Pharmacology of Opioids, Assessment and Management

of Opioid Dependence

© 2009 University of Sydney

Opioids Part 2

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

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• 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

• 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

• 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

Drug Dose

Full Agonists: Heroin, morphine, methadone, codeine

Partial Agonists: Buprenorphine

Antagonists: Naltrexone, naloxone

Threshold for respiratory depression

Siz

e of

Opi

ate

Ago

nist

Effe

ct.

.

100

0

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 Unpublished data.Reprinted with permission.

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• 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)

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

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)

3 occurring at any time in the same 12 month period:

1. Tolerance

2. Withdrawal

3. Opioids taken in larger amounts or longer than intended.

4. Persistent desire or unsuccessful attempts to cut down or control use.

5. A great deal of time is spent in activities necessary to obtain opioids, use opioids, or recover from their effects.

6. Important social, occupational, or recreational activities are given up or reduced because of opioid use.

7. Opioid use is continued despite knowledge of harms caused or exacerbated by opioids.

Factors affecting drug abuse & dependence

• Drug

• User

• Environment

Drug• Pharmacological effects

• Onset of action

• Duration of action

• Route of administration

• Purity

• Availability

• Cost

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• 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

• 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

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

Assessment

Role of assessmentAssessment 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

• 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• 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

Track marks provide evidence for IDU and last occasion of use

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.

PREPARATIONPREPARATION

RELAPSERELAPSE

MAINTENANCEMAINTENANCE

ACTIONACTION

CONTEMPLATION

CONTEMPLATION

• 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

Treatment Options

Treatment pathways for dependent heroin users

Dependent Heroin User

Substitution Maintenance

Treatment

Detox from maintenance

treatment

Post Detox Treatment Options

Detox

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• 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

• Assessment & client-treatment matching• Supportive care

– ‘safe’ environment (inpatient / outpatient)– patient information – supportive counselling– regular monitoring

• Medication• Post-withdrawal linkages

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

0 1 2 3 4 5 6 7 8 9 10

Day

Wit

hd

raw

al s

ever

ity

Unmedicated

Lofexidine / clonidine

Methadone (7 day)

Buprenorphine (7 day)

Rapid detox' (naltrexone)

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

Short buprenorphine detox regimes

Day Proposed regime

Upper & lower limits

1 8 mg 4 to 8mg

2 12 mg 4 to 12mg

3 10 mg 4 to 16mg

4 8 mg 2 to 12mg

5 4 mg 0 to 8mg

6 - 0 to 4mg

7 - 0 to 2mg

Day Proposed regime

Daily dose

1 4mg BD 8 mg

2 4mg BD 8 mg

3 4mg mane

2mg nocte

6 mg

4 2mg BD 4 mg

5 2 mg mane 2 mg

6 No dose

Outpatient Inpatient

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

…but beware of limitations of 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

• 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• 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

Dependent Heroin User

Substitution Maintenance

Treatment

Detox from maintenance

treatment

Post Detox Treatment Options

Detox

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• 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

Dependent Heroin User

Substitution Maintenance

Treatment

Detox from maintenance

treatment

Post Detox Treatment Options

Detox

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

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

• 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?

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?

• 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• 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

• 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

• 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

Drug Dose

Full Agonists: Heroin, morphine, methadone, codeine

Partial Agonists: Buprenorphine

Antagonists: Naltrexone, naloxone

Threshold for respiratory depression

Siz

e o

f Op

iate

Ag

on

ist E

ffect

.

.100

0

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

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• 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 DosesInduction• 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®)• 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?

• 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

• 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• 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.

• 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.

• 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

Selecting Treatment Approaches

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

Heroin use / retention

Mortality Cost

Detox <5% long term abstinence

? increase / no change

$1000 / week

Maintenance 50% retention 1yr

25% no heroin use 1yr 3 – 4 fold reduction

$3000 / year

Naltrexone 5-10% retention 1 yr. Most drop outs relapse

? increase / no change

$4,000/year

Therapeutic community

Few stay in Rx unless ++ motivation /

pressure

? $10-15,000

Prison Good retention rates increase on release

$40-70,000

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

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

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• 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 ….• 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• Associate Professor Nicholas Lintzeris Drug Health Services, SSWAHS

Central Clinical School, University of Sydney

• Dr Olga LopatkoUniversity of Sydney

All images used with permission, where applicable