 detoxes Stopped using for 3/12 in rehab, but relapsed on return to community Would like to stop using … fed up & desperate Needs admission for Ix endocarditis

Learning Objectives : 

Learning Objectives To be able to: Describe the pharmacology of opioids Assess the presence of dependence on heroin or other opioids Discuss the role of different treatment options Describe the management of opioid withdrawal

Overview of presentation : 

Overview of presentation Heroin and other opioids Opioid pharmacology Opioid effects and withdrawal Overdose Patterns of use Features of dependence Assessment Treatment approaches Detoxification Post-detoxification responses Substitution treatment: methadone, buprenorphine, prescribed heroin, LAAM Selecting treatment: evidence-based practice

What is heroin?Di-acetylmorphine : 

What is heroin?Di-acetylmorphine Semi-synthetic opiate, derived from opium poppy Vast majority of effects = morphine In Australia Most from South East Asia Water soluble for injecting >$300 /‘gram’, 10-20% purity

Agonists, partial agonists, antagonists : 

Agonists, partial agonists, antagonists Opioids produce their effect by acting at the opioid receptors in the nervous system -opioid receptor most important Agonists bind to the receptor and stimulate physiological activity Partial agonists bind to the receptor but do not produce maximum stimulation Antagonists have no intrinsic pharmacological effect, but bind to the receptor and can block the action of an agonist Lintzeris, N (2008). Unpublished data. Reprinted with permission.

Opioid effects & withdrawal : 

Opioid effects & withdrawal Analgesia Sedation Euphoria Pinpoint pupils Low BP, PR, RR Dry skin, mouth, urine Constipation, bowel action Nausea, vomiting Increased pain Agitation, poor sleep Dysphoria Dilated pupils Increased BP, PR, RR Sweaty, urine Diarrhoea, abdo cramps Nausea, vomiting Opioid effects Opioid withdrawal

Opioid Overdose : 

Opioid Overdose Signs Major feature - respiratory depression (slow deep respiration 2-7/min) - risk of death Pinpoint pupils (but may be dilated if brain damage occurred) Low BP, PR Low BT, skin cool, clammy Stuporose/comatose Treatment Reversal with naloxone (short-acting opioid antagonist)

Slide 9: 

Source: NSW Department of Health (2007) NSW Drug and Alcohol Withdrawal Clinical Practice Guidelines

Patterns of Heroin Use : 

Patterns of Heroin Use The experimental user The 'recreational' or occasional user May or may not be associated with harms (overdose, infections, other health risks, legal complications) The dependent user Degrees of severity Severe dependence characterised by a protracted course with multiple remissions and relapses

Dependence (DSM IV-TR) : 

Dependence (DSM IV-TR)  3 occurring at any time in the same 12 month period: Tolerance Withdrawal Opioids taken in larger amounts or longer than intended. Persistent desire or unsuccessful attempts to cut down or control use. A great deal of time is spent in activities necessary to obtain opioids, use opioids, or recover from their effects. Important social, occupational, or recreational activities are given up or reduced because of opioid use. Opioid use is continued despite knowledge of harms caused or exacerbated by opioids.

Factors affecting drug abuse & dependence : 

Factors affecting drug abuse & dependence Drug User Environment

Drug : 

Drug Pharmacological effects Onset of action Duration of action Route of administration Purity Availability Cost

User : 

User Genetic predisposition or protection Expectancy of the effects Personality Impulsiveness, risk-taking, sensation seeking Psychosocial Poor coping skills, low self-esteem, history of psychological trauma Psychiatric co-morbidity Anxiety, depression, psychosis

Environment : 

Environment Family factors Attitudes towards substance use, parenting skills Peer factors Attitudes towards substance use; role models Social factors School and neighbourhood attitudes towards substance use; education; employment status; socio-economic status; opportunities for recreational activities; crime

‘Natural history’ of heroin dependence : 

‘Natural history’ of heroin dependence Chronic, relapsing – remitting condition Usually starts several years after 1st heroin use 2 – 5 % remission rate per annum 1 – 2 % mortality rate per annum >10 x greater than age, gender matched non-users Overdose, liver disease (HCV, HBV), HIV, trauma 10 year outcomes (treatment seekers): 40 – 50% still using / imprisoned 30 – 40% abstinent 10 – 20% dead Most stop heroin use by late 30s to 40s.

Natural history40 year follow-up study : 

Natural history40 year follow-up study Hser et al, 2001, Arch Gen Psychiatry, 58(5): 503-508, © 2001 American Medical Association. Reprinted with permission.

Slide 18: 


Role of assessment : 

Role of assessment Assessment serves two key functions: To ascertain valid information in order to identify the most suitable management plan; To engage the patient in the treatment process Establishing rapport with the patient Facilitating treatment plans

Key features of the assessment : 

Key features of the assessment Presenting problem Drug use (include all drug classes) Quantity – frequency – route of administration Duration of use – when & amount last used Severity of dependence Withdrawal, tolerance, capacity to control use Drug related harms & risk practices Other conditions impacting upon treatment Medical / psychiatric / social Patient goals / expectancy

Conducting assessments : 

Conducting assessments History Examination Features of intoxication / withdrawal Evidence of drug use (e.g. injecting sites) Evidence of drug related harm (infections, liver, heart murmurs) Investigations Urine drug screen Viral serology & LFTs

Evidence of drug use : 

Evidence of drug use Track marks provide evidence for IDU and last occasion of use

Stages of change model(Prochaska & Di Clemente) : 

Stages of change model(Prochaska & Di Clemente) Pre-contemplation: People do not have major concerns regarding their drug use and are not interested in changing behaviour Contemplation: People aware that there are both benefits and problems arising from their drug use, and are weighing up whether or not to make changes - or what those changes should be Action: People are implementing strategies in order to change Maintenance: holding onto the behaviour changes Relapse: can be volitional, or triggered by physical, emotional, social factors Prochaska, JO et al (1985) Addict Behav, 10(4): 395-406.

Slide 24: 

Some authors recognise a preparation stage before the action stage In this diagram the pre-contemplation stage is merged with relapse Proude, E (2009), unpublished data

Slide 25: 

Treatment Options

Treatment pathways for dependent heroin users : 

Treatment pathways for dependent heroin users

Opioid withdrawal syndrome : 

Opioid withdrawal syndrome Increased pain Agitation, poor sleep Dysphoria Dilated pupils Increased BP, PR, RR Sweaty, urine Diarrhoea, abdo cramps Nausea, vomiting Image source: NSW Department of Health (2007) NSW Drug and Alcohol Withdrawal Clinical Practice Guidelines

Objectives of detoxification : 

Objectives of detoxification Detox is not a ‘cure’ for heroin dependence Most heroin users relapse after withdrawal Need long-term treatment to achieve long-term changes Short-term intervention that aims to: Interrupt a pattern of heavy & regular drug use Alleviate withdrawal discomfort Prevent complications of withdrawal Facilitate post-withdrawal treatment linkages

Components of detox program : 

Components of detox program Assessment & client-treatment matching Supportive care ‘safe’ environment (inpatient / outpatient) patient information supportive counselling regular monitoring Medication Post-withdrawal linkages

Medication approaches for detox : 

Medication approaches for detox Symptomatic medications Clonidine BZDs, NSAIDS, antiemetics, antidiarrhoeal agents, etc. Methadone or buprenorphine Reducing doses over days / weeks Minimises severity of withdrawal symptoms Buprenorphine increasingly used internationally Antagonist assisted (‘rapid detox’) Uses naloxone / naltrexone as prelude to longer term antagonist treatment

Heroin withdrawal : 

Heroin withdrawal Lintzeris, N (2008) unpublished data. Reprinted with permission.

Short buprenorphine detox regimes : 

Short buprenorphine detox regimes Outpatient Inpatient Lintzeris, N et al (2006) National clinical guidelines and procedures for the use of buprenorphine in the treatment of opioid dependence.

Slide 33: 

…but beware of limitations of detox…

RCT BPN Maintenance vs Detox : 

RCT BPN Maintenance vs Detox 40 subjects randomised to 1 week detox / 1 yr maintenance All provided counselling for 1 year Heroin use Detox = all relapsed Maintenance=75% Opiate (-)ve UDS Mortality (p=0.015) Detox 4/20 (20%) Maintenance 0/20 Reprinted from The Lancet. Kakko et al (2003) Lancet, 361:662-8 with permission from Elsevier.

RCT Methadone maintenance vs gradual detox : 

RCT Methadone maintenance vs gradual detox N=179 randomised to 1 year methadone maintenance, or 6 months gradual reduction + intensive psychosocial Results: MMT had significantly Better treatment retention Less heroin use Fewer HIV risk practices Fewer legal problems Sees et al, 2000 JAMA, 283:1303. Copyright © 2000 American Medical Association. All rights reserved. Reprinted with permission.

Key points about detox : 

Key points about detox Do not expect ‘cures’ from detox programs Short term treatment usually = short term changes Medication only one aspect to good detox BPN optimal detox medication & increases post-detox options NB: Detox is not a treatment for dependence but rather a pre-treatment phase for some more comprehensive treatments.

Treatment pathways for dependent heroin users : 

Treatment pathways for dependent heroin users

Post-withdrawal interventions : 

Post-withdrawal interventions Counselling Various models (supportive, behavioural, dynamic) Cochrane review: limited efficacy of outpatient counselling alone Residential rehabilitation (long term > 3/12) Self – help (Narcotics Anonymous) Naltrexone Opioid antagonist that blocks effects of heroin use Effective for those who take it, but high drop out rate (< 10% retention at 6 months)

Naltrexone : clinical issues : 

Naltrexone : clinical issues Induction >7 days after last heroin use, >10 days after last methadone use, 1-5 days after last BPN use Naloxone challenge test recommended (not post-BPN) Maintenance Daily dosing of 25 to 50 mg per day Recommended duration of 6 to 12 months Cessation ? Increased sensitivity & risk of OD with opiates Interest in development of long-acting NTX (e.g. depot injection, implant) to overcome problems of poor adherence

Treatment pathways for dependent heroin users : 

Treatment pathways for dependent heroin users

Substitution treatment : 

Substitution treatment Provision of a long-acting prescribed opioid enables patient to cease / reduce heroin use & related behaviors Long term approach: opportunity for client to distance themselves from drug-using lifestyle Combines medication with psychosocial services Medication options: methadone & buprenorphine Other medication options (not approved in Australia): prescribed heroin, LAAM.

Methadone stabilisation : 

Methadone stabilisation Reprinted from The Lancet. Haber, PS et al (2009) “Management of injecting drug users admitted to hospital” Lancet, 374(9697):1284-93. © 2009 with permission from Elsevier.

Principles of effective treatment : 

Principles of effective treatment Long duration of treatment Adequate dose of medication Quality of therapeutic relationship Psycho-social supports for the patient Regular review, supervision & monitoring Participation in counselling Environment, family, friends, employment Bio-psycho-social model for chronic condition

Does substitution treatment work? : 

Does substitution treatment work? Despite considerable variation between programs, almost all patients reduce heroin use ~ 1/2 of patients stop using heroin ~ 1/3 of patients use heroin infrequently ~ 1/6 of patients continue to use heroin frequently Heroin use

Does substitution treatment work? : 

Does substitution treatment work? Mortality rates Heroin users not in treatment = 1 - 2% per annum (p.a.) Methadone maintenance treatment = 0.5 to 0.75 % p.a. HIV transmission Lower risk practices than users not in treatment (placebo or wait list controls) Lower rates of HIV transmission Criminality Reduced crime in most patients after treatment

Methadone : 

Methadone Full agonist at - opioid receptor Onset 30 - 60 min after dose, Peak after ~ 2 - 6 hrs Long-acting: t1/2= 24-30 hrs: one dose / day Opioid toxicity with too much methadone: sedation, respiratory depression, death 1 dose of 20-40mg can kill child Repeated doses of 30–40mg can kill an adult (opiate naïve) 1 dose of 70mg can kill an adult (opiate naïve) Widespread diversion & methadone related deaths where no supervision (e.g. UK) Daily supervised dispensing at clinics / pharmacies Henry-Edwards et al (2003) Clinical Guidelines and Procedures for the Use of Methadone in the Maintenance Treatment of Opioid Dependence.

Principles of methadone dosing : 

Principles of methadone dosing Induction Require slow induction (‘start low & go slow’) 20-30mg / day & increase dose by 5-10mg every 3 days until reach target dose (over 2-6 weeks) Maintenance Doses of 20 – 40mg prevent opiate withdrawal Doses >60mg most effective in reducing heroin use Withdrawal Gradual dose reductions (at rate of 10mg / month) Henry-Edwards et al (2003) Clinical Guidelines and Procedures for the Use of Methadone in the Maintenance Treatment of Opioid Dependence.

Buprenorphine : 

Buprenorphine Partial agonist at the  opioid receptor - Low intrinsic activity only partially activates receptors High affinity for the  receptor Binds more tightly to receptors than other opioids Developed in 1980s as analgesic

Classification of Opioids : 

Classification of Opioids Lintzeris, N (2008). Unpublished data. Reprinted with permission.

Safety Aspects of BPN : 

Safety Aspects of BPN Less risk of overdose c/w full opiate agonists Less respiratory depression & sedation than methadone BPN ‘tolerated’ by individuals with low levels of opiate dependence Potential concerns re: safety BPN related deaths reported in combination with other sedatives (EtOH, BZDs) … BUT less of a concern than other opiates (e.g. methadone, heroin)

Clinical Pharmacology : 

Clinical Pharmacology Sublingual tablets 0.4, 2 & 8 mg tablets available 3 to 10 minutes to dissolve Time course Onset: 30–60 min, peak: 1–4 hours Duration of action dose-related (1 dose / day) Side effects Typical for opioid class: less sedating than methadone Withdrawal syndrome Milder than full agonists Lintzeris et al (2006) National clinical guidelines and procedures for the use of buprenorphine in treatment of opioid dependence.

Overview BPN Doses : 

Overview BPN Doses Induction Delay first dose of BPN until early opiate withdrawal Commence 4 to 8 mg daily Frequent & rapid dose increases possible (by 2 to 8mg/day) Maintenance Daily doses: 8 – 16mg (max 32mg) required initially Alternate day dosing possible for many clients Withdrawal More rapid dose reductions possible than methadone (e.g. 2 – 4 mg / week usually well tolerated) Lintzeris et al (2006) National clinical guidelines and procedures for the use of buprenorphine in treatment of opioid dependence.

Buprenorphine-naloxone tablet (Suboxone®) : 

Buprenorphine-naloxone tablet (Suboxone®) Sublingual tablet in 4:1 ratio (BPN:NLX) Naloxone (antagonist) poorly absorbed sublingually & inactive Naloxone produces antagonist (withdrawal) effects if tablet injected by heroin user Enables take-away doses with greater convenience for patients & less risk of tablet misuse

When should we stop substitution treatment? : 

When should we stop substitution treatment? Chronic condition needs long term treatment Premature cessation of treatment usually results in relapse to dependent heroin use Consider ending treatment when: No illicit drug use for months / years Stable social environment Stable medical / psychiatric conditions Patient ‘has a life’ that does not revolve around drugs Patient informed consent When do we stop anti convulsants/antidepressants?

Common objections to substitution treatment : 

Common objections to substitution treatment Swapping ‘one drug for another’ Prolongs ‘addiction career’ Methadone-related deaths (e.g. accidental deaths in children) Cannot treat a bio-psycho-social condition just with drugs Giving up on the ‘war on drugs’ Form of ‘social control’ over minorities / marginalised groups

Heroin Maintenance : 

Heroin Maintenance A controversial treatment approach Was limited to Britain until 1990 Currently licensed and available for prescription in several European countries Usually prescribed IV injections of 300-500mg/day in 3 divided doses Uncommon but serious side effects Seizures and respiratory depression immediately following injection Lintzeris N (2009) CNS Drugs, 23(6):463-476.

Slide 57: 

Effectiveness is comparable to methadone in retaining patients in treatment and improving health More effective than methadone in reducing additional heroin use More expensive to deliver than methadone but significant savings can be made in the criminal justice sector The main rationale for heroin maintenance is treatment of refractory patients who do not respond to methadone or buprenorphine treatment delivered under optimal conditions Heroin Maintenance (cont.) Lintzeris N (2009) CNS Drugs, 23(6):463-476.

Slide 58: 

Levo-alpha-acetylmethadol (LAAM) is a long acting congener of methadone. Two active metabolites are responsible for most of the effect of LAAM nor-LAAM (half-life >30 hours) dinor-LAAM (half-life >100 hours) The parent drug (also active) and the metabolites all have selective affinity for the µ-opioid receptor LAAM White JM and Lopatko OV (2007) Expert Opin Pharmacother., 8(1):1-11. Review


LAAM Administered as an oral solution LAAM can be administered every second day, or 3 times/week. At least as effective as methadone in opioid maintenance treatment The parent drug was found to prolong QT interval (a potential cause in cases of Torsades de Pointes) and was subsequently withdrawn by the manufacturer. There is the potential for the metabolite nor-LAAM to be used therapeutically, and for the re-introduction of LAAM with careful monitoring. White JM and Lopatko OV (2007) Expert Opin Pharmacother., 8(1):1-11. Review

Slide 60: 

Selecting Treatment Approaches

Selecting treatment modalities:Evidence-based medicine : 

Selecting treatment modalities:Evidence-based medicine Patient circumstances Patient goals & expectations of treatment Past history of what has worked before Available resources Treatment services available Cost of different treatment approaches Evidence regarding safety & effectiveness

Comparing outcomes & costs : 

Comparing outcomes & costs Lintzeris, N (2008). Unpublished data. Reprinted with permission.

Retention in treatment: methadone, buprenorphine & LAAM vs. naltrexone : 

Retention in treatment: methadone, buprenorphine & LAAM vs. naltrexone Mattick RP et al. (2001) “National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD): Report of Results and Recommendations”. National Drug and Alcohol Research Centre, Sydney. © Commonwealth of Australia reproduced by permission.

‘Public health’ vs ‘Treatment’ models : 

‘Public health’ vs ‘Treatment’ models The balance between Services oriented to ‘public health’ outcomes Increased numbers in treatment, general reductions in drug use, mortality, HIV transmission Low intensity & less expensive services Services oriented to maximise ‘treatment’ outcomes Comprehensive programs, more expensive, fewer numbers Oriented towards rehabilitation Manage medical and psychiatric comorbidity

Conclusions : 

Conclusions Heroin dependence is a long term condition Long term conditions (e.g. heroin dependence) usually require long-term interventions Public health response requires treatment approaches that can be disseminated effectively & inexpensively Most treatment approaches work, as long as patients remain in treatment Substitution treatment has greatest retention rates for most patients & reduces harms associated with heroin use Need range of treatment interventions to suit different patients

Treating James …. : 

Treating James …. James is a 29 year old man with >10 yr history heroin use Injects heroin 2-3 times a day Part time-work & deals to support habit Pregnant girlfriend using heroin infrequently In treatment 4 times before … Relapsed after detox & rehab Presents with infected arm & ?endocarditis. Wants to stop using. Needs admission ………. detox … likely relapse ………. rehab … working & girlfriend pregnant .……… initiate BPN whilst in hospital, stabilise medical condition & review treatment plans

Contributors : 

Contributors Associate Professor Nicholas Lintzeris Drug Health Services, SSWAHS Central Clinical School, University of Sydney Dr Olga Lopatko University of Sydney All images used with permission, where applicable

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