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

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

3. 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

4. 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

5. 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

6. 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 Unpublished data.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.

7. Opioid effects & withdrawal
Opioid 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

8. Opioid Overdose Signs Treatment
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)

9. Source: NSW Department of Health (2007) NSW Drug and Alcohol Withdrawal Clinical Practice Guidelines9

10. 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

11. 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.

12. Factors affecting drug abuse & dependence
User
Environment

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

14. 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

15. Environment Family factors Peer factors Social 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

16. ‘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.

17. Natural history 40 year follow-up study
Hser et al, 2001, Arch Gen Psychiatry, 58(5): , © 2001 American Medical Association.
Reprinted with permission.

18. Assessment

19. 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

20. 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

21. 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

22. Evidence of drug use Track marks provide evidence for IDU and
last occasion of use
Clinical photograph taken by P. Haber. ©

23. 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):

24. Some authors recognise a preparation stage before the action stage
RELAPSE
MAINTENANCE
ACTION
CONTEMPLATION
A version of this diagram will be included in the online publication: Proude et al (2009) The Treatment of Alcohol Problems
A Review of the Evidence. Commonwealth Department of Health and Aging, Canberra.
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

25. Treatment Options

26. Treatment pathways for dependent heroin users

27. 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

28. 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

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

30. 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

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

32. Short buprenorphine detox regimes
Outpatient
Inpatient
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
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 3
4mg mane
2mg nocte
6 mg 4
2mg BD
4 mg 5
2 mg mane
2 mg 6
No dose
Lintzeris N, Clark N, Winstock A, Dunlop A, Muhleisen P, Gowing L, Ali R, Ritter A, Bell J, Quigley A, Mattick RP, Monheit B, White J. (2006) National clinical guidelines and procedures for the use of buprenorphine in the treatment of opioid dependence. Australian Government Department of Health and Ageing, Canberra.
Lintzeris, N et al (2006) National clinical guidelines and procedures for the use of buprenorphine in the treatment of opioid dependence.

33. …but beware of limitations of detox…

34. 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, Vol 361. Kakko et al, “1-year retention and social function after buprenorphine-assistedrelapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial”, 662-8, 2003, with permission from Elsevier.
Reprinted from The Lancet. Kakko et al (2003) Lancet, 361:662-8 with permission from Elsevier.

35. 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.

36. 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.

37. Treatment pathways for dependent heroin users

38. 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)

39. 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

40. Treatment pathways for dependent heroin users

41. 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.

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

43. 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

44. Does substitution treatment work?
Heroin use
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

45. 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

46. Methadone Full agonist at - opioid receptor
Onset min after dose, Peak after ~ hrs
Long-acting: t1/2= 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. Commonwealth Government of Australia, Canberra.
Henry-Edwards et al (2003) Clinical Guidelines and Procedures for the Use of Methadone in the Maintenance Treatment of Opioid Dependence.

47. 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. Commonwealth Government of Australia, Canberra.
Henry-Edwards et al (2003) Clinical Guidelines and Procedures for the Use of Methadone in the Maintenance Treatment of Opioid Dependence.

48. 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

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

50. 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)

51. 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. Commonwealth Government of Australia, Canberra.
Lintzeris et al (2006) National clinical guidelines and procedures for the use of buprenorphine in treatment of opioid dependence.

52. 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. Commonwealth Government of Australia, Canberra.
Lintzeris et al (2006) National clinical guidelines and procedures for the use of buprenorphine in treatment of opioid dependence.

53. 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

54. 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?

55. 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

56. 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 mg/day in 3 divided doses
Uncommon but serious side effects
Seizures and respiratory depression immediately following injection
Lintzeris N (2009) Prescription of heroin for the management of heroin dependence. CNS Drugs, 23(6):
Lintzeris N (2009) CNS Drugs, 23(6):

57. Heroin Maintenance (cont.)
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
Lintzeris N (2009) CNS Drugs, 23(6):

58. LAAM
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
White JM and Lopatko OV, 2007 “Opioid maintenance: a comparative review of pharmacological strategies”, Expert Opin Pharmacother., 8(1):1-11. Review
White JM and Lopatko OV (2007) Expert Opin Pharmacother., 8(1):1-11. Review

59. 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

60. Selecting Treatment Approaches

61. 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

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

63. 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.

64. ‘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

65. 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

66. 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

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