karran a. phillips, md, msc nida intramural research program amersa annual meeting november 8, 2014
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BehavioralPharmacology
Laboratory Studies
RandomizedClinical Trials
Archway - Outpatient Treatment Research
Clinic
TechnologyDevelopment
GPS – Real Time
Location
EMA – Real Time
Self Report
Geographical Momentary Assessment
Treatment Treatment SectionSection
•Opiate agonists effective treatments for opiate addiction block drug cue reinstatement no effect on stress-induced reinstatement patients still relapse
•Alpha-2 agonists • block stress-induced reinstatement• possible effect on drug cue-induced reinstatement
Is there a role for Alpha-2 agonists Is there a role for Alpha-2 agonists in Relapse Prevention?in Relapse Prevention?
Alpha-2 agonists for Relapse Alpha-2 agonists for Relapse PreventionPrevention
with buprenorphineIf we combine clonidine
can we reduce time to lapse or relapse?
Randomized Clinical TrialRandomized Clinical TrialClonidine for Relapse PreventionArchway
Clinic
Clonidine 0 mg vs. 0.3 mg
Opioid-dependent treatment seekers
EMA
TechnologyDevelopment
GPS – Real Time
Location EMA – Real Time
Self Report
Geographical Momentary Assessment
Relapse Prevention
119
C-I – clonidine induction
Contingent Vouchers
Maintenance
Counseling
Buprenorphine
5 21
(8-24 mg SL)/d
weeks
Clonidine
3 7 13 15 17 19 23 25 27
BaselineIntervention
Quit deadline
Randomization
Urine/breath/ 3 per week
C-I
1
Environmental cues• In the past hour did you see heroin? (yes/no)• Right now, do you crave heroin?
Stressors• Right now, are you stressed?
• NO!!
• no??
• yes??
• YES!!Asked at four randomly prompted times during
participant’s waking hours
Ecological Momentary AssessmentEcological Momentary Assessment
Does clonidine prevent lapse? • Time to Lapse - first opiate positive or missed urine
Does it prevent relapse?• Time to Relapse - any 2 or more consecutive
positive or missed urines • Cox regression
Does it increase duration of abstinence?• Longest period of consecutive opioid-negative
urines• 2-way ANOVA
Statistical Analysis Statistical Analysis
Does clonidine decouple stress or cue exposure from craving?
•Probability of reporting heroin/opiate craving (either yes? or YES!!) from:
• Reports of stress
• Reports of seeing heroin in the past hour
•Generalized Linear Mixed Model (SAS PROC GLIMMX)
Statistical Analysis Statistical Analysis
Results: Results: Participants Participants Placebo (n = 57) Clonidine (n = 61)
M (SD) / n (%) M (SD) / n (%)
Age (years) 38.3 (8.5) 39.2 (7.8)
Gender: Male 46 (80.7%) 46 (75.4%)
Race: Black 31 (54.4%) 40 (65.6%)
Education (years) 12.0 (2.0) 11.9 (1.3)
Heroin/Rx Opioid use (days in the last 30)
24.4 (7.9) 25.1 (8.0)
Cocaine use (days in the last 30)
3.4 (7.5) 3.4 (7.3)
# of drug treatments
1.8 (1.8) 1.7 (1.4)
0
20
40
60
80
100
14 28 42 56 70 84 98
ClonidinePlacebo
Days of clonidine/placebo
Induction Intervention
0
Time to Lapse Time to Lapse
Time to Relapse – not significant; p = .71Hazard ratio 1.09; 95% CI .70 – 1.67
Hazard ratio = .6795% CI = .45 – 1.0p =.05
0
10
20
30
40
50
60
70
80
Days
of
con
secu
tive o
pio
id a
bst
inen
ce
Placebo Clonidine
Longest Duration of Continuous Abstinence Longest Duration of Continuous Abstinence
t(109)=2.04, P≤0.05, Cohen’s d: 0.375
*
Individual participant
*
Stress Rating
Main effect of stress (F(3,257)=65.6, P≤0.001)
EMA: Stress and Heroin Craving EMA: Stress and Heroin Craving Li
kelih
ood
of
rep
ort
ing
hero
in c
ravin
g (
%)
30
20
25
15
5
10
0
*
Like
lihood
of
rep
ort
ing
hero
in c
ravin
g (
%)
Stress Rating
Main effect of Clonidine (F(1,105)=71.5, P≤ 0.001)
6.3%11.8%
EMA: Stress and Heroin Craving EMA: Stress and Heroin Craving 30
20
25
15
5
10
0
*
Stress Rating
Drug X Stress interaction(F(3,257)=8.8, P≤0.001)
EMA: Stress and Heroin EMA: Stress and Heroin CravingCraving
Like
lihood
of
rep
ort
ing
hero
in c
ravin
g (
%)
30
20
25
15
5
10
0
*
Cue Exposure
NO! no?Did Not See Heroin
Saw Heroin
Main effect of exposureF(3,257)=65.6, P≤0.001
Main effect of clonidineF(3,257)=65.6, P≤0.001
EMA: Drug Cues and Heroin EMA: Drug Cues and Heroin CravingCraving
Like
lihood
of
rep
ort
ing
hero
in c
ravin
g (
%)
30
20
25
15
5
10
0
Drug x Exposure Interaction, p=n.s.
Does it work?• Yes, clonidine given in conjunction with
buprenorphine increased duration of abstinence and time to lapse.
Does clonidine work in humans using the same mechanism as in animals?
• Evidence suggests yes.
• Stress and craving were decoupled by clonidine, while cue exposure and craving were not.
Summary of Findings Summary of Findings
For clinicians and patients:
The EMA results identify the circumstances under which clonidine maintenance is most likely to be beneficial: exposure to moderate (though not severe) levels of daily-life stress.
Discussion Discussion
For animal & human laboratory researchers:
Our EMA results suggest that the seemingly contrived stressors used in the lab can indeed stand in for stressors encountered spontaneously by humans, outside the control of the investigator.
Discussion Discussion
Kenzie PrestonDavid EpsteinUdi GhitzaBill KowalczykMichelle Jobes Ashley Kennedy Daniel Agage John Schmittner
Yavin Shaham
Archway Staff and participants
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