1. Do Alcoholics Respond to Placebo? Results from COMBINE
Roger D. Weiss, MD
For the COMBINE Study Research Group

2. Placebo Medication Standard in most medication trials
Required for FDA trials
Standard in alcoholism medication trials

3. Why Use Placebo?
Many people improve on placebo (a mean of 30% in major depressive disorder trials)
Ensures that superior outcome from an active treatment can be attributed to the treatment itself

4. Role of Placebo Medication
Controls for
Expectancy
Optimism
Attention (RA and clinician visits, health checks)
Opportunity to discuss problems
Increased awareness of disorder, with resultant behavioral changes

5. Placebo Medication Is Never Delivered in a Vacuum
It is always delivered in the context of medical visits, which typically also cover other health-related topics

6. Placebo Medication Is Never Delivered in a Vacuum
Usually cannot disentangle ‘placebo response’ from ‘participation response,’ which includes motivation to enter trial as well as other trial-related non-specific factors

7. How Strong is the Placebo Response?
Hrobjartsson & Gotzche (NEJM, 2001)
Reviewed 114 studies of placebo vs. no treatment
Among 32 studies with binary outcomes, placebo did no better
For studies with continuous outcomes, placebo had a positive effect, but only with subjective outcomes
Placebo beneficial for pain

8. What do we know about the placebo response for alcoholism?
Wilson et al. (1980):
90 pts seeking disulfiram implant were given either disulfiram (40), placebo (40), or no (10) implant; 10 pts desiring abstinence but no implant were ‘pseudocontrols’
Both implant groups abstained longer
Since disulfiram works through fear of effect, not an ideal study of placebo
What do we know about the placebo response for alcoholism?

9. Complications of Using Placebo in a Combination Medication/Behav’l Tx Trial
Behavioral therapy for alcoholism is often not delivered with active medications
Behavioral therapy for alcoholism is never delivered with placebo medication
Interaction of behavioral therapy with placebo is not known

10. Potential Interactions of Behavioral Tx and Placebo in a Combined Trial
Positive placebo effect could improve results of behavioral tx
Attribution of gains to medication could reduce effort at behavioral tx, a ‘negative placebo effect’
Neither of the above

11. Original COMBINE Treatment Conditions (8 cells)
Behavioral Therapy
Naltrexone
Acamprosate
Cell MM
Placebo 1 2 3 4
MM + CBI 5 6 7 8

12. Final COMBINE Treatment Conditions (9 cells)
Behavioral Therapy
Naltrexone
Acamprosate
Cell MM
Placebo 1 2 3 4
MM + CBI 5 6 7 8
CBI alone
No Pills 9

13. Advantages of a “CBI with no Pills” Condition (Cell 9):
Tests CBI alone, without placebo or MM
Thus, delivers CBI in an ecologically valid way
Examines the nature of the placebo effect in alcohol-dependent patients

14. Baseline Sociodemographic Characteristics by Treatment
CBI alone
(%, n = 157)
CBI+MM+Placebo
(%, n = 156)
MM+Placebo
(%, n = 153)
Age < 44 52 56
Non-minority 77 73 78
Male 68 71 67
Married 41 50 44
Employed 69 72 80
Income > $30K 74
Education < 12 years 28 30 29

15. Baseline Clinical Characteristics by Treatment
CBI alone
(mean)
n = 157
CBI+MM+Placebo
n = 156
MM+Placebo
n = 153
% Days Abstinent
(past 30 days) 24 25
Drinks/Drinking Day 12 13
% Days Heavy Drinking (past 30 days)
65.3
67.0
ADS Score (max 47) 17 16
DrInC Score
(max 135) 46 47
OCDS Score (max 56) 19

16. Results

17. Percent Days Abstinent at Baseline (Previous 90 Days) and Week 16
(mean)
Week 16*
Mixed model
p-value
CBI+MM+Placebo
(n = 156) 25 80
0.0002
MM+Placebo
(n = 153) 74
CBI Alone
(n = 157) 24 67
*Pair-wise comparison tests:
1 vs. 2, p = 0.04
2 vs. 3, p = 0.03
1 vs. 3, p < 0.001

18. Comparison with CBI, No Pills: PDA+ MM + MM
No MM

19. Relapse to Heavy Drinking, Comparison with CBI alone CBI + MM + Placebo vs. CBI alone, p=0.05 MM + Placebo vs. CBI alone, p=0.46 MM MM
No MM

20. Good Clinical Outcome During last 8 Weeks of Treatment: Comparison with CBI AloneNS
P=0.07 + MM + MM
No MM

21. Causes of “Placebo Response ” in Alcohol Dependence
Expectancies
Optimism related to seeing a medical professional, taking a (new) medication
Treatment retention due to seeing medical professional, expectation of pill response
Content of Medical Management meetings
Pill-taking as a reminder of recovery efforts

22. Expectancies Can be positive (taking a medication)
Could be negative, i.e., a “disappointment effect” among participants not receiving pills
Related to COMBINE study design: 8 of 9 participants received pills

23. Treatment Retention

24. Content of Medical Management Meetings
MM focused on
Discussion of drinking, support for abstinence
Medication adherence
Referral to support groups, e.g., AA

25. Percentage of Patients Attending AA in the Week Before Baseline and During Treatment
MM+Placebo
CBI+MM+Placebo
CBI Alone
Chi-square = 7.38, df = 2, p < 0.03

26. Did AA Attendance Account for Better Drinking Outcomes in the Two Groups Receiving MM + Placebo?
Partially
AA attendance during treatment was a significant predictor of PDA during treatment (p=.03)
But
When the overall PDA analysis was adjusted for AA attendance during treatment, the differences remained significant (p<0.001)

27. Pill-Taking A daily reminder of the reason for the pill-taking
Reinforces recovery efforts
Could acamprosate have a larger placebo effect because of its tid dosing?

28. Summary Positive expectations of medication
“Placebo response” in COMBINE appears to be related to
Positive expectations of medication
Disappointment over receiving no pills, perhaps leading to faster dropout
Meeting with a healthcare professional
Content of MM Meetings
AA Attendance
Pill-taking as a reminder of recovery efforts