Symposium on Emerging Data on Efficacy and Clinical Applications of Extended
Release Naltrexone Formulations, presented at 75th Annual Meeting - College on
Problems of Drug Dependence - June 15-20, 2013, San Diego, CA
Valgerður Rúnarsdóttir, M.D.,
Vogur Hospital Iceland
SAA National Center of Addiction Medicine
Ingunn Hansdóttir, PhD,
Assistant Professor University of Iceland
Research Counsil Member SAA National Center of Addiction
Medicine
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• Extended Release Naltrexone for Treating
Amphetamine Dependence in Iceland
• NIDA research grant (2P50-DA012756-11)
• Alkermes provided study drug
Naltrexone/placebo extended release formulation
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• George Woody, M.D
Lead investigators
University of Pennsylvania: Vogur Hospital:
• Thor Tyrfingsson, M.D.
• Helen Pettinati, PhD • Val Runarsdottir, M.D.
Project co-ordinators
• Charlotte Royer-Malvestuto • Ingunn Hansdottir, PhD
• Biostatistician:
Kevin Lynch, PhD
NIDA project Manager
Jamie Biswas, MD
Data analysis
• Data Manager:
Magnus Einarsson
Other collaborators
Alkermes Brown University
Avani Desai, PharmD Milunka Kojic, MD
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• Amphetamine addiction is a growing problem
– Number of patients seeking treatment for amphetamine addiction has almost tripled over the past two decades
– Proportion of patients has risen, gone from <10% in 1984 to a current rate around 36%
• Amphetamines used intravenously, increased risk of
HIV and Hepatitis
• Increased use among youth
• No medications approved for treating amphetamine addiction
• Several suggestions that Naltrexone might be effective.
4

• Jayaram-Lindstrom et al Am.J. Psychiatry, 2008
• Significant effect using oral naltrexone in ramdomized, placebo-controlled 12 week trial of 80 amphetmine dependent outpatients.
5

6

• Can these results be replicated with extended release formula?
• Study proposed in Iceland – why Iceland?
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• Centralized addiction treatment
• Good access to treatment, free or minimal fee
• Vogur hospital lynchpin in addiction trmt
• Population endorses disease concept
• Well trained staff
• Evidence based practice
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Detox
• Hospitalization 7-10 days
Residential:
• 4 weeks
Intensive outpatient
• 5x week for 1 mo (60 hrs)
• 1x week for 3 mo (12 hrs)
Outpatient follow-up
• 2x week for 3 mo (24 hrs)
• 1x week for 9 mo (36 hrs)
Residential
4 weeks
Detox
7-10 days
Outpatient intensive
Outpatient follow-up
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• 100 amphetamine dependent treatment seeking patients at Vogur Hospital
• Randomized, double blind trial and 6 month trmt with VIVITROL® or VIVITROL®placebo and
Treatment as usual
• Stratified by gender and IV status.
• All participants detoxed at Vogur Hospital and consented.
• Randomized before going to outpatient status.
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Detox baseline
N=100
First study injection
First study injection
Residential treatment
N=61
Treatment n=23
Intensive
Outpatient
N=39
Placebo n=16
Treatment n=28
Placebo n=33
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169 assessed for eligibility
69 excluded
27 did not complete detox
7 refused participation
7 did not start trmt
28 other reasons
100
Randomized
49 assigned to receive placebo 51 assigned to receive Vivitrol
11 lost to follow-up
10 completed assessments
6 withdrew consent
7 lost to follow-up
13 completed assessment
4 withdrew consent
24 completed study 25 completed study
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Wk 8 Wk 16
Wk 24
Wk 1
Wk 4 Wk 12 Wk 20
• Repeat injections weeks 4, 8, 12, 16, 20
• Baseline assessments:
Medical & social history, liver panel (wk3, 11, 23), HepC
& HIV (wk24), ASI (wk 12, 24), Fagerström (wk 12, 24)
RAB (wk 24), AUDIT (wk 24), Blood for genetics
• Brief weekly assessments urine, alcohol breath, AE‘s, TLFB, TSR, Craving
• Monthly assessments relapse, pregnancy, BDI, EuroQol,
• Month 12, mail-in assessment
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Primary outcome
• Proportion of amphetamine negative urines during weeks 1-24 of outpatient treatment
Secondary outcomes
Time to relapse
HIV risk behavior
Treatment retention
Amphetamine craving
Drug use
Criminal activity
Depression
Quality of Life
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• Aged 18 or above.
• Primary diagnosis of current amphetamine dependence as defined by DSM-IV-TR with
=>10 days of amphetamine use in past month.
• Successfully complete 7-10 day assessment and study baseline measures at Vogur.
• Abstinent from substances for at least 7 days
• Provision of contacts of 3 people
• Written consent
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• AST or ALT >5 times the top limit of normal.
• Physiologically dependent on opioids or other substances (nicotine excepted) or known concomitant or planned use of opioid analgesics, positive opioid urine drug test or positive naloxone challenge,
• No severe psychiatric, cognitive, or medical problems and no known hypersensitivity to naltrexone
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• No significant differences between treatment grps on sample characteristics.
• Males 75%
• Caucasian 100%
• Average age 31 years
– (19-30 years 49%; 30-40 36%; 40-58 15%)
• IV injecting 20
• HIV + 0
• HEP C 9
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• No significant differences between treatment grps on baseline demographics.
• Stable housing
• Never married
• Living with partner (>1year)
• Education completed 10th grade
• Not completed 13%
• Employment (>11 days past mo)
88%
37%
14%
59%
12%
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DSM-IV checklist physician diagnosis
Amphetamine dependence
Alcohol dependence
N (%)
100
75
Cannabis dependence
Cocaine dependence
69
26
Methylphenidate dependence 15
Sedative dependence 30
Opiate dependence 0
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Placebo Treatment
(N = 49) (N = 51)
• Prior admissions, mean #
3 3
• BDI score
• RAB drug risk
13
0.8
14
1.5
• RAB sex risk 5.2
5.7
• Amphetamine craving 47 41
(VAS 0-100)
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TLFB
Amphetamine use past month mean
18 days
Methylphenidate use past motnh 0,6
Craving – VAS 44 (0-100)
No difference at baseline between trmt grps
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• 53% of treatment grp provided UDS at wk 24
• 47% of placebo grp provided UDS at wk 24
• No differences in distributions of time to drop out between the trmt grps (log-rank test)
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100
90
80
70
60
50
40
30
20
10
0
Number of subjects receiving study treatment
100
72
56
47
Four or more injections:
22 treatment (29<4)
28 placebo (21<4)
46
37
Total
Treatment
Placebo injection 1 injection 2 injection 3 injection 4 injection 5 injection 6
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1247 urines collected (1194-/53+) 2400 urines target
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Observed
Treatment
Observed
Placebo
Imputed
Treatment
Imputed
Placebo

• Amphetamine: 4.25
• Benzodiazepines: 8.26
• Marijuana: 6.98
• Cocaine:
• Opioids:
1.44
0.96
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Treatment Placebo
35
30
25
20
50
45
40
15
10
5
-
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Weeks 0-24

• 29 subjects self-reported amphetamine relapse (3 days or more) over 6 months
– Treatment group: 14
– Placebo group: 15
• 32 subjects self-reported alcohol relapse (3 days or more) over 6 months
– Treatment group: 19
– Placebo group: 13
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• 15 participants had a SAE with 20 events
• 17 hospitalization due to relapse
• 1 pneumothorax
• 1 abdominal pain, elevated liver enzymes
• 1 potential suicide attempt with relapse
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Treatment
Severe; 5%
mild, moderate, severe
Treatment
Total AE reports 188
Placebo
Total AE reports 194
Placebo Severe 2%
Placebo
Moderate 16%
Treatment
Moderate 28%
Treatment
Mild 67%
Placebo Mild 82%

64 subjects reported an adverse event
38 subjects reported pain/swelling injection site
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Placebo
BSL n=49
BDI score 14.8
RAB drug risk 0.8
RAB sex risk
Amphetamine craving
5.2
47
Placebo
W24
Treatm
BSL n=28 n=51
8
0.15
4.5
16
15
1.5
5.7
41
Treatm
W24 n=24
6
1.0
4.0
12
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• Robust response to treatment as usual for those who stayed in trmt with no additional benefit from Naltrexone.
• Results did not replicate previous findings
• Similarties to other studies: in regards to severity of dependence BSL and retention
• Difference in amount of treatment received, start off in detox and 61% residential trmt before getting study drug.
• Trend towards worse outcome for those going directly to outpatient (37% /56% +UDS res/out)
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• Thank you!
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