Interaction Between Drug and Placebo Effect:Randomized Placebo Controlled Trials May Not be Accurate in Determining Drug Effect Size

• Area-under-the-curve for drowsiness [ Time Frame: seven hours ] [ Designated as safety issue: No ]
  Seven-hour-area-under-the-curve of drowsiness on 100 mm visual analog scales will be determined
  
  
• Area-under-the-curve for dryness of the mouth [ Time Frame: seven hours ] [ Designated as safety issue: No ]
  Seven-hour-area-under-the-curve of dryness of the mouth on 100 mm visual analog scales will be determined
  
  

• Mean percent of time of reporting drowsiness on a dichotomous scale. [ Time Frame: seven hours ] [ Designated as safety issue: No ]
  Mean percent of time of reporting drowsiness on a dichotomous scale will also be determined.
  
  
• Mean percent of time of reporting dryness of mouth [ Time Frame: seven hours ] [ Designated as safety issue: No ]
  Mean percent of time of reporting dryness of mouth on a dichotomous scale will also be determined.
  
  

BACKGROUND:

The total effect of a medication is the sum of its drug effect, placebo effect (meaning response of placebo), and their possible interaction. Current interpretation of the results of clinical trials (the gold standard in evidence based medicine) assumes no such interaction. Using a novel cross-over balanced placebo design and caffeine as a model drug we have recently shown that a negative interaction does exist; suggesting that the size of drug effect as currently measured by clinical trials may not be accurate. Due to the novelty of the findings and their important clinical practice and research implications, they need to be confirmed using another drug; and the size of drug effect measured using the novel design need to be directly compared to that measured using conventional clinical trial design.

DESIGN:

A cross-over balanced placebo plus randomized placebo-controlled clinical trial design.

METHODS:

480 adults will be double-blindly randomized to three groups: first generation H-1 receptor antagonist- hydroxyzine (25 mg), placebo, or hydroxyzine+placebo group. The first two groups will receive the assigned intervention described by the investigators as hydroxyzine or placebo, in a randomized crossover design. The third group will receive hydroxyzine and placebo in a randomized double-blind placebo-controled crossover design. Group assignment will be concealed from volunteers and recruiters. Data collectors will be blinded to group assignment and intervention assignment. Volunteers will be partially deceived to the intervention assignment in the first two groups and blinded in the third group. The interventions to the third group will be also administered blindly. Serum hydroxyzine levels will be determined 3 hours post intervention from all volunteers to verify compliance and help maintain deception/blinding. The results of the study are expected to further our understanding of a widely used medical intervention, i.e., placebo, and help assess the appropriateness of randomized clinical trials in determining the size of drug effect.