Conclusions regarding the role of expectations in placebo analgesia studies may depend on how we investigate it: A meta-analysis, systematic review, and proposal for methodological discussions.

OBJECTIVE: Expectations are highlighted as a key component in placebo effects. However, there are different approaches to whether and how placebo studies should account for expectations, and the direct contribution has yet to be estimated in meta-analyses. Using different methodological approaches, this meta-analysis and systematic review examines the extent to which expectations contribute to pain in placebo studies. METHODS: The databases PubMed, PsycINFO, Embase, and Web of Science were searched for placebo analgesia mechanism studies with numerical measures of both expectations and pain. Thirty-one studies, comprising 34 independent study populations (1566 individuals, patients and healthy participants) were included. Two meta-analyses were conducted: Meta-analysis 1, using study-level data, estimated the effect of expectation interventions without taking measures of expectations into account (expectations assumed). Meta-analysis 2, using individual-level data, estimated the direct impact of participants' expectations on pain (expectations assessed). Risk of bias was assessed using the Cochrane Risk-of-bias tool. RESULTS: Meta-analysis 1 showed a moderate effect of expectation interventions over no expectation intervention on pain intensity (Hedges g = 0.45, I2 = 54.19). Based on 10 studies providing individual-level data, meta-analysis 2 showed that expectations predicted pain intensity in placebo and control groups (b = 0.36, SE = 0.05), although inconsistently across study methodologies. CONCLUSIONS: Participants' expectations contributed moderately to pain in placebo analgesia studies. However, this may largely be influenced by how we measure expectations and how their contribution is conceptualized and analyzed - both within and across studies.

Effects of deep brain stimulation and verbal suggestions on pain in Parkinson's disease.

BACKGROUND AND OBJECTIVES: In Parkinson's disease (PD) patients, verbal suggestions have been shown to modulate motor and clinical outcomes in treatment with subthalamic deep brain stimulation (DBS). Furthermore, DBS may alleviate pain in PD. However, it is unknown if verbal suggestions influence DBS' effects on pain. METHODS: Twenty-four people with PD and DBS had stimulation downregulated (80-60 to 20%) and upregulated (from 20-60 to 80%) in a blinded manner on randomized test days: (1) with negative and positive suggestions of pain for down- and upregulation, respectively, and (2) with no suggestions to effect (control). Effects of DBS and verbal suggestions were assessed on ongoing and evoked pain (hypertonic saline injections) via 0-10 numerical rating scales along with motor symptoms, expectations, and blinding. RESULTS: Stimulation did not influence ongoing and evoked pain but influenced motor symptoms in the expected direction. Baseline and experimental pain measures showed no patterns in degree of pain. There was a trend toward negative suggestions increasing pain and positive suggestions decreasing pain. Results show significant differences in identical stimulation with negative vs positive suggestions (60% conditions AUC 38.75 vs 23.32, t(13) = 3.10, p < 0.001). Expectations to pain had small to moderate effects on evoked pain. Patients estimated stimulation level correctly within 10 points. CONCLUSION: Stimulation does not seem to influence ongoing and evoked pain, but verbal suggestions may influence pain levels. Patients appear to be unblinded to stimulation level which is an important consideration for future studies testing DBS in an attempted blind fashion.

Expectations: How and when do they contribute to placebo analgesia?

In placebo research, expectations are highlighted as one of the most influential subjective factors. While some studies have shown a relationship between expectations and pain relief, others have not. However, little is known about how methods of assessment of expectations may affect these conclusions. One of the fundamental considerations is that participants in placebo trials rate their expectations when prompted to rate them on scales in advance, but are less likely to report their prior expectations, when asked to report their experience retroactively in an unprompted manner, often expressing, for example, prior hope or wishes of recovery. This article presents previously unpublished data to elucidate and explore the concepts highlighted by individuals in a placebo analgesia trial when assessed in a prompted and unprompted manner. The data corroborates the role of expectations involved in placebo effects, particularly in placebo analgesia. Thus, the question may be a matter of how and when expectations contribute to placebo effects, rather than if.

Does Certainty of Genuine Treatment Increase the Drug Response in Alzheimer's Disease Patients: A Meta-Analysis and Critical Discussion.

BACKGROUND: Non-specific treatment effects, such as expectations, contribute to the effectiveness of pharmacological treatments across diseases. However, the contribution of expectancy, i.e., certainty of receiving treatment, in patients with Alzheimer's disease (AD) is unknown. OBJECTIVE: The aim is to investigate whether certainty of receiving a genuine treatment influences the response to active treatment in AD patients. METHODS: The efficacy of active treatments in open-label trials, where patients are certain of receiving treatment (100%certainty), was compared to the same active treatments in randomized controlled trials (RCT), where patients are uncertain of receiving treatment or placebo (50%certainty). RESULTS: In the seven open-label trials, there was no significant difference between post- and pre-treatment scores (difference in means = 0.14, 95%CI [-0.51; 0.81], p = 0.66). In the eight RCT trials, there was a significant difference between post- and pre-treatment (difference in means = -0.91, 95%CI [-1.43; -0.41], p < 0.001). There was a statistically significant difference between open-label and RCT trials (difference = 1.06, 95%CI [0.23; 1.90], p = 0.001). CONCLUSION: Patients with AD did not benefit from certainty of receiving genuine treatment. This could be due to the nature/progression of the disease, but it could also be related to an order effect in the practice of running AD trials, where RCTs are conducted prior to open label. These findings have implications for the understanding of non-specific treatment effects in AD patients as well as for the design of clinical trials that test pharmacological treatments in AD.