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Amphetamine Addiction in Iceland and efficacy of pharmacotherapy

Valgerður Rúnarsdóttir, M.D.,Vogur Hospital IcelandSAA National Center of Addiction Medicine

Ingunn Hansdóttir, PhD,Assistant Professor University of IcelandResearch Counsil Member SAA National Center of Addiction Medicine

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

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Disclosure of relevant financial relationships

• 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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Investigators

University of Pennsylvania: • George Woody, M.D• Helen Pettinati, PhD

• Charlotte Royer-Malvestuto

• Biostatistician: Kevin Lynch, PhD

NIDA project ManagerJamie Biswas, MD

Vogur Hospital:• Thor Tyrfingsson, M.D.• Val Runarsdottir, M.D.

• Ingunn Hansdottir, PhD

• Data Manager: Magnus Einarsson

Lead investigators

Project co-ordinators

Data analysis

Other collaboratorsBrown UniversityMilunka Kojic, MD

AlkermesAvani Desai, PharmD

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Background

• 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.

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Swedish studies

• 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.

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Rationale

• Can these results be replicated with extended release formula?

• Study proposed in Iceland – why Iceland?

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Icelandic setting

• 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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Icelandic setting - Treatment as usual: Detox• Hospitalization 7-10 daysResidential: • 4 weeksIntensive 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)

Detox 7-10 days

Residential4 weeks

Outpatient intensive

Outpatient follow-up

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Study Design -I

• 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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Study Design-IIDetox

baseline N=100

Residential treatment

N=61

Treatment n=28

Placebo n=33

Intensive Outpatient

N=39

Treatment n=23

Placebo n=16

First study injection

First study injection

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Screening and randomization 169 assessed for eligibility

100 Randomized

51 assigned to receive Vivitrol

11 lost to follow-up

10 completed assessments

6 withdrew consent

24 completed study

49 assigned to receive placebo

7 lost to follow-up

13 completed assessment

4 withdrew consent

25 completed study

69 excluded27 did not complete detox

7 refused participation 7 did not start trmt

28 other reasons

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Study design - III

• 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 assessmentsrelapse, pregnancy, BDI, EuroQol,

• Month 12, mail-in assessment

Wk 1

Wk 4

Wk 8

Wk 12

Wk 16

Wk 20

Wk 24

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Study Design- outcomes

Primary outcome• Proportion of amphetamine negative urines

during weeks 1-24 of outpatient treatment Secondary outcomes

Time to relapse Drug useHIV risk behavior Criminal activityTreatment retention DepressionAmphetamine craving Quality of Life

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Inclusion criteria• 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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Exclusion criteria

• 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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Sample characteristics• 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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Baseline demographics

• No significant differences between treatment grps on baseline demographics.

• Stable housing 88% • Never married 37%• Living with partner (>1year) 14%

• Education completed 10th grade 59%• Not completed 13%

• Employment (>11 days past mo) 12%

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Baseline diagnosis

DSM-IV checklist physician diagnosis

N (%)

Amphetamine dependence 100Alcohol dependence 75Cannabis dependence 69Cocaine dependence 26Methylphenidate dependence 15Sedative dependence 30Opiate dependence 0

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Baseline

Placebo Treatment(N = 49) (N = 51)

• Prior admissions, mean # 3 3• BDI score 13 14• RAB drug risk 0.8 1.5• RAB sex risk 5.2 5.7• Amphetamine craving 47 41

(VAS 0-100)

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Self-reported amphetamine use 4 weeks prior to study

TLFB meanAmphetamine use past month 18 daysMethylphenidate use past motnh 0,6Craving – VAS 44 (0-100)

No difference at baseline between trmt grps

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Missing data and retention

• 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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RetentionNumber of subjects receiving study treatment

injection 1 injection 2 injection 3 injection 4 injection 5 injection 60

10

20

30

40

50

60

70

80

90

100100

72

56

47 46

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TotalTreatmentPlacebo

Four or more injections: 22 treatment (29<4) 28 placebo (21<4)

Negative urines;%1247 urines collected (1194-/53+) 2400 urines target

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 240%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Observed Treatment

Observed Placebo

Imputed Treatment

Imputed Placebo

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% Drug Positive Urines(N=1257)

• Amphetamine: 4.25• Benzodiazepines: 8.26 • Marijuana: 6.98• Cocaine: 1.44• Opioids: 0.96

Ampetamine Craving Scale by trmt grp

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 -

5

10

15

20

25

30

35

40

45

50

Weeks 0-24

Amph

etam

ine

crav

ing

scor

e

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Relapse

• 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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SAE

• 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

AE severitymild, moderate, severe

Treatment Mild 67%

Treatment Moderate 28%

Treatment Severe; 5%

TreatmentTotal AE reports 188

Placebo Mild 82%

Placebo Moderate 16%

Placebo Severe 2%

PlaceboTotal AE reports 194

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Adverse Events (total)64 subjects reported an adverse event38 subjects reported pain/swelling injection site

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Placebo BSL

Placebo W24

Treatm BSL

TreatmW24

n=49 n=28 n=51 n=24

BDI score 14.8 8 15 6RAB drug risk 0.8 0.15 1.5 1.0RAB sex risk 5.2 4.5 5.7 4.0Amphetamine craving

47 16 41 12

Secondary outcomes

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Conclusions

• 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!

Thanks for your attention