Karran A. Phillips, MD, MScNIDA Intramural Research Program

AMERSA Annual MeetingNovember 8, 2014

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

Other Drug UseOther Drug Use

F(1,108)=6.32, P≤0.01,

Cohen’s d=0.48 P=.40