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1.
Cult Med Psychiatry ; 2022 Jun 28.
Article in English | MEDLINE | ID: mdl-35764862

ABSTRACT

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.

2.
Front Psychiatry ; 13: 842030, 2022.
Article in English | MEDLINE | ID: mdl-35401282

ABSTRACT

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.

3.
Psychosom Med ; 84(6): 738-746, 2022.
Article in English | MEDLINE | ID: mdl-35412513

ABSTRACT

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.


Subject(s)
Irritable Bowel Syndrome , Adult , Anxiety/drug therapy , Anxiety/psychology , Catastrophization , Double-Blind Method , Female , Humans , Irritable Bowel Syndrome/drug therapy , Male , Treatment Outcome
4.
J Integr Complement Med ; 28(7): 552-568, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35475679

ABSTRACT

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.


Subject(s)
Acupuncture Therapy , Infertility , Acupuncture Points , Case-Control Studies , Female , Humans , Skin Temperature
5.
Pain ; 163(4): e605-e606, 2022 04 01.
Article in English | MEDLINE | ID: mdl-35302977
6.
Article in English | MEDLINE | ID: mdl-35339669

ABSTRACT

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.

7.
BMC Psychol ; 10(1): 20, 2022 Feb 04.
Article in English | MEDLINE | ID: mdl-35120572

ABSTRACT

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 (Χ2 [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.


Subject(s)
Irritable Bowel Syndrome , Double-Blind Method , Humans , Irritable Bowel Syndrome/drug therapy , Retrospective Studies , Treatment Outcome
8.
JAMA Netw Open ; 5(1): e2143955, 2022 01 04.
Article in English | MEDLINE | ID: mdl-35040967

ABSTRACT

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.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Placebos/adverse effects , Arm Injuries/etiology , Fatigue/etiology , Headache/etiology , Humans , Injections, Intramuscular/adverse effects , SARS-CoV-2
9.
JAMA Pediatr ; 176(4): 349-356, 2022 04 01.
Article in English | MEDLINE | ID: mdl-35099543

ABSTRACT

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.


Subject(s)
Irritable Bowel Syndrome , Abdominal Pain/drug therapy , Adolescent , Adult , Child , Double-Blind Method , Female , Humans , Irritable Bowel Syndrome/drug therapy , Pain Measurement , Research Design , Treatment Outcome
10.
J Clin Gastroenterol ; 56(5): 452-456, 2022.
Article in English | MEDLINE | ID: mdl-34091518

ABSTRACT

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.


Subject(s)
Antidepressive Agents, Tricyclic , Brain , Antidepressive Agents, Tricyclic/adverse effects , Female , Humans , Male , Pilot Projects
11.
Transl Psychiatry ; 12(1): 44, 2022 01 28.
Article in English | MEDLINE | ID: mdl-35091536

ABSTRACT

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 study1, 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.


Subject(s)
Brain , Nonverbal Communication , Brain/diagnostic imaging , Empathy , Facial Expression , Humans , Magnetic Resonance Imaging , Pain/diagnostic imaging
12.
Mol Psychiatry ; 27(3): 1658-1666, 2022 03.
Article in English | MEDLINE | ID: mdl-34903861

ABSTRACT

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.


Subject(s)
Depression , Placebo Effect , Depression/therapy , Gyrus Cinguli , Humans , Magnetic Resonance Imaging , Neuroimaging , Prefrontal Cortex , Transcranial Magnetic Stimulation/methods
13.
Sleep Med ; 87: 56-61, 2021 11.
Article in English | MEDLINE | ID: mdl-34509775

ABSTRACT

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.


Subject(s)
Hypnotics and Sedatives , Sleep Initiation and Maintenance Disorders , Double-Blind Method , Humans , Pyridines , Sleep Initiation and Maintenance Disorders/drug therapy , Zolpidem
14.
Psychol Sci Public Interest ; 22(2): 52-95, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34541967

ABSTRACT

The high prevalence and societal burden of chronic pain, its undertreatment, and disparities in its management have contributed to the acknowledgment of chronic pain as a serious public-health concern. The concurrent opioid epidemic, and increasing concern about overreliance on opioid therapy despite evidence of limited benefit and serious harms, has heightened attention to this problem. The biopsychosocial model has emerged as the primary conceptual framework for understanding the complex experience of chronic pain and for informing models of care. The prominence of psychological processes as risk and resilience factors in this model has prompted extensive study of psychological treatments designed to alter processes that underlie or significantly contribute to pain, distress, or disability among adults with chronic pain. Cognitive-behavioral therapy is acknowledged to have strong evidence of effectiveness; other psychological approaches, including acceptance and commitment therapy, mindfulness, biofeedback, hypnosis, and emotional-awareness and expression therapy, have also garnered varying degrees of evidence across multiple pain conditions. Mechanistic studies have identified multiple pathways by which these treatments may reduce the intensity and impact of pain. Despite the growing evidence for and appreciation of these approaches, several barriers limit their uptake at the level of organizations, providers, and patients. Innovative methods for delivering psychological interventions and other research, practice, and policy initiatives hold promise for overcoming these barriers. Additional scientific knowledge and practice gaps remain to be addressed to optimize the reach and effectiveness of these interventions, including tailoring to address individual differences, concurrently addressing co-occurring disorders, and incorporating other optimization strategies.


Subject(s)
Acceptance and Commitment Therapy , Chronic Pain , Cognitive Behavioral Therapy , Mindfulness , Adult , Chronic Pain/therapy , Humans , Psychosocial Intervention
15.
Front Psychiatry ; 12: 684556, 2021.
Article in English | MEDLINE | ID: mdl-34267689

ABSTRACT

Previous studies have identified catechol-O-methyltransferase (COMT), as a key enzyme influencing sympathetic function. Although the COMT SNP rs4680 and rs4818, are well-studied, little is known about their influence on cancer-related fatigue (CrF) and placebo response. In this study, we examined whether genetic variation in COMT, at the functional SNP rs4680 and linked rs4818, influenced open-label placebo (OLP) responses found in cancer survivors reporting moderate to severe CrF. We randomized cancer survivors (N = 74) reporting moderate-to-severe CrF to receive OLP or to treatment-as-usual (TAU) and assessed if rs4680 and rs4818 were associated with changes in fatigue severity and fatigue-distressed quality of life. At the end of the initial 21 days, the treatments were crossed over and both groups were re-assessed. Participants with the rs4680 high-activity G-allele (G/G or G/A) or rs4818 C/G genotypes reported significant decreases in fatigue severity and improvements in fatigue-distressed quality of life. The COMT rs4818 findings replicated findings in a similar study of OLP in cancer fatigue. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02522988.

16.
Am J Gastroenterol ; 116(11): 2279-2285, 2021 11 01.
Article in English | MEDLINE | ID: mdl-34319275

ABSTRACT

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.


Subject(s)
Irritable Bowel Syndrome/drug therapy , Plant Oils/therapeutic use , Adult , Double-Blind Method , Female , Humans , Male , Mentha piperita , Middle Aged
17.
Acta Orthop ; 92(5): 507-512, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34165044

ABSTRACT

Background and purpose - Emerging evidence from sham-controlled trials suggest that surgical treatment entails substantial non-specific treatment effects in addition to specific surgical effects. Yet, information on surgeons' actual behaviors and beliefs regarding non-specific treatment and placebo effects is scarce. We determined surgeons' clinical behaviors and attitudes regarding placebo effects.Methods - A national online survey was developed in collaboration with surgeons and administered via an electronic link.Results - All surgical clinics in Sweden were approached and 22% of surgeons participated (n = 105). Surgeons believed it was important for them to interact and build rapport with patients before surgery rather than perform surgery on colleagues' patients (90%). They endorsed the importance of non-specific treatment effects in surgery generally (90%) and reported that they actively harness non-specific treatment effects (97%), including conveying confidence and calm (87%), building a positive interaction (75%), and making eye contact (72%). In communication regarding the likely outcomes of surgery, surgeons emphasized accurate scientific information of benefits/risks (90%) and complete honesty (63%). A majority felt that the improvement after some currently performed surgical procedures might be entirely explained by placebo effects (78%). Surgeons saw benefits with sham-controlled surgery trials, nevertheless, they were reluctant to refer patients to sham controlled trials (46%).Interpretation - Surgeons believe that their words and behaviors are important components of their professional competence. Surgeons saw the patient-physician relationship, transparency, and honesty as critical. Understanding the non-specific components of surgery has the potential to improve the way surgical treatment is delivered and lead to better patient outcomes.


Subject(s)
Attitude of Health Personnel , Orthopedic Procedures , Orthopedic Surgeons/psychology , Physician-Patient Relations , Placebo Effect , Adult , Aged , Female , Humans , Male , Middle Aged , Surveys and Questionnaires , Sweden
18.
Proc Natl Acad Sci U S A ; 118(19)2021 05 11.
Article in English | MEDLINE | ID: mdl-33941677

ABSTRACT

Harnessing placebo and nocebo effects has significant implications for research and medical practice. Placebo analgesia and nocebo hyperalgesia, the most well-studied placebo and nocebo effects, are thought to initiate from the dorsal lateral prefrontal cortex (DLPFC) and then trigger the brain's descending pain modulatory system and other pain regulation pathways. Combining repeated transcranial direct current stimulation (tDCS), an expectancy manipulation model, and functional MRI, we investigated the modulatory effects of anodal and cathodal tDCS at the right DLPFC on placebo analgesia and nocebo hyperalgesia using a randomized, double-blind and sham-controlled design. We found that compared with sham tDCS, active tDCS could 1) boost placebo and blunt nocebo effects and 2) modulate brain activity and connectivity associated with placebo analgesia and nocebo hyperalgesia. These results provide a basis for mechanistic manipulation of placebo and nocebo effects and may lead to improved clinical outcomes in medical practice.


Subject(s)
Analgesia/methods , Brain/physiopathology , Hyperalgesia/physiopathology , Pain/physiopathology , Prefrontal Cortex/physiopathology , Transcranial Direct Current Stimulation/methods , Adult , Analysis of Variance , Brain/diagnostic imaging , Double-Blind Method , Female , Humans , Magnetic Resonance Imaging/methods , Male , Nocebo Effect , Pain Management/methods , Placebo Effect , Prefrontal Cortex/diagnostic imaging , Surveys and Questionnaires , Young Adult
19.
Pain ; 162(9): 2428-2435, 2021 09 01.
Article in English | MEDLINE | ID: mdl-33605656

ABSTRACT

ABSTRACT: It is commonly believed that blinding to treatment assignment is necessary for placebos to have an effect. However, placebos administered without concealment (ie, open-label placebos [OLPs]) have recently been shown to be effective in some conditions. This study had 2 objectives: first, to determine whether OLP treatment is superior to no-pill control (NPC) in irritable bowel syndrome (IBS) and, second, to compare the efficacy of OLP against double-blind placebo (DBP). In a 6-week, 3-arm, randomized clinical trial, participants were randomized in equal proportions to 3 arms: OLP, DBP, or NPC. Two hundred sixty-two adults (72.9% women), with a mean age of 42.0 (SD = 18.1) years, participated in the primary study. The mean improvement on the IBS Severity Scoring System from baseline to the 6-week end point was significantly greater in OLP compared with that in NPC (90.6 vs 52.3, P = 0.038). Open-label placebo and DBP did not differ significantly on IBS Severity Scoring System improvement (100.3 vs 90.6, P = 0.485). Standardized effect sizes were moderate for OLP vs NPC (d = 0.43) and small for OLP vs DBP (d = 0.10). Participants treated with OLP reported clinically meaningful improvements in IBS symptoms that were significantly greater than those on NPC. Open-label placebo and DBP had similar effects that did not differ significantly, suggesting that blinding may not be necessary for placebos to be effective and that OLP could play a role in the management of patients with refractory IBS.


Subject(s)
Irritable Bowel Syndrome , Adult , Double-Blind Method , Female , Humans , Irritable Bowel Syndrome/complications , Irritable Bowel Syndrome/drug therapy , Male , Middle Aged , Research , Treatment Outcome
20.
Pain ; 162(6): 1828-1839, 2021 06 01.
Article in English | MEDLINE | ID: mdl-33449503

ABSTRACT

ABSTRACT: Placebo effects have traditionally involved concealment or deception. However, recent evidence suggests that placebo effects can also be elicited when prescribed transparently as "open-label placebos" (OLPs), and that the pairing of an unconditioned stimulus (eg, opioid analgesic) with a conditioned stimulus (eg, placebo pill) can lead to the conditioned stimulus alone reducing pain. In this randomized control trial, we investigated whether combining conditioning with an OLP (COLP) in the immediate postoperative period could reduce daily opioid use and postsurgical pain among patients recovering from spine surgery. Patients were randomized to COLP or treatment as usual, with both groups receiving unrestricted access to a typical opioid-based postoperative analgesic regimen. The generalized estimating equations method was used to assess the treatment effect of COLP on daily opioid consumption and pain during postoperative period from postoperative day (POD) 1 to POD 17. Patients in the COLP group consumed approximately 30% less daily morphine milligram equivalents compared with patients in the treatment as usual group during POD 1 to 17 (-14.5 daily morphine milligram equivalents; 95% CI: [-26.8, -2.2]). Daily worst pain scores were also lower in the COLP group (-1.0 point on the 10-point scale; 95% CI: [-2.0, -0.1]), although a significant difference was not detected in average daily pain between the groups (-0.8 point; 95% CI: [-1.7, 0.2]). These findings suggest that COLP may serve as a potential adjuvant analgesic therapy to decrease opioid consumption in the early postoperative period, without increasing pain.


Subject(s)
Analgesics, Opioid , Opioid-Related Disorders , Analgesics , Analgesics, Opioid/therapeutic use , Double-Blind Method , Humans , Opioid-Related Disorders/drug therapy , Pain, Postoperative/drug therapy
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