Transcript Phillips 2014

Karran A. Phillips, MD, MSc
NIDA Intramural Research Program
AMERSA Annual Meeting
November 8, 2014
Behavioral
Pharmacology
Laboratory
Studies
Treatment
Section
Technology
Development
GPS – Real
Time
Location
Randomized
Clinical Trials
Archway - Outpatient
Treatment Research
Clinic
EMA – Real
Time
Self Report
Geographical Momentary Assessment
Is there a role for Alpha-2 agonists in
Relapse Prevention?
• 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
Alpha-2 agonists for Relapse
Prevention
If we combine clonidine with buprenorphine
can we reduce time to lapse or relapse?
Randomized Clinical Trial
Clonidine for Relapse Prevention
Archway
Clinic
Technology
Development
Opioid-dependent treatment seekers
GPS – Real
Time
Location
EMA – Real
Time
Self Report
Clonidine 0 mg vs. 0.3 mg
Geographical Momentary
Assessment
Relapse Prevention
Baseline
C-I
Intervention
Maintenance
Counseling
Buprenorphine
(8-24 mg SL)/d
Contingent
Vouchers
Clonidine
3 per week
Urine/breath/
EMA
1
3
5
7
9
Quit
deadline
Randomization
11
13
15
weeks
17
19
21
23
25
C-I – clonidine induction
27
Ecological Momentary Assessment
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
Statistical Analysis
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
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)
Results: Participants
Placebo (n = 57)
Clonidine (n = 61)
M (SD) / n (%)
M (SD) / n (%)
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
24.4 (7.9)
25.1 (8.0)
3.4 (7.5)
3.4 (7.3)
1.8 (1.8)
1.7 (1.4)
Age (years)
(days in the last 30)
Cocaine use
(days in the last 30)
# of drug treatments
Participants with no opioid lapse (%)
Time to Lapse
100
Clonidine
Placebo
Hazard ratio = .67
95% CI = .45 – 1.0
p =.05
80
60
40
20
0
Induction Intervention
0
14
28
42
56
70
84
Days of clonidine/placebo
Time to Relapse – not significant; p = .71
Hazard ratio 1.09; 95% CI .70 – 1.67
98
Days of consecutive opioid abstinence
Longest Duration of Continuous Abstinence
80
70
60
50
40
*
30
20
10
0
Placebo
t(109)=2.04, P≤0.05, Cohen’s d: 0.375
Clonidine
Individual participant
EMA: Stress and Heroin Craving
Main effect of stress
(F(3,257)=65.6, P≤0.001)
Likelihood of reporting
heroin craving (%)
30
25
20
15
*
10
5
0
Stress Rating
EMA: Stress and Heroin Craving
Likelihood of reporting
heroin craving (%)
30
25
11.8%
6.3%
Main effect of Clonidine
(F(1,105)=71.5, P≤ 0.001)
20
15
*
10
5
0
Stress Rating
EMA: Stress and Heroin Craving
Likelihood of reporting
heroin craving (%)
30
25
Drug X Stress interaction
(F(3,257)=8.8, P≤0.001)
20
15
*
10
5
0
Stress Rating
EMA: Drug Cues and Heroin Craving
Likelihood of reporting
heroin craving (%)
30
Main effect of exposure
F(3,257)=65.6, P≤0.001
25
Main effect of clonidine
F(3,257)=65.6, P≤0.001
20
Drug x Exposure
Interaction, p=n.s.
15
*
10
5
0
Did Not See
Heroin
NO!
Saw
Heroin
no?
Cue Exposure
Summary of Findings
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.
Discussion
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
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.
Kenzie Preston
David Epstein
Udi Ghitza
Bill Kowalczyk
Michelle Jobes
Ashley Kennedy
Daniel Agage
John Schmittner
Yavin Shaham
Archway Staff
and participants
Other Drug Use
Marijuana Use
100
100
F(1,108)=6.32, P≤0.01,
Cohen’s d=0.48
80
80
%
Marijuana
60
Negative
Urine
Specimens
40
%
Cocaine 60
Negative
Urine
Specimens
40
20
20
0
Placebo
Clonidine
0
Cocaine Use
P=.40
Placebo
Clonidine