John M. Kelley’s research while affiliated with Endicott College and other places

This book sheds light on the translation of current mechanistic research on placebo effects to develop comprehensive and adequate strategies for better symptom management and treatment. This book identifies three core aspects to bridge state-of-the-art concepts with day-to-day clinical practice. First, lessons from mechanistic placebo research indicate a neurobiological basis underlying placebo effects. Second, placebo research can improve the design of clinical trials to advance drug development. Third, placebo effects can be exploited in daily clinical practice to optimize patient-clinician communication and relationships and clinical outcomes. Together, these three core aspects provide a new perspective with which to appraise the implications of Placebo Research for healthcare systems, clinicians, patients, and caregivers. New patient-centered approaches, mental health, and pain-related issues are discussed while describing technologically advanced and novel research applications that will shift current clinical practice to improve treatment outcomes.

Social interactions such as the patient-clinician encounter can influence pain, but the underlying dynamic interbrain processes are unclear. Here, we investigated the dynamic brain processes supporting social modulation of pain by assessing simultaneous brain activity (fMRI hyperscanning) from chronic pain patients and clinicians during video-based live interaction. Patients received painful and nonpainful pressure stimuli either with a supportive clinician present (Dyadic) or in isolation (Solo). In half of the dyads, clinicians performed a clinical consultation and intake with the patient prior to hyperscanning (Clinical Interaction), which increased self-reported therapeutic alliance. For the other half, patient-clinician hyperscanning was completed without prior clinical interaction (No Interaction). Patients reported lower pain intensity in the Dyadic, relative to the Solo, condition. In Clinical Interaction dyads relative to No Interaction, patients evaluated their clinicians as better able to understand their pain, and clinicians were more accurate when estimating patients' pain levels. In Clinical Interaction dyads, compared to No Interaction, patients showed stronger activation of the dorsolateral and ventrolateral prefrontal cortex (dlPFC and vlPFC) and primary (S1) and secondary (S2) somatosensory areas (Dyadic-Solo contrast), and clinicians showed increased dynamic dlPFC concordance with patients' S2 activity during pain. Furthermore, the strength of S2-dlPFC concordance was positively correlated with self-reported therapeutic alliance. These findings support that empathy and supportive care can reduce pain intensity and shed light on the brain processes underpinning social modulation of pain in patient-clinician interactions. Our findings further suggest that clinicians' dlPFC concordance with patients' somatosensory processing during pain can be boosted by increasing therapeutic alliance.

Objective: Placebo responses are significantly higher in children than in adults, suggesting a potential underused treatment option in pediatric care. To facilitate the clinical translation of these beneficial effects, we explored physicians' current practice, opinions, knowledge, and likelihood of recommending placebos in the future. Methods: A cross-sectional web-based survey administered by REDCap was conducted at Boston Children's Hospital between October 2021 and March 2022. Physicians (n = 1157) were invited to participate through an email containing a link to a 23-item survey designed to assess physicians' attitudes and perceptions towards the clinical use of placebo in pediatrics. Results: From 207 (18%) returned surveys, 109 (9%) were fully completed. Most respondents (79%) believed that enhancing the therapeutic components that contribute to the placebo response may be a way of improving pediatric care. However, whereas most (62%) found placebo treatments permissible, only one-third reported recommending them. In pediatrics, placebos are typically introduced as a medicine that "might help" (43%). The most common treatments recommended to enhance placebo effects are physical therapy, vitamins, and over-the-counter analgesics. Physicians most frequently recommend placebos for occasional pain, headaches, and anxiety disorders. Finally, the great majority of physicians (87%) stated they would be more likely to recommend placebo treatments if there were safety and ethical guidelines for open-label placebos. Conclusions: Placebo treatments seem permissible to physicians in pediatric care, but the development of safety and ethical guidelines may be necessary before physicians systematically incorporate the benefits of the placebo effect in pediatrics.

The patient-clinician therapeutic alliance is a powerful modulator shaping patients’ treatment experience and clinical outcomes. Before and after a 3-week electro-acupuncture intervention (6 sessions), fMRI hyper-scanning was applied to investigate the influence of either an Augmented (warm/attentive) or a Limited (neutral/business-like) clinician interaction style. Eighteen women with fibromyalgia (mean age=41.41, SD=12.20, each group N=9), randomly assigned to an Augmented or Limited patient-clinician dyadic interaction style (trained acupuncturists), underwent a simultaneously recorded fMRI hyper-scanning procedure with a video connection between two scanners and an evoked cuff pressure pain/treatment paradigm. Questionnaires were used to assess the patients’ experience by targeting treatment-related changes such as clinical pain levels, therapeutic alliance, trust, the clinician's warmth and competence, and the probability of continuing the treatment with this clinician after study participation. As rated by patients, pooled therapeutic alliance and clinicians’ warmth in the Augmented (mean_alliance=43.21, SD=2.40; mean_warmth=4.00, SD=0.0) were significantly higher than in the Limited group (mean_alliance=22.79, SD=13.15; mean_warmth=2.54, SD=1.10; t_alliance(16)=4.31, p<0.001; t_warmth(16)=3.74; p=0.002). Additionally, over the course of all 6 acupuncture treatment sessions, most patients experienced immediate clinical pain relief after each treatment session (p<0.001), irrespective of augmented or limited group assignment. Pain catastrophizing was significantly reduced after the intervention (t(16)=3.79; p=0.002) in the Augmented (∆-7.88) but not the Limited group (∆1.44). Importantly, only the Augmented group reported a high probability to continue with the treatment after the study as well as a high pain relief expectation for future acupuncture treatments even though both groups experienced similar pain relief treatment outcomes over the course of the study intervention. Brain imaging data analysis focused on social mirroring areas such as the temporo-parietal junction (TPJ). In summary, this study highlights the importance of investigating variable interaction quality during longitudinal clinical therapies and its influence on clinical outcomes, treatment compliance, and brain processing of nociceptive signaling. Grant support from NIH - National Center for Complementary and Integrative Health (NCCIH: R61-AT009306, R33-AT009306), Neuroimaging Pilot Funding Initiative at the Martinos Center for Biomedical imaging (MGH R90DA023427), Korea Institute of Oriental Medicine (KIOM), Foundation for the Science of the Therapeutic Encounter, National Center for Research Resources (P41RR14075; CRC 1 UL1 RR025758), Harvard Clinical and Translational Science Center, Martinos Computing facilities, and National Institutes of Health (Grant Nos. S10RR023401, S10RR019307, S10RR019254, and S10RR023043). The funders had no role in study design, data collection and/or interpretation of the results. Also, all authors declare no existence of competing conflicts of interest.

Objective: There is growing evidence that open-label placebo (OLP) may be an efficacious treatment for chronic and functional conditions. However, patient-level predictors of response to OLP have not been clearly identified. The aim of this study is to evaluate psychological predictors of response to OLP and to compare this to double-blind placebo (DBP) and no-pill control (NPC). Methods: This study is a secondary analysis of data collected in a six-week randomized controlled trial evaluating placebo effects in irritable bowel syndrome (IBS). The primary outcome was change in IBS severity. Hierarchical linear regression identified predictors of placebo response in general and compared them between those randomized to OLP, DBP, and NPC. Predictor variables included personality traits, generalized anxiety, depression, visceral sensitivity (a measure of symptom-specific anxiety), and pain catastrophizing. Results: 210 participants (mean age 42.3, 73.3% female) were included. Regression models revealed that visceral sensitivity was a predictor of response to OLP and NPC but not DBP. Interestingly, the effects were opposite, with high visceral sensitivity predicting less improvement in NPC and more improvement in OLP. Pain catastrophizing was a negative predictor of response to OLP (i.e. high pain catastrophizing was associated with less improvement in OLP). Neither visceral sensitivity nor pain catastrophizing played a significant role for response to DBP. Conclusions: IBS participants who score low on the pain catastrophizing scale but high on the visceral sensitivity index seem to benefit particularly from OLP. Our study suggests that different psychological mechanisms may be involved in double-blind and open-label placebo interventions.

Background & Aims Many of the reported adverse events in clinical trials of IBS are extra-intestinal symptoms, which are typically assessed by open-ended questions during the trial and not at baseline. This may lead to misattribution of some pre-existing symptoms as side effects to the treatment. Methods The current study analyzed data from a 6-week clinical trial of irritable bowel syndrome (IBS). Participants were randomized to receive double-blind peppermint oil (DBM), double-blind placebo (DBP), or treatment as usual (TAU). Extra-intestinal symptoms were assessed at baseline and end-of-study. Results This analysis included 173 participants (30 in DBM, 72 in TAU, and 71 in DBP). At baseline, each group reported approximately five extra-intestinal symptoms per participant. The number of symptoms per participant decreased to an average of three by the end-of-study visit, and this change was statistically significant in all groups (p<0.001 for each group). When evaluating individual extra-intestinal symptoms, the majority of participants did not report new/worse symptoms. In fact, between the baseline assessment and the final assessment, the average symptom severity decreased significantly in all three groups (p<0.001,). Conclusions Our study suggests that participants with IBS often experience extra-intestinal symptoms at baseline and that these symptoms generally improve in severity over the course of a clinical trial, regardless of the treatment arm. Systematic assessment of extra-intestinal symptoms at the beginning of a clinical trial is necessary to determine more definitively whether these symptoms may be considered an adverse event attributable to a study medication.

Importance: Although it is widely believed that concealment or deception is required to elicit a placebo response, recent studies with adults suggest that open-label placebo (OLP) (ie, honestly prescribed placebos) can yield significant benefits. No studies of OLP have been performed with children. Objective: To evaluate the efficacy of OLP for the treatment of children and adolescents with functional abdominal pain or irritable bowel syndrome. Design, setting, and participants: This multicenter crossover randomized clinical trial was conducted from July 1, 2015, to June 15, 2018, at 3 US centers among children and adolescents aged 8 to 18 years with functional abdominal pain or irritable bowel syndrome defined per Rome III criteria. Statistical analysis was performed from March 1, 2019, to September 30, 2020, on an intention-to-treat basis. Interventions: Patients completed 1 week of observation prior to randomization to 1 of 2 counterbalanced groups: OLP for 3 weeks followed by a 3-week control period or control period for 3 weeks followed by OLP for 3 weeks. During the OLP period, participants took 1.5 mL of an inert liquid placebo twice a day. A standardized method for explaining the OLP was used, and the interaction with clinicians had the same duration and style for both time periods. Hyoscyamine was allowed as a rescue medication. Main outcomes and measures: The primary outcome was the mean daily pain score during each of the interventions, measured on a 0- to 100-mm visual analog scale, where higher scores indicated greater pain. The number of rescue medications taken during each intervention served as an objective secondary measure. Results: Thirty patients (mean [SD] age, 14.1 [3.4] years; 24 female participants [80.0%]; 16 [53.3%] with functional abdominal pain and 14 [46.7%] with irritable bowel syndrome) completed the study. The mean (SD) pain scores were significantly lower during OLP treatment compared with the control period (39.9 [18.9] vs 45.0 [14.7]; difference, 5.2; 95% CI, 0.2-10.1; P = .03). Patients took nearly twice as many hyoscyamine pills during the control period compared with during the OLP period (mean [SD] number, 3.8 [5.1] pills vs 2.0 [3.0] pills; difference, 1.8 pills; 95% CI, 0.5-3.1 pills). Conclusions and relevance: During OLP, patients with functional abdominal pain or irritable bowel syndrome reported significantly less pain and took significantly fewer pain medications. Open-label placebo may be an effective treatment for children and adolescents with functional abdominal pain or irritable bowel syndrome. Trial registration: ClinicalTrials.gov Identifier: NCT02389998.