Nocebo effects in fibromyalgia pain progression

Somatic symptoms, such as pain, can progress or become chronic due to sensitization processes. Nocebo effects, i.e., adverse treatment outcomes not attributable to active treatment components, could be playing a role in symptom progression. In this 3-part study, we examine whether: -susceptibility to nocebo effects predicts future pain progression in patients with chronic widespread pain, i.e. fibromyalgia (part 1), - nocebo-related learning processes differ between patients and healthy controls (part 2), and - nocebo-related learning processes are stable after one-month follow-up (part 3).
In a lab procedure, participants’ susceptibility to nocebo effects and their recovery therefrom will be measured with conditioning and extinction paradigms, respectively, combined with verbal suggestions. A sham Transcutaneous Electrical Nerve Stimulation (TENS) device will serve as the “placebo device” such that participants will be told when the device is activated pain sensitivity increases. After the baseline lab measurements, patients’ clinical pain levels will be followed-up at one-year to assess the role of nocebo effects in pain progression. Next to this, patients will also fill in a digital diary app (Experience Sampling Method; ESM) at baseline and one-year follow-up to assess possible changes in daily pain fluctuations (part 1). Furthermore, the baseline lab measurements will be compared between patients and healthy controls (part 2) and the within-group stability thereof will be investigated at one-month follow-up (part 3).

Part 1:
Primary: Patients who are more susceptible to nocebo effects at baseline will have greater clinical pain progression from baseline to one-year follow-up.
Secondary 1: Patients who are more resilient to extinction will have greater clinical pain progression from baseline to one-year follow-up.
Secondary 2: Nocebo-related learning processes (conditioning and extinction) predict the progression of secondary outcome measures (fibromyalgia disability and daily pain fluctuations) from baseline to one-year follow-up.

Part 2:
Primary: Compared to healthy controls, patients will show higher susceptibility to nocebo effects.
Secondary: Compared to healthy controls, patients will be more resilient to extinction.

Part 3:
Because the stability of nocebo effects has not been examined before, the research questions from this part (within- and between-group stability of susceptibility to nocebo effects and extinction) will be explored without specific hypotheses.

All participants will fill out baseline questionnaires to assess demographic, psychological, and clinical characteristics. All patients and healthy controls, matched to the first 34 patients, will participate in the baseline lab session. Next, the first 34 patients and matched healthy controls will be invited for a follow-up lab session at one-month. Only patients will be additionally contacted at one-year to follow-up up on clinical measures (clinical pain and fibromyalgia disability). Moreover, all patients will be asked to fill out a digital diary app on their phone (ESM) for 3 weeks and 3 times a day at baseline and one-year follow-up.

In a lab procedure, nocebo effects will be induced with the associative learning mechanism of classical conditioning combined with verbal suggestions. In the learning phase of the conditioning paradigm, announcing the activation of a placebo device (a sham TENS) will be paired with a higher intensity pressure pain applied to the thumb nail than the control trials where it is announced that the placebo device is de-activated. In the testing phase, participants will receive the same intensity of pressure pain regardless of the presumed (de)activation of the placebo device. To recover from nocebo effects, an extinction procedure will take place whereby in both learning and testing phases participants will receive the same intensity of pressure pain regardless of placebo device (de)activation. Pain intensity will be rated after each trial on a 0-10 Numeric Rating Scale (NRS). At one-month follow-up, the same lab procedure will be repeated, except it will begin with an additional testing phase to assess the amount of remaining nocebo effects from the baseline session.
Moreover, questionnaires on demographic (e.g. age), psychological (e.g. pain catastrophizing, optimism), and clinical characteristics (e.g., baseline pain levels) will be assessed in all participants. Additionally, in patients a digital diary app (ESM) will be used for momentary assessments of daily pain levels and psychological states.