Open-Label-Placebos can reduce pain, but not indigestion during gluten challenge in chronic pain patients

Abstract

Background: Dietary interventions have become a management tool for chronic pain conditions over the past few decades. Certain diets, such as gluten-free diets, are perceived as particularly beneficial by patients, although there is no evidence to support this. Studies that have investigated this topic have focused little on possible expectation effects that could be involved in symptom development or pain increase.

Methods: In a 2×2 study design with repeated measurements to test treatment effects, we investigated 26 patients with fibromyalgia (FMS). Additional chronic pain conditions were included and analyzed exploratively. However, the main analysis focused on fibromyalgia patients. Participants underwent an oral food challenge (OFC) with double-blinded gluten or alleged gluten (sham gluten). All of them received an OLP with different instructions to treat negative effects of the porridge. Treatment expectations were modulated by either neutral or positive instructions regarding the OLPs. Participants were randomly assigned to one of four groups: (1) gluten and neutral instructions; (2) gluten and positive instructions; (3) sham gluten and neutral instructions; and (4) sham gluten and positive instructions. Expectations before (T0) and after the instructions (T0.1) as well as pain and indigestion before (T0) and after the OFC (T1 30min, T2 30-180min, T3 240min) were assessed.

Results: In FMS patients, a significant interaction with instructions were observed (p = 0.048). Positive instructions led to a decrease in pain (T0-T2) while neutral instructions led to an increase in pain. However, post-hoc comparisons did not reveal significant group differences. No interaction was found with gluten (p = 0.65). Positive instructions increased positive treatment expectations but missed significance marginally (p = 0.06), while negative expectations decreased for all participants regardless of instructions (p < 0.001). A strong correlation was found between expected and actual pain relief (p < 0.001). Digestive discomfort increased temporarily post-intervention (p < 0.004) but returned to baseline after 4 h. No significant effects of gluten (p = 0.15) or instructions (p = 0.8) on indigestion were observed.

Conclusion: This study highlights the complex interplay of disease type, placebo effects, and expectations in chronic pain conditions during gluten provocation. While gluten itself showed no significant impact on pain or indigestion, positive instructions significantly enhanced perceived pain relief. These findings suggest that expectation effects, rather than gluten, may play a more central role in symptom modulation, at least for pain. Future research should focus on expectation-driven mechanisms to better understand and optimize dietary interventions in chronic pain management and differences across pain diseases.

Keywords: Open-Label-Placebo; chronic pain; expectation; fibromyalgia; gluten intolerance.

Figure 1

2×2 experimental design. Participants were divided into four groups according to expectations (low or high) and type of food (sham-gluten porridge or gluten porridge). The instructions for the OLP varied depending on the level of expectation (Adapted from Paschke et al., 2023, licensed under CC BY-NC 4.0). OLP, Open-Label-Placebo.

Figure 2

Flowchart of chronic pain patients undergoing an oral food challenge and Open-Label-Placebo intervention. (Adapted from Paschke et al., 2023, licensed under CC BY-NC 4.0).

Figure 3

Course of pain in patients with fibromyalgia (n = 26) before and after the oral food challenge (OFC) and intake of Open-Label-Placebos (OLP) dependent on positive or neutral instructions about the OLP mechanism of action. Pain was measured on a numerical rating scale (NRS; 0 = no pain, 10 = worst pain). The diagram is zoomed in on the range of the y-axis, as the effects would not be visible if the full scale were used.

Figure 4

Course of positive expectation (SETS – positive subscale) in patients with fibromyalgia (N = 26). Patients’ expectations before and after positive or neutral instructions about the mechanism of action of OLP were measured with the positive scale of the Stanford Expectation Scale (SETS) with these items: (1) This treatment will be completely effective; (2) My condition will be completely resolved after the treatment; and (3) I have complete confidence in this treatment. The diagram is zoomed in on the range of the y-axis, as the effects would not be visible if the full scale were used (full scale = 1–7; 1 = strongly disagree, 4 = neither agree nor disagree, 7 = strongly agree).

Figure 5

Correlation between expected and real change in pain increase or decrease before and after the instruction about the mechanism of action of OLP in patients with fibromyalgia (N = 26). The correlation is based on the real and expected difference values. Expected change in pain: Patients were asked what change in pain they believed to experience after OLP intake. Subjective change in pain: Differences in the scores of patients’ pain ratings on the numerical rating scale ranging 0–10 (10 = worst pain) were measured before and after the instructions.

Figure 6

Course of indigestion in patients with fibromyalgia (N = 26) before and after the oral food challenge (OFC) and intake of Open-Label-Placebos (OLP) dependent on positive or neutral instructions about the OLP mechanism of action. Indigestion were measured on a numerical rating scale of 11 digestion-related symptoms (NRS; 0 = no symptom, 10 = severe symptom). The diagram is zoomed in on the range of the y-axis, as the effects would not be visible if the full scale were used.