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.

Placebo analgesia and nocebo hyperalgesia in patients with Alzheimer disease and healthy participants.

ABSTRACT: The role of placebo analgesia and nocebo hyperalgesia in patients with Alzheimer disease (AD) is largely unknown, with only few studies in the area. Therefore, this study aims to investigate to which extent placebo analgesia and nocebo hyperalgesia effects are present in patients experiencing mild-to-moderate AD. Twenty-one patients with AD (test population) and 26 healthy participants (HP; design validation) were exposed to thermal pain stimulation on 3 test days: Lidocaine condition (open/hidden lidocaine administration), capsaicin condition (open/hidden capsaicin administration), and natural history (no treatment), in a randomized, within-subject design. Open lidocaine and open capsaicin were accompanied by verbal suggestions for pain relief and pain increase, respectively. Expected pain and actual pain intensity were measured on a numerical rating scale (0-10). Placebo and nocebo effects were calculated as pain differences in open-hidden lidocaine and capsaicin, respectively, controlled for no treatment. Healthy participants obtained a placebo effect ( P = 0.01) and a trend for a nocebo effect ( P = 0.07). Patients with AD did not obtain a placebo effect ( P = 0.44) nor a significant nocebo effect ( P = 0.86). Healthy participants expected lower and higher pain with open vs hidden lidocaine and capsaicin, respectively ( P < 0.001). The same expectation effects were seen in patients with AD (open vs hidden lidocaine, P = 0.008; open vs hidden capsaicin, P < 0.001). With a well-controlled experimental setting, this study suggests that patients with AD may not experience placebo analgesia effects. Nocebo hyperalgesia effects in patients with AD needs further research. These findings may have implications for the conduction of clinical trials and the treatment of patients with AD in clinical practice.

A Systematic Review and Meta-analysis of Narrative Language Abilities in Children with Attention-Deficit/Hyperactivity Disorder.

While children with ADHD are reported to have language problems, it is less clear if their ability to use language to tell a story (i.e., form a narrative) is impaired. Therefore, a systematic review and meta-analysis of studies examining the oral production of fictional stories in children with ADHD was conducted. Databases were systematically searched in January 2019 and December 2020 (follow-up). Studies comparing children (≤ 18 years) with ADHD to a control group of typically developing children were included. The meta-analysis adhered to PRISMA guidelines and was preregistered with PROSPERO [CRD42019122040]. Sixteen studies were retained. Results indicated that compared to typically developing children, children with ADHD produced less coherent narratives (Hedges' g = 0.58 p < .001), gave more ambiguous references (Hedges' g = 0.52, p < .001), made more disruptive errors (Hedges' g = 0.41, p < .001), and produced language that was less syntactically complex (Hedges' g = 0.39, p < .05). Children with ADHD also produced less language overall (Hedges' g = 0.27, p < .05), although this result appeared to be an artefact of publication bias. Two studies investigated internal state language and both found children with ADHD to produce narratives with less internal state language. Children with ADHD did not produce less fluent narratives (Hedges' g = 0.23, p = .47), although a scarcity of studies [K = 4] preclude firm conclusions. In conclusion, children with ADHD were impaired in several areas of oral narrative production and screening for narrative language problems should be considered when assessing language and communicative abilities in children with ADHD.

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.

Placebo analgesia effects across central nervous system diseases: what do we know and where do we need to go?

Placebo effects are well established in healthy participants experiencing experimental or acute pain. Yet, little is known about the mechanisms of placebo analgesia effects in patients with chronic pain and even less is known in patients suffering from central nervous system (CNS) diseases where pain is prevalent, difficult to manage, and often undertreated. This article briefly reviews the current knowledge of placebo analgesia effects in healthy participants with the aim of discussing how the mechanisms in placebo analgesia differ between healthy participants and patients. The focus will be on placebo analgesia effects in chronic pain conditions as well as in 2 CNS diseases: Alzheimer disease and Parkinson disease. Finally, strengths and weaknesses of the current knowledge will be discussed and it will be demonstrated how insights from the placebo literature may point to new ways of improving treatments among patients experiencing pain in relation to CNS diseases.

The effect of age and gender on pressure pain thresholds and suprathreshold stimuli.

OBJECTIVES: The study investigates the impact of age and gender on (1) experimental pressure pain detection thresholds (PPDT) and pressure pain tolerance thresholds (PPTolT) and (2) participants' self-reports of pain intensity and unpleasantness at suprathreshold and subthreshold levels. METHODS: twenty young (20-34, mean age = 24.6 ± 3.6 years, ten female) and twenty elderly (65-88, mean age = 73.6 ± 6.6 years, ten female) healthy volunteers were compared. Mini-Mental State Examination (MMSE 28-30) assessed intact cognitive functioning. Pain thresholds were assessed together with the sensory intensity ratings to 1.3 x PPDT (pain) and 0.2 x PPDT (no pain). RESULTS: PPDT and PPTolT significantly decreased with age and were lower in young females as compared with young males. No gender differences were observed in the elderly group. PPDT decreased significantly with age in males but not in females. Conversely, the intensity and unpleasantness of the pain stimulus were significantly rated lower in the elderly as compared with the young. No gender differences were observed in the report of intensity and unpleasantness of the stimulations. DISCUSSION: A mismatch in pain sensitivity, tolerance, and pain self-reports was observed. Findings suggest that pain experiences in the elderly differ from the experiences in the young on multiple dimensions: sensory, affective, and cognitive. Findings may also indicate that the elderly appraise pain experiences using different psychological strategies.