This study investigated for the first time the effects of individual and combined application of 3 learning techniques (verbal suggestions, classical conditioning, and observational learning) on placebo analgesia and extinction. Healthy participants (N = 206) were assigned to 8 different groups in which they were taught through either a verbal suggestion, a conditioning paradigm, a video observing someone, or any combination thereof that a placebo device (inactive transcutaneous electric nerve stimulation [TENS]) was capable of alleviating heat pain, whereas one group did not (control). Placebo analgesia was quantified as the within-group difference in experienced pain when the placebo device was (sham) ‘activated’ or ‘inactivated’ during equal pain stimuli, and compared between groups. Placebo analgesia was induced in groups with 2 or 3 learning techniques. Significantly stronger placebo analgesia was induced in the combination of all 3 learning techniques as compared to the individual learning techniques or control condition, underlining the additional contribution of 3 combined techniques. Extinction did not differ between groups. Furthermore, pain expectancies, but not state anxiety or trust, mediated placebo analgesia. Our findings emphasize the added value of combining 3 learning techniques to optimally shape expectancies that lead to placebo analgesia, which can be used in experimental and clinical settings. Perspective: This unique experimental study compared the individual versus combined effects of 3 important ways of learning (verbal suggestions, classical conditioning, and observational learning) on expectation-based pain relief. The findings indicate that placebo effects occurring in clinical practice could be optimally strengthened if healthcare providers apply these techniques in combination.

Learning and negative outcome expectations can increase pain sensitivity, a phenomenon known as nocebo hyperalgesia. Here, we examined how a targeted pharmacological manipulation of learning would impact nocebo responses and their brain correlates. Participants received either a placebo (n = 27) or a single 80 mg dose of d-cycloserine (a partial NMDA receptor agonist; n = 23) and underwent fMRI. Behavioral conditioning and negative suggestions were used to induce nocebo responses. Participants underwent pre-conditioning outside the scanner. During scanning, we first delivered baseline pain stimulations, followed by nocebo acquisition and extinction phases. During acquisition, high intensity thermal pain was paired with supposed activation of sham electrical stimuli (nocebo trials), whereas moderate pain was administered with inactive electrical stimulation (control trials). Nocebo hyperalgesia was induced in both groups (p < 0.001). Nocebo magnitudes and brain activations did not show significant differences between d-cycloserine and placebo. In acquisition and extinction, there were significantly increased activations bilaterally in the amygdala, ACC, and insula, during nocebo compared to control trials. Nocebo acquisition trials also showed increased vlPFC activation. Increased opercular activation differentiated nocebo-augmented pain aggravation from baseline pain. These results support the involvement of integrative cognitive-emotional processes in nocebo hyperalgesia.

Background and Objective: The current treatments of primary musculoskeletal low back pain (LBP) have a low to moderate efficacy, which might be improved by looking at the contribution of placebo effects. However, the size of true placebo effects in LBP is unknown. Therefore, a systematic review and meta-analysis were executed of randomized controlled trials investigating placebo effects in LBP. Databases and Data Treatment: The study protocol was registered in the international prospective register of systematic reviews Prospero (CRD42019148745). A literature search (in PubMed, Embase, The Cochrane Library, CINAHL and PsycINFO) up to 2021 February 16th yielded 2,423 studies. Two independent reviewers assessed eligibility and risk of bias. Results: Eighteen studies were eligible for the systematic review and 5 for the meta-analysis. Fourteen of the 18 studies were clinical treatment studies, and 4 were experimental studies specifically assessing placebo effects. The clinical treatment studies provided varying evidence for placebo effects in chronic LBP but insufficient evidence for acute and subacute LBP. Most experimental studies investigating chronic LBP revealed significant placebo effects. The meta-analysis of 5 treatment studies investigating chronic LBP depicted a significant moderate effect size of placebo for pain intensity (SMD = 0.57) and disability (SMD = 0.52). Conclusions: This review shows a significant contribution of placebo effects to chronic LBP symptom relief in clinical and experimental conditions. The meta-analysis revealed that placebo effects can influence chronic LBP intensity and disability. However, additional studies are required for more supporting evidence and evidence for placebo effects in acute or subacute LBP. Significance: This systematic review and meta-analysis provides evidence of true placebo effects in low back pain (LBP). It shows a significant contribution of placebo effects to chronic LBP symptom relief. The results highlight the importance of patient- and context-related factors in fostering treatment effects in this patient group. New studies could provide insight into the potential value of actively making use of placebo effects in clinical practice.