Pavlovian and other learning mechanisms: what works best to facilitate placebo analgesia?

Background:
Placebo analgesia can be established by means of different learning techniques, with most evidence existing for classical (Pavlovian) conditioning, observational learning, and verbal suggestions. However, not all studies show consistent results, often multiple techniques are used simultaneously (e.g., conditioning combined with verbal suggestions), which makes it impossible to determine each specific effects, and no studies have directly compared the effects of all three techniques separately and in combination. In addition, individual characteristics (e.g., personality traits, genetics) might play a role in determining the degree of placebo analgesia and the mechanisms through which these learning techniques have their effects. Although many studies have examined specific predictor or mediator variables, because of the same reasons as mentioned for the learning techniques, the current evidence is inconsistent. Within the current study, we aim to examine each learning mechanism both in itself and in combination with the others to shed more light on how to best induce placebo analgesia. Next to this, we will study the role of individual characteristics in placebo analgesia.

Design
In this 8-arm between-subjects randomized controlled trial, healthy participants will learn through different (combinations of) learning techniques that a sham medical device, when turned on, relieves them from experimentally-induced thermal pain (placebo analgesia); a natural history group is also included that will receive sham learning techniques and a similar amount of thermal pain stimuli to ensure comparability. The 8 arms are: 1. Natural history, 2. Verbal suggestions, 3. Observational learning, 4. Conditioning, 5. Verbal suggestions & Observational learning, 6. Verbal suggestions & Conditioning, 7. Observational learning & Conditioning, 8. Verbal suggestions & Observational learning & Conditioning. Questionnaires and saliva swabs will be administered to assess individual characteristics that might impact placebo analgesia.

The combination of all three different learning techniques will elicit a stronger placebo analgesic effect than individual application for experimentally-induced thermal pain.

Participants will visit the laboratory once with a total duration of 165 minutes. Initially, participants are asked to fill in questionnaires to assess individual characteristics. Afterwards, a calibration phase is started to determine individual pain thresholds, followed by 72 low or moderate thermal pain stimuli; 36 learning stimuli and 36 test stimuli. Participants in the conditioning groups will receive low thermal pain stimuli when the sham device is turned on during the learning phase and moderate thermal pain stimuli when the sham device in turned off. Participants in the verbal suggestion groups receive a positive suggestion about the sham device. Lastly, participants in the observational learning groups watch a video that depicts a confederate reporting lower pain when the sham device is turned on. The three different learning techniques are also combined, and a natural history group is included, yielding a total of 8 groups. In groups that contain a single learning procedure, we will implement sham learning techniques to level out the amount of time invested in someone.

In the testing phase, all participants receive moderate pain stimuli and the difference between the pain reported in response to the stimuli given when the sham device is turned on (placebo trials) and turned off (control trials) is the total amount of placebo analgesia.

After the testing phase, participants are asked to donate their saliva for DNA analysis.

Individual application or any combination of the placebo-related learning techniques verbal suggestion, observational learning and conditioning.