Treatment approaches in the addiction field
Professor John StrangNational Addiction Centre, London, UK
2MMF conference Palermo, September 2008
declaration
* DH, NTA, Home Office, NACD, WHO, UNODC
* Diamo, Reckitt-Benkiser, Schering-Plough, Genus-Britannia, GW, Napp, Titan, Catalent, Auralis
* Phoenix House, Clouds House, Action on Addiction, Society for the Study of Addiction
NHS University
Development and pilot testing of new
Prevention and Treatment Interventions
Research into the causes,consequences and influences
upon Addictions
Policy analysis and input into
Policy formation
Structure of today’s talk
Some initial thoughts
Old wine in old bottles
Old wine in new bottles
New wine, well worth drinking
Wine still in development
Structure of today’s talk
Some initial thoughts
Old wine in old bottles
Old wine in new bottles
New wine, well worth drinking
Wine still in development
… from Faith to Science …
How do we define ‘drug’?
‘les drogues sont des substances qui provoquent des comportements irrationnels et deliriants …..
…chez ceux qui n’en prennent jamais’.
(Timothy Leary)
Opiate, stimulant, hallucinogen, sedative, alcohol, nicotine
Outcome measures
Outcome Measures
Drug use UDS & self-report
((Treatment retention)) Clinic records (& self report)
Injecting practices Frequency, risk & complications
Psychosocial functioning & Quality of Life Measures
SF-36, EQ-5D, OTI
((Crime)) Self-report (drug related expenditure & criminal activity)
((Cost effectiveness)) Service costs (internal & external)
((Community Impact Evaluation))
‘Nuisance’ issues for local community
benefit matrix
Health Social Economic
Individual
Community
Societal
Which harms and benefits are the most important?
Scientist must measure
Society must assign weightings
Structure of today’s talk
Some initial thoughts
Old wine in old bottles
Old wine in new bottles
New wine, well worth drinking
Wine still in development
Old wine in old bottles
MMT (and, more recently, BMT)
… but …
(a) Methadone maintenance
• Major treatment for heroin dependence: highly effective
• 40 years of experience
• Oral, long half-life (daily), cross-tolerant: • prevents withdrawal symptoms• ‘universal anodyne’ psychological effect• To some extent it “blocks” euphoric effects of heroin
• Reduces illicit heroin use more than no treatment (USA, Australia), drug-free treatment (Sweden), placebo (Hong Kong, USA) and detoxification (Thailand, USA) in RCTs
• Better retention than placebo, drug-free treatment, detoxification and wait-list controls (Mattick, 2002)
Evidence and interpretation:Clinical effectiveness
Most trials used a fixed-dose designMTD 50-150mg/dayBP 1-15mg/day
2 main outcomes reported:Retention in treatment Illicit use of opioids [proportion of people taking illicit
opioids, mean rate of heroin intake assessed by self-report and/or urinalysis]
Gunne & Gronbladh (1981) RCT:Methadone versus no methadone
34 subjects using heroin by injection 17 experimental (methadone)
17 controls (no methadone)
Controls not allowed to enter MMT for 2 years
Followed up at 2 years and again at 4 years
Gunne & Gronbladh (1981): Baseline
Experimental Group (methadone)
Control group (no methadone)
U U U U U U U U
U U U U U U U U
U U U U U U U U
U U U U U U U U
U U
U – ongoing daily heroin Use
Gunne & Gronbladh (1981): 2 years
Experimental group (methadone)
Control group (no methadone)
U U U A
U U U U
U U U U
U U U D
D
A – Abstinent U – on-going daily UseD – Deceased
Gunne & Gronbladh (1981): 2 years
Experimental group (methadone)
Control group (no methadone)
A A A A U U U A
A A A A U U U U
A A A A U U U U
U U U U U U U D
U D
A – Abstinent U – on-going daily UseD – Deceased
Gunne & Gronbladh (1981): 4 years
Experimental Group (methadone)
Control group (methadone)
Control group (no methadone)
U A
U U
U D
D D
D
A – Abstinent U – on-going daily UseD – Deceased
Gunne & Gronbladh (1981): 4 years
Experimental Group (methadone)
Control group (methadone)
Control group (no methadone)
A A A A U A
A A A A U U
A A A A U D
U U U A D D
U D
A – Abstinent U – on-going daily UseD – Deceased
Gunne & Gronbladh (1981): 4 years
Experimental Group (methadone)
Control group (methadone)
Control group (no methadone)
A A A A U U U A
A A A A A A U U
A A A A A A U D
U U U A A A D D
U D
A – Abstinent U – on-going daily UseD – Deceased
29
42
89
15
85
1716 14
82
13
2228
0
20
40
60
80
100
Heroin (Weekly)*
Cocaine (Weekly)*
Heavy Alcohol
Illegal Activity*
No FT Work SuicidalIdeation
Pre Post
% of DATOS Sample (N=727)
USA - Outpatient Methadone Treatment
Changes from Before to After Treatment
*p<.001
Hubbard, Craddock, Flynn, Anderson, & Etheridge 1997, PAB
29
42
89
15
85
1716 14
82
13
2228
0
20
40
60
80
100
Heroin (Weekly)*
Cocaine (Weekly)*
Heavy Alcohol
Illegal Activity*
No FT Work SuicidalIdeation
Pre Post
% of DATOS Sample (N=727)
USA - Outpatient Methadone Treatment
Changes from Before to After Treatment
*p<.001
Hubbard, Craddock, Flynn, Anderson, & Etheridge 1997, PAB
29
42
89
15
85
1716 14
82
13
2228
0
20
40
60
80
100
Heroin (Weekly)*
Cocaine (Weekly)*
Heavy Alcohol
Illegal Activity*
No FT Work SuicidalIdeation
Pre Post
% of DATOS Sample (N=727)
USA - Outpatient Methadone Treatment
Changes from Before to After Treatment
*p<.001
Hubbard, Craddock, Flynn, Anderson, & Etheridge 1997, PAB
The benefit of retaining patients in treatment - HIV infection rates in and
out of methadone maintenance treatment (Metzger et al. 1993)
21
273536 3639 39 42484951
13
15 1617 1718 19 1921
Out of tx %
In tx %
The benefit of retaining patients in treatment - HIV infection rates in and
out of methadone maintenance treatment (Metzger et al. 1993)
21
273536 3639 39 42484951
13 15 16 17 17 18 18 19 19 20 21Out of tx %
In tx %
The benefit of retaining patients in treatment - HIV infection rates in and
out of methadone maintenance treatment (Metzger et al. 1993)
2127
35 3636
39 39 42 48 49 51
13 15 16 17 17 18 18 19 19 20 21Out of tx %
In tx %
(b) Buprenorphine maintenance
• Agonist with very high affinity for opiate receptor (heroin cannot compete at opioid receptor)
• Similar treatment retention as methadone, but not quite as good (MMT: 63%, Bup:53%; Mattick, 2002)
• No significant difference between methadone and buprenorphine in reducing heroin use, cocaine use, benzodiazepine use or crime (Mattick, 2002)
• Probably less overdose risk (but not yet firmly demonstrated how much better)
1 year retention during buprenorphine
maintenance (16 mg qd)
Kakko et al. (2003)Treatment duration (days)
# R
emai
ning
in t
reat
men
t
0
5
10
15
20
0 50 100 150 200 250 300 350
Control (6 day taper)
buprenorphine maintained
75% retained at 1 year; no deaths
75% of urine drug screens negative
0 1 2 4 8 16 32
10
11
12
13
14
15
16
17
Bre
aths
/Min
ute
PL Buprenorphine (mg, sl)
Human respiratory rate
Adapted from Walsh et al., 1994
Ceiling effect on respiratory depression
(c) Levo-alpha-acetylmethadol (LAAM)
• Full opiate agonist with longer duration of action than methadone (48 or 72 hours or longer), 3x week dosing
• 10 cases of life threatening cardiac arrhythmias: withdrawn (Europe) and not be used as first line therapy (US)
• Need to clarify risks of LAAM treatment, particularly cardiac arrhythmia from QT prolongation
Retention in treatment: methadone, buprenorphine, LAAM maintenance
(d) Prolonged-release oral morphine
Oral, long duration of action (24 hours)
comparable retention and illicit drug use to methadone treatment and significantly lower depression, anxiety and physical complaints (Eder, 2005)
An open label 3-week study of 110 opioid dependent subjects showed high retention, reduced somatic complaints and reduced cravings (Kraigher, 2005)
MMT patients transferring to SROM (n=18) showed similar outcomes as methadone, improved social functioning, and less side-effects (Mitchell, 2004)
(e) Codeine or dihydrocodeine
Naltrexone – the classic antagonist
• Opioid antagonist – oral, 24-hour, remarkably effective
• However - only rarely prescribed by doctors
• Widespread disappointment of poor uptake by patients
• Also - separately used (unlicensed) in opiate detox
• Also - long-acting depot form recently developed (2006)
• Separate alcohol interest in relapse-preventing benefit (perhaps ?? anti-craving effect for alcohol??)
… but …
Retention in treatment: methadone, buprenorphine, LAAM maintenance
Retention in treatment methadone, buprenorphine & LAAM vs. naltrexone
Move to NICE slides
U.K. Methadone treatment:benefits in the first month
(Strang, Finch et al, Addiction Research)
4.7
6.36
1.2
2.2
3.5
1.8
2.56
0.50.8
0.5
0
1
2
3
4
5
6
7
herointimes/ wk
heroinmgX10
cocainetimes/ wk
coc mgX10 shopliftingper week
pre-entry1 month
U.K. Methadone treatment:benefits in the first month
(Strang, Finch et al, Addiction Research)
4.7
6.36
1.2
2.2
3.5
1.8
2.56
0.50.8
0.5
0
1
2
3
4
5
6
7
herointimes/ wk
heroinmgX10
cocainetimes/ wk
coc mgX10 shopliftingper week
pre-entry1 month
U.K. Methadone maintenance –changes in heroin use over time
0
0.5
1
1.5
2
2.5
3
3.5
Am
ou
nt
of
he
roin
in
Gm
pe
r w
eek
Methadone maintenance
Source: Finch 2000 MD thesis
U.K. Methadone maintenance –changes in heroin use over time
0
0.5
1
1.5
2
2.5
3
3.5
Am
ou
nt
of
he
roin
in
Gm
pe
r w
eek
Methadone maintenance
Source: Finch 2000 MD thesis
Opioid Overdose Deaths 1964-1997 (per million Australian adults, 15-44 years)
(Hall, Degenhardt & Lynskey, 1999)
15 44 yrs
0
10
20
30
40
50
60
70
80
1964
1966
1968
1970
1972
1974
1976
1978
1980
1982
1984
1986
1988
1990
1992
1994
1996
15 44 yrs
Structure of today’s talk
Some initial thoughts
Old wine in old bottles
Old wine in new bottles
New wine, well worth drinking
Wine still in development
Old wine in new bottles
(Naltrexone in alcohol field)
(Disulfiram with cocaine)
Heroin maintenance (re-conceptualisation)
Naloxone ‘technology transfer’
WHAT INJECTABLE PRODUCTS?
Two products:
- heroin ampoules (dry amps) (1%)
- methadone ampoules (wet amps) (3-10%)
What is the RIOTT trial?
Results
…… to follow ……
However, as a clinician I can tell you …We are seeing some transformational changesEnough to guide policy-making process?
Retention approx 85% at 6/12 (vs 50% typical)Follow-up approx 95% (vs 75% typical)
Opioid Overdose Deaths 1964-1997 (per million Australian adults, 15-44 years)
(Hall, Degenhardt & Lynskey, 1999)
15 44 yrs
0
10
20
30
40
50
60
70
80
1964
1966
1968
1970
1972
1974
1976
1978
1980
1982
1984
1986
1988
1990
1992
1994
1996
15 44 yrs
Oxygen saturation: IV versus IM
0 10 20 30 40 50 60
90
92
94
96IV
IM
Minutes post-injection
Sp
O2
(%)
Oxygen saturation: case study
0 10 20 30 40 50 60
84
87
90
93
96
Male, age 49Intravenous diamorphine (6 years)This dose = 120 mgDaily dose = 400mg
Minutes post-injection
Sp
O2
(%)
Actions on Discovering Overdose
CALL AMBULANCE
Check Airway – clear if blocked, Check breathing.
If breathing, place in recovery position – if not breathing, begin basic life support or place in recovery position to maintain a good airway and prevent them from choking
Administer naloxone
Naloxone Administration
Quickest route of injection is intravenous However INTRAMUSCULAR injection
recommended as easier. Inject into a muscle Upper outer buttock, thigh area or upper arm. Hold needle 90 degree above skin Insert needle into muscle Slowly and Steadily push plunger all the way down
Client confidence in administering naloxone
0
10
20
30
40
50
60
V.confident Confident Unsure Not confident Not at allconfident
level of confidence
%
pre-training
post-training
Interviews in confidence (n=1009)
Face-to-face
Independent research staff
Enquiry about sexual and injecting behaviours
Now; recent past; distant past
Table 1. Persistence of drug use on imprisonment
Ever used(n=557 out of 1009)
Year beforeprison
Month beforeprison
Heroin (n=324) 63% a (n=204)
52%(n=169)
Cocaine (n=387)
72%(n=280)
54%(n=209)
Amphetamines (n=417)
52%(n=216)
30%(n=125)
a All percentages are calculated based on the numbers who have ever used
Table 1. Persistence of drug use on imprisonment
Ever used(n=557 out of 1009)
Year beforeprison
Month beforeprison
Heroin (n=324) 63% a (n=204)
52%(n=169)
Cocaine (n=387)
72%(n=280)
54%(n=209)
Amphetamines (n=417)
52%(n=216)
30%(n=125)
a All percentages are calculated based on the numbers who have ever used
Table 1. Persistence of drug use on imprisonment
Ever used Year beforeprison
Month beforeprison
First month in
prison
Ever used it in
prison
Ever injected it
inprison
Amphetamines (n=417)
52%(n=216)
30%(n=125)
5%(n=19)
26%(n=108)
4%(n=15)
a All percentages are calculated based on the numbers who have ever used
Table 1. Persistence of drug use on imprisonment
Ever used Year beforeprison
Month beforeprison
First month in
prison
Ever used it in
prison
Ever injected it
inprison
Cocaine (n=387)
72%(n=280)
54%(n=209)
11%(n=41)
35%(n=135)
3%(n=10)
Amphetamines (n=417)
52%(n=216)
30%(n=125)
5%(n=19)
26%(n=108)
4%(n=15)
a All percentages are calculated based on the numbers who have ever used
Table 1. Persistence of drug use on imprisonment
Ever used Year beforeprison
Month beforeprison
First month in
prison
Ever used it in
prison
Ever injected it
inprison
Heroin (n=324) 63% a (n=204)
52%(n=169)
36%(n=118)
71%(n=230)
16%(n=51)
Cocaine (n=387)
72%(n=280)
54%(n=209)
11%(n=41)
35%(n=135)
3%(n=10)
Amphetamines (n=417)
52%(n=216)
30%(n=125)
5%(n=19)
26%(n=108)
4%(n=15)
a All percentages are calculated based on the numbers who have ever used
Post-release ‘carnage’
Seaman Brettle Gore, BMJ, 1998
Bird & Hutchinson, Addiction, 2002
Farrell & Marsden, Addiction, 2008
Prevalence of drug dependence
15%
11%
17%
9%
10%
8%
16%
8%
24%
17%
11%
2%
13%
10%
12%
5%
0
10
20
30
40
50
60
%
M remand M sentenced F remand F sentenced
Opiates & stimulants Opiates only Stimulants only Cannabis only
Drug dependence prior to prison
Substance Misuse in Prisoners 2002 Singleton N, Farrell M, Meltzer H ONS.
Excess mortality ratio for different time periods post-release by cause of death (Singleton, Farrell, Marsden et al 2003)
05
1015202530354045
Time since release (w eeks)
Exce
ss m
orta
lity ra
tio
Drug-related deaths Not drug-related
N-ALIVE trial – pilot & main phase
N-ALIVE research trial proposal to test/prove reduced deaths post-release
Pilot – n=5600 Main study – n=56000 (28k + 28k)
Structure of today’s talk
Some initial thoughts
Old wine in old bottles
Old wine in new bottles
New wine, well worth drinking
Wine still in development
Treatment Research Institute Mc Lellan et al
Levels of Treatment in Methadone Maintenance Programs
Random Assignment 6 Months
‘Bare-bones’ Standard ‘deluxe’ (n=29) (n=34) (n=36)
Methadone: > 65mg >65mg >65mgCounseling: Regular RegularOther Services Employment
Family Therapy Psychiatric Care
Levels of care Study
0
10
20
30
40
50
60
70
Using Heroin Using Cocaine Sharing Needles Illegal Acts Unemployed
barebones standard deluxe
Target behaviors at 6 months
Levels of care Study
0
10
20
30
40
50
60
70
Using Heroin Using Cocaine Sharing Needles Illegal Acts Unemployed
barebones standard deluxe
Target behaviors at 6 months
Levels of care Study
0
10
20
30
40
50
60
70
Using Heroin Using Cocaine Sharing Needles Illegal Acts Unemployed
barebones standard deluxe
Target behaviors at 6 months
Move to NICE Forest plots of meta-analyses
Structure of today’s talk
Some initial thoughts
Old wine in old bottles
Old wine in new bottles
New wine, well worth drinking
Wine still in development
Wines in development
(migrant medications)
Tele-prompting/monitoring
Vaccines
Ultra-long duration meds (nx; bup; …)
HR moderation medications (?nalmef; ?)
… add cocaine vaccine slide …
conclusion
… exciting times
Thank you
Bup-nalox effects –by different routes
(version 1)
Bup Nalox
Su
b-lingu
alBup Nalox
Bup Nalox
Inject
Bup Nalox