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

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

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

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

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

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

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

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?

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

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

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

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

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

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

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

Results

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

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

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

Good Clinical Outcome During last 8 Weeks of Treatment: Comparison with CBI Alone NS P=0.07 + MM + MM No MM

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

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

Treatment Retention

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

Percentage of Patients Attending AA in the Week Before Baseline and During Treatment MM+Placebo 35 23 24 32 CBI+MM+Placebo 34 22 51 33 CBI Alone 35 22 32 20 Chi-square = 7.38, df = 2, p < 0.03

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)

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?

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