Search

Hojjat Daniali,1 Mollie A Ruben,2 Per M Aslaksen,3 Charlotte Fiskum,1 Ted J Kaptchuk,4 Magne A Flaten1 1Department of Psychology, Norwegian University of Science and Technology, Trondheim, Norway; 2Department of Psychology, University of Rhode Island, Kingston, RI, USA; 3Department of Psychology, UiT The Arctic University of Norway, Tromsø, Norway; 4Program in Placebo Studies, Beth Israel Deaconess Medical Center/ Harvard Medical School, Boston, MA, USACorrespondence: Hojjat Daniali, Department of Psychology, Norwegian University of Science and Technology, Trondheim, NO-7491, Norway, Email hojjat.daniali@ntnu.noIntroduction: Studies suggest facial expressions of caregivers may be important in placebo effects; however, this has not been systematically tested. This experiment investigated the effects of caregivers’ singular positive nonverbal behaviours (NBs) on pain reports.Methods: Fifty-one males and 53 females (total of 104) participants were randomized to four groups that were displayed positive facial expressions, tone of voice, body movement, or neutral NBs of videotaped experimenters. Subjective reports of pain, stress, arousal, and cardiac activity were obtained in a pre-test, a conditioning phase, and at a post-test. Four minutes of heat pain was induced in each test, and a placebo cream was administered before the conditioning and post-test in all groups.Results: There were no differences between the NB groups in the reduced pain. Males had larger reduction in pain in the post-test, and females had lower arousal than the opposite sex. During the conditioning, females had larger reduction in pain ie, unconditioned pain response (UPR). In females, the UPR predicted the reinforced expectation ie, increase in expectations from conditioning to post-test, and fear of minor pain negatively predicted both the UPR and reinforced expectation.Discussion: Singular NBs of caregiver were weak to enhance placebo effects. Females had lower pain during conditioning, and the UPR amplitude in females was associated with positive expectations. Moreover, for females, fear of minor pain weakened the UPR and expectations of cream.Conclusion: No NB of caregivers is more effective in reducing pain. Caregivers’ NBs are less effective when displayed individually. Males and females may be different in underlying mechanisms of placebo effects.Keywords: placebo effects, subtle factors, nonverbal behaviours, heat pain, experimenter effects, pain report

Introduction: The concept of acupoints is a key defining feature of acupuncture, yet the scientific basis of acupoints remains unclear. In recent years, there has been an emerging body of animal studies demonstrating an association between cutaneous sensitivity and visceral pathophysiology, through which acupoints over the skin are sensitized in pathologic conditions. Several studies with humans have also been conducted to assess whether the sensitivity of acupoints is distinct in healthy versus clinical populations. However, no systematic review has been conducted to collate and synthesize the status and quality of human studies on this topic. Methods: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). Literature search was performed by combining variations of search terms related to acupoints and pain sensitivity in PubMed, EMBASE, and Alt HealthWatch (EBSCOHost). Screening of titles and abstracts and review of full-text articles for eligibility were performed by two independent investigators. Using a predefined template, information on subject characteristics, pathologic conditions, names of assessed acupoints, and relevant main findings were extracted from the included studies. The methodological quality of included studies was assessed using a modified Newcastle-Ottawa Scale (NOS) for case-control studies. A quality assessment checklist was also developed by the present authors to examine the quality of reporting of experimental variables that were considered important for evaluating acupoint sensitivity. Results: A total of 3453 studies were identified from the database search, of which 11 met the eligibility criteria to be included in this review. Six studies examined the mechanical sensitivity of body acupoints, and the remaining five studies examined the mechanical sensitivity of auricular points. Overall, findings suggest that the sensitivity of acupoints may be distinct in healthy versus clinical populations. However, there were various potential sources of bias and substantial heterogeneity across included studies in clinical conditions and acupoints. Conclusion: There is at present insufficient evidence to support or refute that acupoints in humans are sensitized in pathologic conditions. There were various methodological issues, including small sample size and poor reporting of experimental design and variables, which limit the ability to draw a definitive conclusion on this topic. It is also largely unclear whether it is the general body regions rather than specific acupoints that may be sensitized, as most studies did not include nonacupoint location(s) for comparison. Thus, further rigorous research is warranted.

Importance: Chronic back pain (CBP) is a leading cause of disability. Placebo treatments often provide as much pain relief as bona fide treatments, such as steroid injections. Open-label (honestly prescribed) placebos (OLPs) may relieve CBP without deception, but OLP mechanisms remain poorly understood., Objective: To investigate the long-term efficacy and neurobiological mechanisms of OLP for CBP., Design, Setting, and Participants: A randomized clinical trial of CBP with longitudinal functional magnetic resonance imaging (MRI) comparing OLP with usual care, with 1-year follow-up, was conducted in a university research setting and a community orthopedic clinic. Participants were individuals aged 21 to 70 years with CBP. The trial was conducted from November 2017 to August 2018, with 1-year follow-up completed by November 2019. Data analysis was performed from April 2020 to May 2024. The primary analysis was conducted on an intention-to-treat sample., Interventions: Participants randomized to OLP received a 1-time subcutaneous lumbar saline injection presented as placebo accompanied by information about the power of placebo to relieve pain, alongside their ongoing care. Usual care participants continued their ongoing care., Main Outcomes and Measures: The primary outcome was pain intensity (0-10, with 0 indicating no pain and 10 the most intense) at 1 month posttreatment. Secondary outcomes included pain interference, depression, anxiety, anger, and sleep quality. Functional MRI was performed before and after treatment during evoked and spontaneous back pain., Results: A total of 101 adults (52 [51.4%] females; mean [SD] age, 40.4 [15.4] years) with moderate severity CBP (mean [SD], 4.10 [1.25] intensity; duration, 9.7 [8.5] years) were enrolled. Compared with usual care, OLP reduced CBP intensity posttreatment (relative reduction, 0.61; Hedges g = 0.45; 95% CI, -0.89 to 0.04; P = .02). Through 1-year follow-up, pain relief did not persist, although significant benefits were observed for depression, anger, anxiety, and sleep disruption (Hedges g = 0.3-0.5; all P < .03). Brain responses to evoked back pain for OLP vs usual care increased in rostral anterior cingulate and ventromedial prefrontal cortex and decreased in somatomotor cortices and thalamus. During spontaneous pain, functional connectivity analyses identified OLP vs usual care increases in ventromedial prefrontal cortex connectivity to the rostral ventral medulla, a pain-modulatory brainstem nucleus. No adverse effects of treatment were reported by participants., Conclusions and Relevance: In this randomized clinical trial of OLP vs usual care, a single nondeceptive placebo injection reduced CBP intensity for 1 month posttreatment and provided benefits lasting for at least 1 year posttreatment. Brain mechanisms of OLP in a clinical population overlap with those of deceptive placebos in healthy volunteers, including engagement of prefrontal-brainstem pain modulatory pathways., Trial Registration: ClinicalTrials.gov Identifier: NCT03294148.

Introduction: Research suggests that a warm and empathic "patient-centered" patient-clinician relationship produces better clinical outcomes when compared with a more neutral "disease-centered" relationship. Acupuncturists performed both styles of therapy for patients with functional dyspepsia in Korea., Methods: The present randomized controlled trial assigned patients (n = 73) to identical acupuncture treatment with either patient-centered augmented care or disease-centered limited care. The Korean version of the Nepean Dyspepsia Index (NDI-K) was the primary outcome measure. Secondary outcome measures included Consultation And Relational Empathy (CARE) scale., Results: Both groups showed improvement in NDI-K. Patient-centered augmented acupuncture produced less effective symptom improvement compared to disease-centered limited acupuncture (NDI-K sum score and frequency; P = 0.008 and P = 0.037 respectively). CARE scores were higher for the augmented versus limited group (P = 0.001), supporting the fidelity of the experimentally controlled patient/clinician relationship. There were no significant differences between the groups in any of other secondary outcomes., Conclusion: Patients demonstrated greater improvement following acupuncture conducted with a more neutral, "disease-centered" style of relationship. This result is counter to similar research conducted in Western countries and suggests that cultural factors can significantly shape optimum styles of acupuncture therapy., Practice Implications: Clinicians should consider cultural differences when applying acupuncture therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Hope is an integral, multi-dimensional part of seeking medical treatment. The aim of this study was to develop a self-report scale, the Hope in Medicine (HIM) scale, to measure different modes of hoping in relation to the course of symptoms, the effects of treatment, and supporting medical research., Method: We examined the psychometric properties of the scale in a sample of 74 allergic rhinitis patients participating in a 2-week randomized-controlled trial comparing open-label placebos (OLP) with treatment as usual (TAU)., Results: The HIM scale had a Cronbach's α of .78. An exploratory factor analysis revealed four factors: realistic hope (i.e., hoping for specific positive outcomes such as improvement in symptoms), transcendent hope (i.e., non-directed hoping that things will turn out positively), utopian hope (i.e., hoping to contribute to greater knowledge), and technoscience hope (i.e., hoping for scientific breakthroughs). Speaking to the convergent validity of the scale, realistic hope was moderately related to treatment expectancies (r = .54); transcendent hope was related to optimism (r = .50), treatment expectancies (r = .37), self-efficacy (r = .36), and inversely correlated with pessimism (r = -.43). Hope subscales predicted neither course of symptoms nor impairment., Conclusion: The HIM scale is a questionnaire with adequate internal consistency allowing to assess four modes of hoping. Preliminary results for its convergent validity are promising. Yet, further validation is needed., Competing Interests: The authors have declared that no competing interests exist.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) includes negative sensations that remain a major chronic problem for cancer survivors. Previous research demonstrated that neurofeedback (a closed-loop brain-computer interface [BCI]) was effective at treating CIPN versus a waitlist control (WLC). The authors' a priori hypothesis was that BCI would be superior to placebo feedback (placebo control [PLC]) and to WLC in alleviating CIPN and that changes in brain activity would predict symptom report., Methods: Randomization to one of three conditions occurred between November 2014 and November 2018. Breast cancer survivors no longer in treatment were assessed at baseline, at the end of 20 treatment sessions, and 1 month later. Auditory and visual rewards were given over 20 sessions based on each patient's ability to modify their own electroencephalographic signals. The Pain Quality Assessment Scale (PQAS) at the end of treatment was the primary outcome, and changes in electroencephalographic signals and 1-month data also were examined., Results: The BCI and PLC groups reported significant symptom reduction. The BCI group demonstrated larger effect size differences from the WLC group than the PLC group (mean change score: BCI vs. WLC, -2.60 vs. 0.38; 95% confidence interval, -3.67, -1.46 [p = .000; effect size, 1.07]; PLC, -2.26; 95% confidence interval, -3.33, -1.19 [p = .001 vs. WLC; effect size, 0.9]). At 1 month, symptoms continued to improve only for the BCI group. Targeted brain changes at the end of treatment predicted symptoms at 1 month for the BCI group only., Conclusions: BCI is a promising treatment for CIPN and may have a longer lasting effect than placebo (nonspecific BCI), which is an important consideration for long-term symptom relief. Although scientifically interesting, the ability to separate real from placebo treatment may not be as important as understanding the placebo effects differently from effects of the intervention., Plain Language Summary: Chemotherapy-induced nerve pain (neuropathy) can be disabling for cancer survivors; however, the way symptoms are felt depends on how the brain interprets the signals from nerves in the body. We determined that the perception of neuropathy can be changed by working directly with the brain. Survivors in our trial played 20 sessions of a type of video game that was designed to change the way the brain processed sensation and movement. In this, our second trial, we again observed significant improvement in symptoms that lasted after the treatment was complete., (© 2023 American Cancer Society.)

Background and Objectives: Although acupuncture is listed as a beneficial treatment for neck/shoulder stiffness, which has increased with the spread of information technology, to date, evidence of its efficacy under double-blind conditions has not been shown. This study aimed to assess whether acupuncture treatment with superficial skin piercing is superior to placebo treatment. Materials and Methods: A randomized, double-blind (practitioner-patient) placebo-controlled trial was performed at a single center with four arms (ISRCTN76896018). Four hundred patients with essential neck/shoulder stiffness were randomly assigned to penetrating needle treatment (acupuncture ritual and skin penetration), skin-touch needle treatment (acupuncture ritual and skin touch), no-touch needle treatment (acupuncture ritual alone), and no-treatment control. Each of the six acupuncturists applied a needle to each of the four acupoints in the neck/shoulder of 50 patients. Results: Each of the three treatments significantly ( p = 0.01) improved neck/shoulder stiffness compared with the no-treatment control immediately and 24 h after treatment. There was a significant improvement in penetrating needle treatment over no-touch needle treatment 24 h later. However, there was no significant difference between the penetrating and skin-touch and skin-touch vs. no-touch. Conclusions: All treatments that received the ritual of acupuncture were better than the no-treatment control. Only genuine acupuncture involves the specific effects of needle insertion into the body. The acupuncture ritual had a significant impact on the subjective improvement of neck/shoulder stiffness; however, improvement with ritual alone versions of placebo acupuncture was not maintained as with superficial skin piercing. Our study provides important evidence of acupuncture efficacy and information regarding inert no-touch placebo control in acupuncture research.

Objective: Randomized controlled trials (RCTs) in epilepsy for drug treatments are plagued by high costs. One potential remedy is to reduce placebo response via better control over regression to the mean (RTM). Here, RTM represents an initial observed seizure rate higher than the long-term average, which gradually settles closer to the average, resulting in apparent response to treatment. This study used simulation to clarify the relationship between eligibility criteria and RTM., Methods: Using a statistically realistic seizure diary simulator, the impact of RTM on placebo response and trial efficacy was explored by varying eligibility criteria for a traditional treatment phase II/III RCT for drug-resistant epilepsy., Results: When the baseline period was included in the eligibility criteria, increasingly larger fractions of RTM were observed (25%-47% vs. 23%-25%). Higher fractions of RTM corresponded with higher expected placebo responses (50% responder rate [RR50]: 2%-9% vs. 0%-8%) and lower statistical efficacy (RR50: 47%-67% vs. 47%-81%). The exclusion of baseline from eligibility criteria was shown to decrease the number of patients needed by roughly 30%., Significance: The manipulation of eligibility criteria for RCTs has a predictable and important impact on RTM, and therefore on placebo response; the difference between drug and placebo was more easily detected. This in turn impacts trial efficacy and therefore cost. This study found dramatic improvements in efficacy and cost when baseline was not included in eligibility., (© 2023 International League Against Epilepsy.)

Tricyclic antidepressants (TCAs) are frequently prescribed for chronic functional pain disorders. Although the mechanism of action targets pain perception, treating patients with TCAs for disorders conceptualized as "functional" can promote stigmatization in these patients because it hints at psychological dimensions of the disorder. The goal of this study was to understand how physicians prescribe TCAs in the face of this challenge. We interviewed eleven gastroenterologists in tertiary care clinics specializing in functional gastrointestinal disorders, such as irritable bowel syndrome. We found that the physicians interviewed (1) were aware of the stigma attached to taking antidepressants for a medical condition, (2) emphasized biological, as opposed to psychological, mechanisms of action, (3) while focusing on biological mechanisms, they nevertheless prescribed TCAs in a way that is highly attentive to the psychology of expectations, making specific efforts to adjust patients' expectations to be realistic and to reframe information that would be discouraging and (4) asked patients to persist in taking TCAs despite common and, at times, uncomfortable side effects. In this context of shared decision making, physicians described nuanced understanding and behaviours necessary for treating the complexity of functional disorders and emphasized the importance of a strong patient-provider relationship., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., Competing Interests: Declaration of Competing Interest Authors declare they have no conflicts of interest relevant to this article to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Little is known about the relative magnitude of placebo responses on objective and subjective measures of sleep continuity. To address this issue, the pre-post effects of placebos on objective and subjective measures (i.e., polysomnography [PSG] and sleep diaries) were evaluated meta-analytically. The guiding hypothesis was that large responses would be observed on sleep diary measures and small responses would be observed on PSG measures., Methods: PubMed searches, 1967-2016, yielded 329 possible articles, 17 of which met the inclusion and exclusion criteria for the present analysis (including 879 subjects with PSG data, 1,209 subjects with diary data, and six studies with both PSG and sleep diary data). Average change and weighted effect sizes (ESs) were computed via modeling for sleep latency (SL), wake after sleep onset (WASO) and total sleep time (TST)., Results: Pre-to-post change on PSG measures were: SL -13.7 min., ES = -0.37; WASO -14.3 min., ES = -0.36; and TST 29.8 min., ES = 0.50. Pre-to-post change on sleep diary measures were: SL -13.5 min., ES = -0.36; WASO -13.3 min., ES = -0.20; and TST 25.5 min., ES = 0.36. The modeled average objective subjective difference per sleep continuity measure was less than 5 minutes. The modeled average objective subjective difference per sleep continuity measure (in effect sizes) was less than 0.17., Discussion: The observed outcomes of this analysis suggest that placebos produce comparable effects on objective and subjective measures of sleep continuity. Thus, objective measures do not appear to protect against placebo responses. This being the case and given the importance of the subjective experience of illness severity and recovery, such data suggests that prospectively sampled sleep continuity data (sleep diaries) may be the optimal data for clinical trials, particularly when only one measure is possible.

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.

Importance: Methadone treatment is the most effective evidence-based treatment for opioid use disorder (OUD), but challenges related to dosing and premature treatment dropout argue for adjunct interventions to improve outcomes. One potential behavioral intervention with low risk involves harnessing placebo effects., Objective: To determine the effect of a pharmacologically conditioned open-label placebo (C-OLP) on 90-day methadone dose, retention, drug use, withdrawal, craving, quality of life, and sleep., Design, Setting, and Participants: This 2-arm, open-label, single-blind randomized clinical trial was conducted between December 5, 2017, and August 2, 2019, in an academically affiliated community opioid treatment program. Analyses were conducted between October 1, 2019, and April 30, 2020. A total of 320 newly enrolled adults seeking treatment for moderate to severe OUD were assessed for study eligibility; 131 met eligibility criteria, provided informed consent, and were randomized to either C-OLP or treatment as usual (TAU) in an unequal-block (3:2) manner. Exclusion criteria were pregnancy, hospital/program transfers, and court-ordered treatment., Interventions: Participants randomized to C-OLP received pharmacologic conditioning and a placebo pill and methadone, and participants randomized to TAU were given methadone only. Participants met with the study team 5 times: at baseline (treatment intake) and 2, 4, 8, and 12 weeks postbaseline. Interactions were balanced between the 2 groups., Main Outcomes and Measures: Outcomes included 90-day methadone dose (primary) and treatment retention, drug use, withdrawal, craving, quality of life, and sleep quality (secondary). Analyses were conducted as intention-to-treat., Results: Of the 131 people enrolled in the study, 54 were randomized to TAU and 77 to C-OLP. Mean (SD) age was 45.9 (11.2) years; most of the participants were Black or African American (83 [63.4%]) and male (84 [64.1%]). No significant group differences were observed in the mean (SD) 90-day methadone dose (83.1 [25.1] mg for group TAU, 79.4 [19.6] mg for group C-OLP; t = 0.621991; P = .43), but the groups differed significantly in their retention rates: 33 (61.1%) for TAU and 60 (77.9%) for C-OLP (χ21 = 4.356; P = .04; number needed to treat for the beneficial outcome of 3-month treatment retention, 6; 95% CI, 4-119). C-OLP participants also reported significantly better sleep quality., Conclusions and Relevance: In this randomized clinical trial, C-OLP had no effect on the primary outcome of 90-day methadone dose. However, C-OLP participants were significantly more likely to remain in treatment. These findings support the use of C-OLP as a methadone treatment adjunct, but larger trials are needed to further examine the use of C-OLP., Trial Registration: ClinicalTrials.gov Identifier: NCT02941809.

Harnessing the placebo effects would prompt critical ramifications for research and clinical practice. Noninvasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation and multifocal transcranial electric stimulation, could manipulate the placebo response by modulating the activity and excitability of its neural correlates. To identify potential stimulation targets, we conducted a meta-analysis to investigate placebo-associated regions in healthy volunteers, including studies with emotional components and painful stimuli. Using biophysical modeling, we identified NIBS solutions to manipulate placebo effects by targeting either a single key region or multiple connected areas. Moving to a network-oriented approach, we then ran a quantitative network mapping analysis on the functional connectivity profile of clusters emerging from the meta-analysis. As a result, we suggest a multielectrode optimized montage engaging the connectivity patterns of placebo-associated functional brain networks. These NIBS solutions hope to provide a starting point to actively control, modulate or enhance placebo effects in future clinical studies and cognitive enhancement studies., (© 2022. The Psychonomic Society, Inc.)

Introduction: Vulvodynia is vulvar pain lasting at least 3-months without clear identifiable cause that may have other associated factors. The aim, to explore motivations of women participating in a double-blind randomized controlled trial of acupuncture for vulvodynia. Methods: Responses to the question: " Tell me about why you decided to participate in this study " were analyzed using conceptual content analysis to identify patterns in motivation for study participation. Results: Four patterns emerged: 1) desire to address uncontrolled pain , 2) desire for understanding , 3) wish to contribute to knowledge generation , and 4) need to remove cost barriers . Conclusion: Motivations indicate vulvodynia-specific aspects of acceptability of acupuncture. Clinical Trial Registration: NCT03364127.

Background & Aims: Many of the reported adverse events in clinical trials of irritable bowel syndrome are extraintestinal symptoms, which typically are 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. Participants were randomized to receive double-blind peppermint oil, double-blind placebo, or treatment as usual. Extraintestinal symptoms were assessed at baseline and at the end of the study., Results: This analysis included 173 participants (30 received double-blind peppermint oil, 72 received treatment as usual, and 71 received double-blind placebo). At baseline, each group reported approximately 5 extraintestinal symptoms per participant. The number of symptoms per participant decreased to an average of 3 by the end-of-study visit, and this change was statistically significant in all groups (P < .001 for each group). When evaluating individual extraintestinal 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 3 groups (P < .001)., Conclusions: Our study suggests that participants with irritable bowel syndrome often experience extraintestinal 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 extraintestinal 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., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Open-label (honestly prescribed) placebos are an ethical way to evoke placebo effects in patients. As part of a mixed-methods study, we conducted in-depth interviews with eight menopausal women who underwent and benefitted from open-label placebo treatment in a randomized-controlled trial of hot flushes. Data were analyzed using Interpretative Phenomenological Analysis. We found that the women had low expectations about the placebo treatment yet endorsed what they referred to as "hope" and openness to "see what happens". Recording hot flushes via the symptom diary was viewed as a valuable opportunity for self-examination and appraising outcomes. Receiving relief from the placebo treatment empowered women and enhanced their sense of control and agency. In summary, participants' initial openness towards placebos, their hopes to get better, monitoring symptoms closely, and taking the initiative to address symptoms were components of a positive open-label placebo experience., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Pan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Vulvodynia, vulvar pain of unknown origin lasting at least 3 months, affects 7% of American women. Dyspareunia, its frequent companion, renders sexual intercourse virtually impossible. Although few therapies are efficacious and rapid pain relief is rarely possible, there have been no sham/placebo-controlled studies of acupuncture for vulvodynia. Aims are to: 1) determine efficacy of acupuncture for vulvodynia, 2) explore duration of the acupuncture effect., Methods: In a pretest/posttest randomized controlled, double-blind (practitioner-patient) efficacy trial of a standardized acupuncture protocol, we will randomize 80 participants 1:1 to either penetrating needle or skin-touch placebo needle groups. Both types of needles are designed to blind both the acupuncturist and participant. Participants with vulvodynia will insert and remove a tampon as a standardized stimulus and complete primary measures of vulvar pain (pain intensity) and secondary measures of dyspareunia (Female Sexual Function Index, FSFI dyspareunia subscale score) and sexual function (FSFI total score) pretreatment, after the 10th acupuncture session, and pain measures weekly until return to pretest levels. Upon study completion control group participants will be offered 10 free real acupuncture sessions., Discussion: This is the first multi-needle multi-session RCT using double-blind acupuncture needles as a reliable sham. We hypothesize that controlling for baseline, at posttest there will be statistically significant less vulvar pain and dyspareunia and more sexual function over five weeks in the penetrating needle group compared to the skin touch placebo group., Conclusion: This study is responsive to the need for efficacious pain management for women with vulvodynia.ClinicalTrials.gov Identifier: NCT03364127., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Nobuari Takakura and the Educational Foundation of Hanada Gakuen possess a US patent 6575992B1, a Canadian patent CA 2339223, a Korean patent 0478177, a Taiwan patent 150135, a Chinese patent ZL00800894.9 (Title: Safe needle, placebo needle and needle set for double blind), and two Japanese patents 4061397 (Title: Placebo needle, and needle set for double-blinding) and 4315353 (Title: Safe needle) on the needles described in this abstract. Dr. Takakura is a salaried employee of the Educational Foundation of Hanada Gakuen. Dr. Diana J. Wilkie is the founder and chairman of eNURSING LLC, a company without current ownership of the PAINReportIt software. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., (© 2022 The Authors.)

Objective: There is growing evidence that open-label placebo (OLP) may be an efficacious treatment of 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 the 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 6-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: A total of 210 participants (mean age = 42.3 years, 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 DBP and OLP interventions., (Copyright © 2022 by the American Psychosomatic Society.)

Introduction: Despite substantial progress made in the field of acupuncture research, the existence and specificity of acupoints remain controversial. In recent years, the concept of acupoint sensitization has emerged as a theoretical framework for understanding acupoints as dynamic functional entities that are sensitized in pathological conditions. Based on this premise, some have claimed that specific acupoints are thermally distinct between healthy and clinical populations, but no systematic review has been conducted to synthesize and evaluate the quality of studies supporting such claims. In this review, we provide a summary and quality assessment of the existing literature addressing the question of whether changes in skin temperature at specific acupoints are indicative of pathological conditions. Methods: A systematic literature search was performed in PubMed, EMBASE, and AltHealthWatch (EBSCO Host), by combining variations of search terms relevant to acupoints and temperature. The search was limited to the English language, and publication dates ranged from database inception to December 2020. Two authors independently screened all resulting abstracts and subsequently read full-text articles for eligibility. Information on study design, sample, acupoints, parameters of skin temperature assessments, and main findings were extracted from included studies. Quality of the thermal sensing methodology was evaluated using a thermal assessment checklist, adapted from the Thermographic Imaging in Sports and Exercise Medicine (TISEM) consensus checklist, and a modified Newcastle-Ottawa Scale (NOS) for case-control studies. Results: The search strategy yielded a total of 1771 studies, of which 10 articles met the eligibility criteria. Eight studies compared skin temperature at acupoints in healthy versus clinical populations, and two studies assessed within-subject changes in temperature of acupoints in relation to changes in health status. There were seven clinical conditions examined in the included studies: chronic bronchial asthma, chronic hepatitis, hyperplasia of mammary glands, infertility, intracranial hypertension, obesity, and primary dysmenorrhea. There were numerous methodological quality issues related to skin temperature measurements. Eight studies with case-control designs reported significant differences between healthy and clinical populations in temperature at certain acupoints. Two studies with pre-post designs reported that changes in health-disease status could be associated with changes in temperature at specific acupoints. Conclusion: A review of the available literature suggests that certain acupoints may be thermally distinct between healthy and unhealthy states. However, given the methodological limitations and heterogeneity across included studies, no definitive conclusion could be drawn as to whether changes in skin temperature at specific acupoints are indicative of pathological conditions.

Objectives: Tricyclic antidepressants (TCAs) are commonly used to treat disorders of gut-brain interaction (DGBI). However, these medications are often associated with side effects that lead to early treatment discontinuation. Research in other chronic medical conditions suggests that many TCA side effects may be caused by nocebo (negative placebo) effects. The current study tests a brief, verbal intervention aimed at improving tolerance of TCAs in DGBI by providing education about nocebo effects., Materials and Methods: This pilot randomized controlled trial was performed in a tertiary care gastroenterology clinic. Participants with DGBI were randomized "standard information," describing the benefits and risks of TCAs, or "augmented information," which included an additional <30-second education about nocebo effects. Two weeks after their visit, participants were emailed a survey evaluating the number and bothersomeness of side effects, adequate relief, global improvement, and treatment satisfaction., Results: Thirty-one patients were randomized and 22 responded to the survey. The average age was 40% and 59% were women. Although not statistically significant, the augmented group attributed nominally fewer symptoms to TCAs than the standard group, with a medium effect size (1.5 vs. 4.2, effect size d=0.56, P=0.212) and reported being significantly less bothered by those symptoms (13.4 vs. 38.1, P=0.037). A nominally larger percentage of the augmented group reported adequate relief of symptoms after 2 weeks of treatment compared with the standard group (55% vs. 27%, respectively)., Conclusions: This pilot study demonstrates that a brief (≈30 s) clinical intervention addressing nocebo effects may improve tolerance of TCAs. These findings provide support for future, fully powered studies to evaluate the impact of framing on clinical outcomes, especially in chronic conditions., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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.

Background: Irritable bowel syndrome (IBS) is a highly prevalent chronic pain disorder with multiple underlying mechanisms and few treatments that have been demonstrated to be effective in placebo controlled trials. One potential reason may be the use of composite outcomes, such as the IBS Symptom Severity Scale (IBS-SSS) which includes descriptive items related to pain frequency and pain intensity as well as bowel dysfunction and bloating. We investigated if different features of IBS pain have distinct genetic associations and if these may be moderated by sex hormones., Participants and Setting: Adult outpatients with moderately severe IBS (>175 on IBS-SSS) enrolled in a clinical trial reported IBS-SSS at baseline and after 6 weeks of therapy., Methods: Fixed effects modeling was used to test the effect of COMT rs4680 genotype to change in pain severity (rated 0-100) and pain frequency (defined as number of days with pain in the past 10 days) from baseline to week 6 with IBS treatment. Parallel exploratory genome-wide association studies (GWAS) were also performed to identify single nucleotide polymorphisms (SNPs) associated with change in pain severity or pain frequency across all participants., Results: A total of 212 participants (74% female) were included. The COMT rs4680 met allele was associated with decreased pain severity over the course of the trial in gene dosage models [beta(SE) -5.9 (2.6), P = 0.028]. Exploratory GWAS for change in pain frequency identified 5 SNPs in close proximity on chromosome 18 near L3MBTL4 which reached genome-wide significance (all P < 5.0E-8). This effect was not mediated by changing estradiol levels. There was also a region of chromosome 7 with 24 SNPs of genome-wide suggestive significance for change in pain severity (all P < 1.0E-5)., Conclusions: Previously reported association between COMT rs4680 genotype and treatment response as measured by IBS-SSS is related to pain severity, but not pain frequency. We also identified new candidate genes associated with changes in IBS pain severity ( SNX13 ) and pain frequency ( L3MBTL4 ) in response to treatment. Further studies are needed to understand these associations and genetic determinants of different components of IBS-SSS. ClinicalTrials.gov, Identifier: NCT0280224., Competing Interests: AL owns stock in Bristol Myer Squibb and Johnson & Johnson and receives income from Vibrant and Mylan. JL is the scientific co-founder of Scipher Medicine, Inc. JN consults for World Clinical Care. JS has received consultancy fees from Alimentiv, Mozart Therapeutics, Takeda Pharmaceuticals, and Teva Pharmaceuticals. JV has received consultancy fees from Vertex Pharmaceuticals and Embody Orthopedics outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vollert, Wang, Regis, Yetman, Lembo, Kaptchuk, Cheng, Nee, Iturrino, Loscalzo, Hall and Silvester.)

There is growing evidence that placebo effects can meaningfully modulate the brain. However, there has been little consideration of whether these changes may overlap with regions/circuits targeted by depression treatments and what the implications of this overlap would be on measuring efficacy in placebo-controlled clinical trials. In this systematic review and meta-analysis, we searched PubMed/Medline and Google Scholar for functional MRI and PET neuroimaging studies of placebo effects. Studies recruiting both healthy subjects and patient populations were included. Neuroimaging coordinates were extracted and included for Activation Likelihood Estimation (ALE) meta-analysis. We then searched for interventional studies of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) for depression and extracted target coordinates for comparative spatial analysis with the placebo effects maps. Of 1169 articles identified, 34 neuroimaging studies of placebo effects were included. There were three significant clusters of activation: left dorsolateral prefrontal cortex (DLPFC) (x = -41, y = 16, z = 34), left sub-genual anterior cingulate cortex (sgACC)/ventral striatum (x = -8, y = 18, z = -15) and the right rostral anterior cingulate cortex (rACC) (x = 4, y = 42, z = 10). There were two significant deactivation clusters: right basal ganglia (x = 20, y = 2, z = 7) and right dorsal anterior cingulate cortex (dACC) (x = 1, y = -5, z = 45). TMS and DBS targets for depression treatment overlapped with the left DLPFC cluster and sgACC cluster, respectively. Our findings identify a common set of brain regions implicated in placebo effects across healthy individuals and patient populations, and provide evidence that these regions overlap with depression treatment targets. We model the statistical impacts of this overlap and demonstrate critical implications on measurements of clinical trial efficacy for this field., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: There is increasing evidence suggesting that open-label placebo (OLP) is an effective treatment for several medical conditions defined by self-report. However, little is known about patients' experiences with OLP, and no studies have directly compared patients' experiences in double-blind placebo (DBP) conditions., Methods: This study was nested in a large randomized-controlled trial comparing the effects of OLP and DBP treatments in individuals with irritable bowel syndrome (IBS). We randomly selected 33 participants for interviews concerning their experiences in the parent trial. The data were qualitatively analyzed using an iterative immersion/crystallization approach. We then compared the qualitative interview data to the quantitative IBS severity data assessed during the parent trial, using a mixed methods approach., Results: Two prominent interview themes were identified: (1) the participants' feelings about their treatment allocation and (2) their reflections about the treatment. Both OLP and DBP participants mentioned hope and curiosity as major feelings driving them to engage with their treatment. However, while DBP participants tended to be more enthusiastic about their allocation, OLP participants were more ambivalent. Furthermore, OLP participants reflected more on their treatment, often involving noticeable cognitive and emotional processes of self-reflection. They offered a variety of explanations for their symptom improvement and were significantly less likely to attribute it to the treatment itself than DBP participants (Χ 2 [3] = 8.28; p = .041). Similarly, the participants' retrospective narratives of symptom improvement were significantly correlated with their corresponding quantitative IBS severity scores only in DBP (p's ≤ .006) but not in OLP (p's ≥ .637)., Conclusion: OLP and DBP participants share feelings of hope, uncertainty and curiosity but differ in the extent of conscious reflection. The counter-intuitive OLP prompts more self-examination, ambivalent feelings and active engagement compared to DBP. At the same time, OLP participants are more reluctant to attribute symptom improvement to their treatment. Our findings substantially add to the emerging picture of factors that distinguish OLP and DBP and their potential mechanisms., (© 2022. The Author(s).)

Patient-clinician concordance in behavior and brain activity has been proposed as a potential key mediator of mutual empathy and clinical rapport in the therapeutic encounter. However, the specific elements of patient-clinician communication that may support brain-to-brain concordance and therapeutic alliance are unknown. Here, we investigated how pain-related, directional facial communication between patients and clinicians is associated with brain-to-brain concordance. Patient-clinician dyads interacted in a pain-treatment context, during synchronous assessment of brain activity (fMRI hyperscanning) and online video transfer, enabling face-to-face social interaction. In-scanner videos were used for automated individual facial action unit (AU) time-series extraction. First, an interpretable machine-learning classifier of patients' facial expressions, from an independent fMRI experiment, significantly distinguished moderately painful leg pressure from innocuous pressure stimuli. Next, we estimated neural-network causality of patient-to-clinician directional information flow of facial expressions during clinician-initiated treatment of patients' evoked pain. We identified a leader-follower relationship in which patients predominantly led the facial communication while clinicians responded to patients' expressions. Finally, analyses of dynamic brain-to-brain concordance showed that patients' mid/posterior insular concordance with the clinicians' anterior insula cortex, a region identified in previously published data from this study 1 , was associated with therapeutic alliance, and self-reported and objective (patient-to-clinician-directed causal influence) markers of negative-affect expressivity. These results suggest a role of patient-clinician concordance of the insula, a social-mirroring and salience-processing brain node, in mediating directional dynamics of pain-directed facial communication during therapeutic encounters., (© 2022. The Author(s).)

In the past decades, numerous clinical researches have been conducted to illuminate the effects of traditional Chinese medicine for better inheritance and promotion of it, which are mostly clinical trials designed from the doctor's point of view. This large-scale data mining study was conducted from real-world point of view in up to 10 years' big data sets of Traditional Chinese Medicine (TCM) in China, including both medical visits to hospital and cyberspace and contemporaneous social survey data. Finally, some important and interesting findings appear: (1) More Criticisms vs. More Visits. The intensity of criticism increased by 2.33 times over the past 10 years, while the actual number of visits increased by 2.41 times. (2) The people of younger age, highly educated and from economically developed areas have become the primary population for utilizing TCM, which is contrary to common opinions on the characteristics of TCM users. The discovery of this phenomenon indicates that TCM deserves further study on how it treats illness and maintains health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Guo, Wang, Chen, Kaptchuk, Li, Gao, Yao, Tang and Xu.)

Importance: Adverse events (AEs) after placebo treatment are common in randomized clinical drug trials. Systematic evidence regarding these nocebo responses in vaccine trials is important for COVID-19 vaccination worldwide especially because concern about AEs is reported to be a reason for vaccination hesitancy., Objective: To compare the frequencies of AEs reported in the placebo groups of COVID-19 vaccine trials with those reported in the vaccine groups., Data Sources: For this systematic review and meta-analysis, the Medline (PubMed) and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched systematically using medical subheading terms and free-text keywords for trials of COVID-19 vaccines published up to July 14, 2021., Study Selection: Randomized clinical trials of COVID-19 vaccines that investigated adults aged 16 years or older were selected if they assessed solicited AEs within 7 days of injection, included an inert placebo arm, and provided AE reports for both the vaccine and placebo groups separately. Full texts were reviewed for eligibility by 2 independent reviewers., Data Extraction and Synthesis: Data extraction and quality assessment were performed independently by 2 reviewers, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline and using the Cochrane risk-of-bias tool. Meta-analyses were based on random-effects models., Main Outcomes and Measures: The primary outcomes were the proportions of placebo recipients reporting overall, systemic, and local (injection-site) AEs as well as logarithmic odds ratios (ORs) to evaluate group differences. Outcomes were tested for significance using z tests with 95% CIs., Results: Twelve articles with AE reports for 45 380 participants (22 578 placebo recipients and 22 802 vaccine recipients) were analyzed. After the first dose, 35.2% (95% CI, 26.7%-43.7%) of placebo recipients experienced systemic AEs, with headache (19.3%; 95% CI, 13.6%-25.1%) and fatigue (16.7%; 95% CI, 9.8%-23.6%) being most common. After the second dose, 31.8% (95% CI, 28.7%-35.0%) of placebo recipients reported systemic AEs. The ratio between placebo and vaccine arms showed that nocebo responses accounted for 76.0% of systemic AEs after the first COVID-19 vaccine dose and for 51.8% after the second dose. Significantly more vaccine recipients reported AEs, but the group difference for systemic AEs was small after the first dose (OR, -0.47; 95% CI, -0.54 to -0.40; P < .001; standardized mean difference, -0.26; 95% CI, -0.30 to -0.22) and large after the second dose (OR, -1.36; 95% CI, -1.86 to -0.86; P < .001; standardized mean difference, -0.75; 95% CI, -1.03 to -0.47)., Conclusions and Relevance: In this systematic review and meta-analysis, significantly more AEs were reported in vaccine groups compared with placebo groups, but the rates of reported AEs in the placebo arms were still substantial. Public vaccination programs should consider these high rates of AEs in placebo arms.

Background and Aims: Irritable bowel syndrome (IBS), a functional pain disorder of gut-brain interactions, is characterized by a high placebo response in randomized clinical trials (RCTs). Catechol-O-methyltransferase ( COMT ) rs4680, which encodes high-activity (val) or low-activity (met) enzyme variants, was previously associated with placebo response to sham-acupuncture in an IBS RCT. Examining COMT effects and identifying novel genomic factors that influence response to placebo pills is critical to identifying underlying mechanisms and predicting and managing placebos in RCTs. Methods: Participants with IBS ( N = 188) were randomized to three placebo-related interventions, namely, double-blind placebo (DBP), open-label placebo (OLP), or simply trial enrollment without placebo treatment [no placebo (i.e., no pill) treatment control (NPC)], for 6 weeks. COMT rs4680, gene-set, and genome-wide suggestive ( p < 10 -5 ) loci effects on irritable bowel symptom severity score (IBS-SSS) across all participants were examined. Results: Participants with IBS homozygous for rs4680 met (met/met) had the greatest improvement across all arms, with significantly greater improvement compared to val/val in DBP (beta (SE), -89.4 (42.3); p = 0.04). Twelve genome-wide suggestive loci formed a gene regulatory network highly connected to EGR1 , a transcription factor involved in placebo-related processes of learning, memory, and response to stress and reward. EGR1 gene expression in peripheral blood mononuclear cells (PBMC) was significantly reduced at the endpoint across all treatment arms (log fold-change, -0.15; p = 0.02). Gene-set enrichment analysis returned three genome-wide significant ontology terms (GO:0032968, GO:0070934, and GO:0070937) linked to transcription regulation and GO:0003918 associated with DNA topoisomerase regulation. Conclusion: These results suggest common molecular mechanisms in response to varying forms of placebo that may inform personalized IBS treatment and placebo response prediction. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT0280224., Competing Interests: AL owns stock in Bristol Myer Squibb and Johnson & Johnson, and receives income from Vibrant and Mylan; JL is the scientific co-founder of Scipher Medicine, Inc. JN consults for World Clinical Care; MR receives research support from Boston Pharmaceuticals and Takeda for unrelated studies, and has consulted for 89Bio. MR's spouse is an employee of Takeda. JS has consulted for Takeda Pharmaceuticals and Teva Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Lembo, Kaptchuk, Cheng, Nee, Iturrino, Rao, Loscalzo, Silvester and Hall.)

Background: Previous research has shown that after one month of full dose nightly treatment with zolpidem (priming), subjects with chronic insomnia (CI) switched to intermittent dosing with medication and placebos were able to maintain their treatment responses. This approach to maintenance therapy is referred to as partial reinforcement. The present study sought to assess whether priming is required for partial reinforcement or whether intermittent dosing with placebos (50% placebos and 50% active medication) can, by itself, be used for both acute and extended treatment., Method: 55 CI subjects underwent a baseline evaluation (Phase-1) and then were randomized to one of two conditions in Phase-2 of the study: one month of (1) nightly medication use with standard-dose zolpidem (QHS [n = 39]) or (2) intermittent dosing with standard-dose zolpidem and placebos (IDwP [n = 16]). In Phase-3 (three months), the QHS group was re-randomized to either continued QHS full dose treatment (FD/FD) or to IDwP dose treatment (FD/VD). Treatment response rates and Total Wake Time (TWT = [SL + WASO + EMA]) were assessed during each phase of the study., Results: In Phase-2, 77% (QHS) and 50% (IDwP) subjects exhibited treatment responses (p = 0.09) where the average change in TWT was similar. In Phase-3, 73% (FD/FD), 57% (FD/VD), and 88% (VD/VD) of subjects exhibited continued treatment responses (p = 0.22) where the average improvement in TWT continued with FD/FD and remained stable for FD/VD and VD/VD (p < 0.01)., Conclusion: These results suggest that intermittent dosing with placebos can maintain effects but do not allow for the additional clinical gains afforded by continuous treatment., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: Peppermint oil is often used to treat irritable bowel syndrome (IBS); however, the overall quality of previous studies is low, and findings have been heterogeneous. This study aimed to compare the effects of peppermint oil vs placebo in relieving IBS symptoms., Methods: In a 6-week, randomized, double-blind, placebo-controlled trial at a single academic center in the United States, individuals diagnosed with IBS (Rome IV criteria), with moderate to severe symptoms based on the IBS Severity Scoring System (IBS-SSS score ≥175), were randomized to enteric-coated peppermint oil 180 mg 3 times daily vs placebo in a 1:2 ratio. The primary outcome was mean change in IBS-SSS scores from baseline to 6-week endpoint., Results: A modified intent-to-treat analysis revealed that there were substantial mean improvements from baseline to 6-week endpoint in the main outcome measure (IBS-SSS) for both peppermint oil (90.8, SD = 75.3) and placebo (100.3, SD = 99.6). Although the peppermint oil group reported numerically lower improvement than the placebo group, the effect size was small (d = -0.11), and the difference between the groups was not statistically significant (P = 0.97). Similarly, both groups reported substantial improvements on the secondary endpoints; but again, there were no statistically significant differences between the groups on any of the secondary measures. Sensitivity analyses using multiple imputation to replace missing data produced similar results and revealed no significant differences between peppermint oil and placebo on any outcome measure., Discussion: Peppermint oil and placebo both showed clinically meaningful improvement in IBS symptoms. However, there were no significant differences between the groups. Further large, rigorous trials are needed to evaluate the role of peppermint oil for the treatment of IBS., (Copyright © 2021 by The American College of Gastroenterology.)