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1
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Bagnis A, Meeuwis SH, Haas JW, O'Keeffe M, Bajcar EA, Babel P, Evers AWM, Glogan E, Oleszczyk M, Portoles A, Vlaeyen JWS, Mattarozzi K, PANACEA Consortium. A scoping review of placebo and nocebo responses and effects: insights for clinical trials and practice. Health Psychol Rev 2025; 19:409-447. [PMID: 40028813 DOI: 10.1080/17437199.2025.2471792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 02/20/2025] [Indexed: 03/05/2025]
Abstract
Placebo and nocebo responses and effects influence treatment outcomes across a variety of conditions. The current scoping review aims to synthesise evidence from systematic reviews and meta-analyses in both clinical and healthy populations, elucidating key determinants of placebo and nocebo responses and effects, including individual, clinical, psychological and contextual factors. Among the 306 publications identified, 83% were meta-analyses and 17% systematic reviews, with a predominance of research in medical specialties (81.7%) such as psychiatry and neurology. Placebo responses were significantly more studied than nocebo responses. Individual determinants (e.g., age), clinical determinants (e.g., baseline symptom severity) and psychological determinants (e.g., expectations) were found to influence placebo and nocebo outcomes. Contextual determinants, including trial design and the method of treatment administration, also played critical roles. Several key underinvestigated areas in the current body of systematic reviews and meta-analyses were also identified. This scoping review highlights valuable insights into the determinants of placebo and nocebo responses and effects on a group level, potentially offering practical implications for optimising clinical trial designs and enhancing patient care strategies in clinical practice. However, to fully leverage these benefits, it is crucial to address the underexplored topics through more rigorous investigations using a person-centred perspective.
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Affiliation(s)
- Arianna Bagnis
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Julia W Haas
- Faculty of Psychology and Educational Sciences, Katholieke Universiteit Leuven, Leuven, Belgium
- Department of Psychology, University of Kaiserslautern-Landau (RPTU), Landau, Germany
| | | | | | - Przemyslaw Babel
- Institute of Psychology, Jagiellonian University, Krakow, Poland
| | | | - Eveliina Glogan
- Faculty of Psychology and Educational Sciences, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Marek Oleszczyk
- Department of Family Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Antonio Portoles
- Department of Farmacología y Toxicología, Universidad Complutense Madrid, Madrid, Spain
| | - Johan W S Vlaeyen
- Faculty of Psychology and Educational Sciences, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Katia Mattarozzi
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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Howick J, Lantos JD, Treweek S, Svobodova M, Jacob N, Edwards A, Bostock J, Bower P, Gillies K, Hood K. Variation in the extent to which patient information leaflets describe potential benefits and harms of trial interventions: a commentary. Trials 2025; 26:132. [PMID: 40229793 PMCID: PMC11998131 DOI: 10.1186/s13063-025-08824-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 03/23/2025] [Indexed: 04/16/2025] Open
Abstract
Clinical trial participants must understand the possible risks and benefits of trial interventions before providing their informed consent to participate. The aim of this commentary is twofold: to summarize the discrepancies in the extent to which patient information leaflets (PILs) list potential benefits and harms of trial interventions; and to highlight subsequent ethical issues that may result from failure to disclose potential benefits or harms . A review of 247 patient information leaflets (PILs) found that the extent to which potential benefits and harms are described varies, with 28 (11%) not describing potential benefits and 23 (9%) not describing potential harms. We argue that there is no principled difference between potential benefits and potential harms (what is helpful for one person could harm another), and the need to disclose potential benefits may be less accepted than the need to disclose all potential harms. Additionally, while it is recognized that failure to mention potential harms may violate the ethical principle of autonomy, it is less well-established that other ethical principles, (the need to avoid harm (non-maleficence) , to help patients (beneficence), and to promote justice) may also be at risk when all potential harms and benefits are not disclosed within PILs. We suggest that the way potential benefits and harms are described within PILs be harmonized according to recently established principles.
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Affiliation(s)
- Jeremy Howick
- Cardiff University Centre for Trials Research, Cardiff University, Cardiff, Wales, UK.
- Stoneygate Centre for Empathic Healthcare, University of Leicester, George Davies Centre, Lancaster Road, Leicester, LE1 7HA, UK.
| | | | - Shaun Treweek
- Aberdeen Centre for Evaluation, University of Aberdeen, Aberdeen, Scotland, UK
| | - Martina Svobodova
- Cardiff University Centre for Trials Research, Cardiff University, Cardiff, Wales, UK
| | - Nina Jacob
- Cardiff University Centre for Trials Research, Cardiff University, Cardiff, Wales, UK
| | - Adrian Edwards
- Division of Population Medicine, Cardiff University, Cardiff, Wales, UK
| | | | - Peter Bower
- Centre for Primary Care, Manchester University, Manchester, UK
| | - Katie Gillies
- Aberdeen Centre for Evaluation, University of Aberdeen, Aberdeen, Scotland, UK
| | - Kerenza Hood
- Cardiff University Centre for Trials Research, Cardiff University, Cardiff, Wales, UK
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Schmidt S, Loef M, Ostermann T, Walach H. Treatment effects in pharmacological clinical randomized controlled trials are mainly due to placebo. J Clin Epidemiol 2025; 179:111658. [PMID: 39733973 DOI: 10.1016/j.jclinepi.2024.111658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/17/2024] [Accepted: 12/23/2024] [Indexed: 12/31/2024]
Abstract
OBJECTIVES The placebo response in clinical trials has four components: regression to the mean (RTM), measurement artifacts, natural tendency (NT) of the disease, and the genuine placebo effect. Our objective is to determine what contributes to the size of the placebo-effect in clinical trials by meta-regressions of randomized placebo-controlled clinical trials. STUDY DESIGN AND SETTING We identified five diseases where data on the rates of NT were available to search for a sample of n = 150 (5x30) randomized controlled trials. We extracted various study descriptors and performed meta-regressions to predict improvement in treatment and placebo groups. RESULTS We sampled 30 trials each from the following diagnoses: osteoarthritis of the knee, irritable bowel syndrome, depression, sleep disorders, migraine, and extracted relevant information. We estimated the effects due to RTM and NT and analyzed the improvement in placebo and treatment groups by fitting two regression models. Both models were highly significant, explaining 72% of the variance. Improvement in the placebo group can be significantly predicted by improvement in the treatment group (beta = .84), whether a study was analyzed according to intention to treat (beta = -.10) or was a multicenter study (beta = .12). Improvement in the treatment group can be explained by the improvement in the placebo group (beta = .83), whether a study was a multicenter trial (beta = -.16), and by RTM (beta = -.18). The treatment effect is smaller in sleep studies (beta = -.17). CONCLUSION The high correlation of r = .73 between placebo improvement and treatment improvement rates is genuine and not explainable by study or disease characteristics. We conclude from our data that the placebo-effect is the major driver of treatment effects in clinical trials that alone explains 69% of the variance. This leaves only limited space for effects due to pharmacological substances. Context effects are more important than pharmacological ones in the conditions studied by us.
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Affiliation(s)
- Stefan Schmidt
- Department of Psychosomatic Medicine and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
| | - Martin Loef
- Change Health Science Institute, Basel, Switzerland; Society for Clinical Research, Berlin, Germany
| | - Thomas Ostermann
- University of Witten/Herdecke, Faculty of Health, Witten, Germany
| | - Harald Walach
- Change Health Science Institute, Basel, Switzerland; Next Society Institute, Kazimieras Simonavicius University, Vilnius, Lithuania
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Niazi SK. Placebo Effects: Neurological Mechanisms Inducing Physiological, Organic, and Belief Responses-A Prospective Analysis. Healthcare (Basel) 2024; 12:2314. [PMID: 39595511 PMCID: PMC11593399 DOI: 10.3390/healthcare12222314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/12/2024] [Accepted: 11/19/2024] [Indexed: 11/28/2024] Open
Abstract
The placebo effect can induce physiological or clinical neurological and organic responses despite the recipient receiving no active ingredients; these responses are based instead on the recipient's perceptions. Placebo effects come from the rostral anterior cingulate cortex, pontine nucleus, and cerebellum of the brain; this information provides a better understanding of placebo effects and can also help us understand the mechanism of the modulation of neurotransmitters from the use of psychedelic substances, activity of selective serotonin reuptake inhibitors, the process of transcranial magnetic stimulation, and deep brain stimulation, as well as aid in developing novel therapies, challenging the validity of controlled clinical trials (RCTs) that the regulatory agencies now appreciate. Education about how placebo effects bring in social, political, and religious beliefs and whether these can be modulated may help reduce global confrontations.
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Affiliation(s)
- Sarfaraz K Niazi
- College of Pharmacy, University of Illinois, Chicago, IL 60612, USA
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Niazi SK. Advice to the FDA to Improve Its Proposed Guidelines to Rationalize Clinical Trials by Restricting Placebo Control, Preventing Low-Powered Studies, and Disallowing Studies Where Bioavailability Is Not Proven. Pharmaceuticals (Basel) 2024; 17:1424. [PMID: 39598336 PMCID: PMC11597071 DOI: 10.3390/ph17111424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 10/12/2024] [Accepted: 10/18/2024] [Indexed: 11/29/2024] Open
Abstract
Randomized controlled trials (RCTs) are the gold standard for testing the safety and efficacy of new drugs and biologicals. The US Food and Drug Administration (FDA) has proactively improved the trial designs to make them scientifically rational while avoiding unnecessary human exposure. Several new guidelines by the FDA have come in 2024 that address consolidating the RCTs with the Real-World Evidence (RWE) trials, decentralizing the testing platforms, and allowing the point-of-use clinicians to participate. However, the issue of placebo control remains, which is part of RCTs, and it should be reduced or removed given the organic impact of placebo that compounds the efficacy evaluation (explanatory trials), as opposed to effectiveness trials (pragmatic trials), which measure the degree of beneficial effects in "real-world" clinical settings. Additionally, clinical trials with low study power should be allowed, and when the proof of bioavailability at the site of action is not present, it should be removed. It is advised that the FDA issue a comprehensive guideline to consolidate its several guidelines and consider the role of placebo in making drug development a more affordable exercise while meeting the requirement to minimize the abuse of humans in such trials.
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Affiliation(s)
- Sarfaraz K Niazi
- College of Pharmacy, University of Illinois, Chicago, IL 60612, USA
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Brączyk J, Bąbel P. Can observational learning reinforce open-label placebo hypoalgesia? Pain 2024; 165:1605-1612. [PMID: 38227574 PMCID: PMC11190895 DOI: 10.1097/j.pain.0000000000003161] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 11/09/2023] [Accepted: 11/14/2023] [Indexed: 01/18/2024]
Abstract
ABSTRACT Previous research has indicated that an open-label placebo can reduce pain in both healthy participants and patients with chronic pain. Because nondeceptive placebos seem to be an effective and more ethical alternative to deceptive placebos, optimizing this kind of treatment is essential. Observational learning was previously shown to induce the deceptive placebo effect; therefore, this study aimed to verify its effectiveness in fortifying the open-label placebo effect. Healthy volunteers (N = 117) were randomly assigned to 4 groups: open-label placebo with observational learning (OLP + OBL), open-label placebo (OLP), deceptive placebo with observational learning (OBL), or control group. Participants underwent baseline and testing measurements, during which they self-reported pain induced by heat stimulation. Between assessments, placebo cream was openly administered in the OLP and OLP + OBL groups. The OLP + OBL group next watched a model experiencing hypoalgesia after cream application. In the OBL group, participants received placebo cream with no information about its effect, and then they watched the model. The placebo effect was successfully evoked in all experimental groups (OLP + OBL, OLP, and OBL), which confirms the effectiveness of both open-label and deceptive placebo interventions for pain reduction. However, the hypoalgesic effect was of similar magnitude in the OLP and OLP + OBL groups, which indicates that observation did not contribute to the effect. The results showed that reinforcing the open-label placebo by observational learning may be redundant, but more research is needed to confirm these findings.
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Affiliation(s)
- Justyna Brączyk
- Jagiellonian University, Institute of Psychology, Pain Research Group, Kraków, Poland
- Doctoral School in the Social Sciences, Jagiellonian University, Kraków, Poland
| | - Przemysław Bąbel
- Jagiellonian University, Institute of Psychology, Pain Research Group, Kraków, Poland
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van Dellen E. Precision psychiatry: predicting predictability. Psychol Med 2024; 54:1500-1509. [PMID: 38497091 DOI: 10.1017/s0033291724000370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Precision psychiatry is an emerging field that aims to provide individualized approaches to mental health care. An important strategy to achieve this precision is to reduce uncertainty about prognosis and treatment response. Multivariate analysis and machine learning are used to create outcome prediction models based on clinical data such as demographics, symptom assessments, genetic information, and brain imaging. While much emphasis has been placed on technical innovation, the complex and varied nature of mental health presents significant challenges to the successful implementation of these models. From this perspective, I review ten challenges in the field of precision psychiatry, including the need for studies on real-world populations and realistic clinical outcome definitions, and consideration of treatment-related factors such as placebo effects and non-adherence to prescriptions. Fairness, prospective validation in comparison to current practice and implementation studies of prediction models are other key issues that are currently understudied. A shift is proposed from retrospective studies based on linear and static concepts of disease towards prospective research that considers the importance of contextual factors and the dynamic and complex nature of mental health.
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Affiliation(s)
- Edwin van Dellen
- Department of Psychiatry and University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands
- Department of Neurology, UZ Brussel and Vrije Universiteit Brussel, Brussels, Belgium
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Saueressig T, Owen PJ, Pedder H, Tagliaferri S, Kaczorowski S, Altrichter A, Richard A, Miller CT, Donath L, Belavy DL. The importance of context (placebo effects) in conservative interventions for musculoskeletal pain: A systematic review and meta-analysis of randomized controlled trials. Eur J Pain 2024; 28:675-704. [PMID: 38116995 DOI: 10.1002/ejp.2222] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 10/04/2023] [Accepted: 11/25/2023] [Indexed: 12/21/2023]
Abstract
BACKGROUND AND OBJECTIVE Contextual effects (e.g. patient expectations) may play a role in treatment effectiveness. This study aimed to estimate the magnitude of contextual effects for conservative, non-pharmacological interventions for musculoskeletal pain conditions. A systematic review and meta-analysis of randomized controlled trials (RCTs) that compared placebo conservative non-pharmacological interventions to no treatment for musculoskeletal pain. The outcomes assessed included pain intensity, physical functioning, health-related quality of life, global rating of change, depression, anxiety and sleep at immediate, short-, medium- and/or long-term follow-up. DATABASES AND DATA TREATMENT MEDLINE, EMBASE, CINAHL, Web of Science Core Collection, CENTRAL and SPORTDiscus were searched from inception to September 2021. Trial registry searches, backward and forward citation tracking and searches for prior systematic reviews were completed. The Cochrane risk of bias 2 tool was implemented. RESULTS The study included 64 RCTs (N = 4314) out of 8898 records. For pain intensity, a mean difference of (MD: -5.32, 95% confidence interval (CI): -7.20, -3.44, N = 57 studies with 74 outcomes, GRADE: very low) was estimated for placebo interventions. A small effect in favour of the placebo interventions for physical function was estimated (SMD: -0.22, 95% CI: -0.35, -0.09; N = 37 with 48 outcomes, GRADE: very low). Similar results were found for a broad range of patient-reported outcomes. Meta-regression analyses did not explain heterogeneity among analyses. CONCLUSION The study found that the contextual effect of non-pharmacological conservative interventions for musculoskeletal conditions is likely to be small. However, given the known effect sizes of recommended evidence-based treatments for musculoskeletal conditions, it may still contribute an important component. SIGNIFICANCE Contextual effects of non-pharmacological conservative interventions for musculoskeletal conditions are likely to be small for a broad range of patient-reported outcomes (pain intensity, physical function, quality of life, global rating of change and depression). Contextual effects are unlikely, in isolation, to offer much clinical care. But these factors do have relevance in an overall treatment context as they provide almost 30% of the minimally clinically important difference.
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Affiliation(s)
| | - Patrick J Owen
- School of Exercise and Nutrition Sciences, Institute for Physical Activity and Nutrition (IPAN), Deakin University, Geelong, Victoria, Australia
| | - Hugo Pedder
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Scott Tagliaferri
- School of Exercise and Nutrition Sciences, Institute for Physical Activity and Nutrition (IPAN), Deakin University, Geelong, Victoria, Australia
| | - Svenja Kaczorowski
- Department of Applied Health Sciences, Division of Physiotherapy, Hochschule für Gesundheit (University of Applied Sciences), Bochum, Germany
| | - Adina Altrichter
- Department of Applied Health Sciences, Division of Physiotherapy, Hochschule für Gesundheit (University of Applied Sciences), Bochum, Germany
| | - Antonia Richard
- Department of Applied Health Sciences, Division of Physiotherapy, Hochschule für Gesundheit (University of Applied Sciences), Bochum, Germany
| | - Clint T Miller
- School of Exercise and Nutrition Sciences, Institute for Physical Activity and Nutrition (IPAN), Deakin University, Geelong, Victoria, Australia
| | - Lars Donath
- Department of Intervention Research in Exercise Training, German Sport University Cologne, Cologne, Germany
| | - Daniel L Belavy
- Department of Applied Health Sciences, Division of Physiotherapy, Hochschule für Gesundheit (University of Applied Sciences), Bochum, Germany
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Rees M. The Social Epistemology of Clinical Placebos. THE JOURNAL OF MEDICINE AND PHILOSOPHY 2024; 49:233-245. [PMID: 38531824 DOI: 10.1093/jmp/jhae010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/28/2024] Open
Abstract
Many extant theories of placebo focus on their causal structure wherein placebo effects are those that originate from select features of the therapy (e.g., client expectations or "incidental" features like size and shape). Although such accounts can distinguish placebos from standard medical treatments, they cannot distinguish placebos from everyday occurrences, for example, when positive feedback improves our performance on a task. Providing a social-epistemological account of a treatment context can rule out such occurrences, and furthermore reveal a new way to distinguish clinical placebos from standard medical treatments.
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Ko SJ, Kim K, Kaptchuk TJ, Napadow V, Kuo B, Gerber J, Ha NY, Lee J, Kelley JM, Park JW, Kim J. Influence of patient-clinician relationship style on acupuncture outcomes in functional dyspepsia: A multi-site randomized controlled trial in Korea. PATIENT EDUCATION AND COUNSELING 2024; 121:108133. [PMID: 38199174 DOI: 10.1016/j.pec.2023.108133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 12/17/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024]
Abstract
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.
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Affiliation(s)
- Seok-Jae Ko
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul, the Republic of Korea
| | - Keumji Kim
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul, the Republic of Korea
| | - Ted J Kaptchuk
- Program in Placebo Studies, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Vitaly Napadow
- Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Network, Harvard Medical School, Boston, MA, USA
| | - Braden Kuo
- Gastroenterology Unit, Center for Neurointestinal Health, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jessica Gerber
- Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Na-Yeon Ha
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul, the Republic of Korea
| | - Junhee Lee
- Department of Sasang Constitutional Medicine, College of Korean Medicine, Kyung Hee University, Seoul, the Republic of Korea
| | - John M Kelley
- Program in Placebo Studies, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Psychology Department, Endicott College, Beverly, MA, USA
| | - Jae-Woo Park
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul, the Republic of Korea.
| | - Jinsung Kim
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul, the Republic of Korea.
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Chamani G, Zarei MR, Rad M, Mafi S. Comparison of low-level laser therapy and standard treatment for temporomandibular disorders: An assessment of therapeutic and placebo effects. J Oral Rehabil 2024; 51:657-665. [PMID: 38012102 DOI: 10.1111/joor.13634] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 11/08/2023] [Accepted: 11/20/2023] [Indexed: 11/29/2023]
Abstract
BACKGROUND Despite extensive research on the use of low-power lasers for TMD treatment, the extent of their effectiveness remains uncertain. OBJECTIVE This study aimed to investigate the therapeutic or placebo effect of LLLT for TMD, and to compare it with standard treatment methods. A unique aspect of this study was the inclusion of a control group that received only standard treatment, allowing for an assessment of the placebo effect of LLLT. METHODS A total of 42 patients with TMD were referred to Kerman Dental School Pain Clinic and were randomly assigned to three groups: group A received LLLT, group B was a placebo group and group C was a control group that received only standard treatment. The laser groups received gallium-aluminium-arsenide laser treatment twice a week for 10 sessions. Patients' jaw movement rate indicators and VAS index were evaluated at the start of treatment, and indicators were re-recorded every week for 5 weeks. SPSS 21 was used for statistical analysis, including ANOVA and Tukey's post hoc tests for inter-group comparisons. The repeated measurement test was used to analyse the data. RESULTS All groups showed significant improvement in VAS indicators (p = .0001), lateral jaw movements (p = .0001), forward jaw movement (p = .007) but not for maximum mouth opening. No significant difference was observed between the groups at the end of the study (p = .000). CONCLUSION Our study provides insights into LLLT's effectiveness for TMD, suggesting it cannot replace standard treatment alone. These findings contribute to the literature and emphasise the importance of including a control group in future studies to assess the placebo effect of LLLT.
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Affiliation(s)
- Goli Chamani
- FAAOP Diplomat, American Board of Orofacial Pain Professor of Oral Medicine and Orofacial Pain Division of Oral Diagnostics and Rehabilitation Department of Dental Medicine, Karolinska Institute Scandinavian Center for Orofacial Neuroscience (SCON) Huddinge, Huddinge, Sweden
| | - Mohammad Reza Zarei
- Oral Medicine Department, Orofacial Pain Clinic, Kerman School of Dentistry, Kerman, Iran
| | - Maryam Rad
- Oral Medicine specialist, PhD by research in Epidemiology, Kerman, Iran
| | - Sahar Mafi
- Department of Oral Medicine, Faculty of Dentistry, Tehran Medical Sciences, Islamic Azad University of Tehran, Tehran, Iran
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12
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Frisaldi E, Shaibani A, Benedetti F, Pagnini F. Placebo and nocebo effects and mechanisms associated with pharmacological interventions: an umbrella review. BMJ Open 2023; 13:e077243. [PMID: 37848293 PMCID: PMC10582987 DOI: 10.1136/bmjopen-2023-077243] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 09/27/2023] [Indexed: 10/19/2023] Open
Abstract
OBJECTIVES This review aimed to summarise the existing knowledge about placebo and nocebo effects associated with pharmacological interventions and their mechanisms. DESIGN Umbrella review, adopting the Assessment of Multiple Systematic Reviews 2 tool for critical appraisal. DATA SOURCES MEDLINE/PubMed, Scopus, Web of Science, PsycINFO, Cochrane Central Register of Controlled Trial were searched in September 2022, without any time restriction, for systematic reviews, narrative reviews, original articles. Results were summarised through narrative synthesis, tables, 95% CI. OUTCOME MEASURES Mechanisms underlying placebo/nocebo effects and/or their effect sizes. RESULTS The databases search identified 372 studies, for a total of 158 312 participants, comprising 41 systematic reviews, 312 narrative reviews and 19 original articles. Seventy-three per cent of the examined systematic reviews were of high quality.Our findings revealed that mechanisms underlying placebo and/or nocebo effects have been characterised, at least in part, for: pain, non-noxious somatic sensation, Parkinson's disease, migraine, sleep disorders, intellectual disability, depression, anxiety, dementia, addiction, gynaecological disorders, attention-deficit hyperactivity disorder, immune and endocrine systems, cardiovascular and respiratory systems, gastrointestinal disorders, skin diseases, influenza and related vaccines, oncology, obesity, physical and cognitive performance. Their magnitude ranged from 0.08 to 2.01 (95% CI 0.37 to 0.89) for placebo effects and from 0.32 to 0.90 (95% CI 0.24 to 1.00) for nocebo effects. CONCLUSIONS This study provides a valuable tool for clinicians and researchers, identifying both results ready for clinical practice and gaps to address in the near future. FUNDING Università Cattolica del Sacro Cuore, Milan, Italy with the 'Finanziamento Ponte 2022' grant. PROSPERO REGISTRATION NUMBER CRD42023392281.
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Affiliation(s)
- Elisa Frisaldi
- Department of Neuroscience "Rita Levi Montalcini", University of Turin, Turin, Italy
| | - Aziz Shaibani
- Muscle and Nerve Center, Houston, Texas, USA
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Fabrizio Benedetti
- Department of Neuroscience "Rita Levi Montalcini", University of Turin, Turin, Italy
| | - Francesco Pagnini
- Department of Psychology, Università Cattolica del Sacro Cuore, Milan, Italy
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Abstract
The randomized controlled trial (RCT) research design assumes that a drug's "specific" effect can be isolated, added, and subtracted from the "nonspecific" effect of context and person. While RCTs are helpful in assessing the added benefit of a novel drug, they tend to obscure the curative potential of extra-pharmacological variables, known as "the placebo effect." Ample empirical evidence suggests that person/context-dependent physical, social, and cultural variables not only add to, but also shape drug effects, making them worth harnessing for patient benefits. Nevertheless, utilizing placebo effects in medicine is challenging due to conceptual and normative obstacles. In this article, we propose a new framework inspired by the field of psychedelic science and its employment of the "set and setting" concept. This framework acknowledges that drug and nondrug factors have an interactive and synergistic relationship. From it, we suggest ways to reintegrate nondrug variables into the biomedical toolbox, to ethically harness the placebo effect for improved clinical care.
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Affiliation(s)
- Chloé Pronovost-Morgan
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, London, UK
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Ido Hartogsohn
- The Program for Science, Technology and Society Studies, Bar-Ilan University, Ramat Gan, Israel
| | - Johannes G Ramaekers
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands
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Howick J, Svobodova M, Treweek S, Jacob N, Gillies K, Bostock J, Bower P, Edwards A, Hood K. Patient reported outcomes and recruitment rates following the introduction of principled patient information leaflets (PrinciPILs): Protocol for a meta-analysis. NIHR OPEN RESEARCH 2023; 3:29. [PMID: 39139272 PMCID: PMC11319896 DOI: 10.3310/nihropenres.13420.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 04/04/2023] [Indexed: 08/15/2024]
Abstract
Background The way potential benefits and harms of trial interventions are shared within patient information leaflets (PILs) varies widely and may cause unnecessary harms ("nocebo effects"). The aim of this meta-analysis will be to evaluate the influence on recruitment rates and early effects on patient reported adverse events of principled patient information leaflets (PrinciPILs) compared with standard PILs. Methods Eligible studies will include those that report the effects on recruitment and patient reported adverse events of PrinciPILs compared to standard PILs. We will include in this meta-analysis all the standard PILs in studies within trials (SWATs) of PrinciPILs that were developed as part of the Medical Research Council (MRC) funded PrinciPIL project. By publishing this as a living meta-analysis, we will allow the meta-analysis to be updated with future SWATs of PrinciPILs. We will use the Cochrane Risk of Bias tool to evaluate the risk of bias for each outcome. We will report the total number of studies and participants analysed and the characteristics of included studies (including details of intervention, comparators, outcomes). For dichotomous data, we will calculate the risk difference and the risk ratio (RR) and 95% confidence intervals (CIs). For continuous outcomes we will use weighted mean differences with 95% CIs or standardized mean differences with 95% CIs. We will investigate heterogeneity by visually inspecting the forest plot and by considering the I 2 test result. We will assess the certainty warranted for each outcome using the Grading of Recommendations Assessment Development and Evaluation (GRADE). Ethics approval is not applicable since no original data will be collected. The results will be disseminated through peer-reviewed publication and conference presentations. Discussion We will discuss the limitations of the meta-analysis including study risk of bias, inconsistency, heterogeneity, and imprecision. A general interpretation of the results and important implications will be provided.
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Affiliation(s)
- Jeremy Howick
- Centre for Trials Research (CTR), College of Biomedical and Life Sciences, Cardiff University, Cardiff, Wales, UK
| | - Martina Svobodova
- Centre for Trials Research (CTR), College of Biomedical and Life Sciences, Cardiff University, Cardiff, Wales, UK
| | - Shaun Treweek
- Health Services Research Unit, University of Aberdeen, Aberdeen, Scotland, UK
| | - Nina Jacob
- Centre for Trials Research (CTR), College of Biomedical and Life Sciences, Cardiff University, Cardiff, Wales, UK
| | - Katie Gillies
- Health Services Research Unit, University of Aberdeen, Aberdeen, Scotland, UK
| | - Jennifer Bostock
- Centre for Trials Research (CTR), College of Biomedical and Life Sciences, Cardiff University, Cardiff, Wales, UK
| | - Peter Bower
- Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, England, UK
| | - Adrian Edwards
- Division of Population Medicine, School of Medicine, Cardiff University, Cardiff, Wales, UK
| | - Kerenza Hood
- Centre for Trials Research (CTR), College of Biomedical and Life Sciences, Cardiff University, Cardiff, Wales, UK
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15
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Blokland A. Can placebo or nocebo pills improve or impair cognition performance? Hum Psychopharmacol 2023; 38:e2869. [PMID: 37140377 DOI: 10.1002/hup.2869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 03/24/2023] [Accepted: 03/28/2023] [Indexed: 05/05/2023]
Abstract
OBJECTIVE Although the placebo effect is well known to affect many behaviors, the effects on cognitive performance are less well investigated. METHODS In this study, the effects of a placebo and a nocebo manipulation on cognitive performance was investigated in healthy young participants in an unblinded between-subjects study. In addition, the participants were asked about their subjective experience in the placebo and nocebo condition. RESULTS The data suggested that the placebo condition induced the feeling of being more attentive and more motivated and the nocebo condition induced a feeling of being less attentive and alert and that they performed less well than normal. However, no placebo or nocebo effects were found on the actual performance on word learning, working memory, Tower of London task, or spatial pattern separation. CONCLUSIONS These findings further support the notion that placebo or nocebo effects are not likely to occur in young healthy volunteers. However, other studies suggest that placebo effects can be found in implicit memory tasks and in participants with memory problems. Further placebo/nocebo studies are indicated using different experimental designs and different populations in order to better understand the placebo effect on cognitive performance.
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Affiliation(s)
- Arjan Blokland
- Faculty of Psychology and Neuroscience, Department of Neuropsychology & Psychopharmacology. EURON, Maastricht University, Maastricht, The Netherlands
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16
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Peña-Martínez VM, Acosta-Olivo C, Tamez-Mata Y, Simental-Mendía LE, Blázquez-Saldaña J, Vilchez-Cavazos F, Simental-Mendía M. Normal saline injection produces a therapeutic effect in patients with plantar fasciitis: A systematic review and meta-analysis of randomized controlled trials. Foot Ankle Surg 2022; 28:1129-1138. [PMID: 35637108 DOI: 10.1016/j.fas.2022.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/15/2022] [Accepted: 04/20/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Injectable therapies have been increasingly investigated to treat plantar fasciitis in randomized controlled trials (RCT) where normal saline injections are frequently used as placebo. The purpose was to quantify the effect of saline injections and compared against available minimal clinically important difference (MCID) criteria specific for plantar fasciitis to assess if changes were clinically meaningful. METHODS RCT including a placebo group (normal saline) and reporting changes in pain and functional outcomes in plantar fasciitis were identified through a search in MEDLINE, Embase, Web of Science, and Scopus to February 2022. PRISMA guidelines and a registered protocol (PROSPERO: CRD42020214035) were followed to conduct the study. RESULTS Pooled analysis of 13 RCT (379 subjects) included for analysis revealed a significant improvement on pain (P < .00001) and functional scores (P < .00001) after normal saline injections. These changes exceeded the established MCID criteria. CONCLUSIONS Normal saline injections in plantar fasciitis showed a therapeutic effect with statistically and clinically meaningful improvement when administered in the setting of an RCT for up to 12 months. The control of potential confounders influencing the effect of saline injections is required for future research.
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Affiliation(s)
- Víctor Manuel Peña-Martínez
- Universidad Autonoma de Nuevo Leon, Orthopedics and Traumatology Service, "Dr. José Eleuterio González" University Hospital, Monterrey, Mexico
| | - Carlos Acosta-Olivo
- Universidad Autonoma de Nuevo Leon, Orthopedics and Traumatology Service, "Dr. José Eleuterio González" University Hospital, Monterrey, Mexico
| | - Yadira Tamez-Mata
- Universidad Autonoma de Nuevo Leon, Orthopedics and Traumatology Service, "Dr. José Eleuterio González" University Hospital, Monterrey, Mexico
| | - Luis E Simental-Mendía
- Instituto Mexicano del Seguro Social, Biomedical Research Unit, Delegación Durango, Durango, Mexico
| | - Jaime Blázquez-Saldaña
- Universidad Autonoma de Nuevo Leon, Orthopedics and Traumatology Service, "Dr. José Eleuterio González" University Hospital, Monterrey, Mexico
| | - Félix Vilchez-Cavazos
- Universidad Autonoma de Nuevo Leon, Orthopedics and Traumatology Service, "Dr. José Eleuterio González" University Hospital, Monterrey, Mexico
| | - Mario Simental-Mendía
- Universidad Autonoma de Nuevo Leon, Orthopedics and Traumatology Service, "Dr. José Eleuterio González" University Hospital, Monterrey, Mexico.
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17
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Placebo administration for dry eye disease: a level I evidence based systematic review and meta-analysis. Int J Clin Pharm 2022; 44:1087-1101. [PMID: 35939178 PMCID: PMC9618542 DOI: 10.1007/s11096-022-01439-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 06/04/2022] [Indexed: 12/05/2022]
Abstract
Background The efficacy of various common treatment options for dry eye disease (DED) has been investigated against placebo. However, the potential beneficial effect of placebo in the management of DED is still unclear. Aim This meta-analysis investigated the impact of placebo administration in DED in Ocular Surface Disease Index (OSDI), Schirmer I test (SIT), tear breakup time (TBUT), corneal staining, and complications. Method This meta-analysis and systematic review was conducted according to the 2020 PRISMA guidelines. In March 2022, Pubmed, Web of Science, Google Scholar, and Embase were accessed. All the randomised clinical trials which investigated any active treatment against a placebo control group were considered. The following data were extracted at baseline and at last follow-up: Ocular Surface Disease Index (OSDI), tear breakup time test (TBUT), Schirmer I test (SIT), corneal staining. Results Data from 56 studies (12,205 patients) were retrieved. Placebo administration is not effective in improving TBUT (P = 0.3), OSDI (P = 0.2), SIT (P = 0.1) and corneal staining (P = 0.1) from baseline to last follow-up. Active treatment led to a higher TBUT and SIT compared to placebo administration (P < 0.0001). The active treatment resulted in a lower OSDI compared to placebo administration (P = 0.0005). Five studies reported data on the corneal staining. No difference was found between placebo administration and active treatment (P = 0.8). Conclusion Placebo administration does not impact symptoms of DED and can be successfully employed to evaluate the efficacy of active treatments. Supplementary Information The online version contains supplementary material available at 10.1007/s11096-022-01439-y.
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18
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Sherriff B, Clark C, Killingback C, Newell D. Impact of contextual factors on patient outcomes following conservative low back pain treatment: systematic review. Chiropr Man Therap 2022; 30:20. [PMID: 35449074 PMCID: PMC9028033 DOI: 10.1186/s12998-022-00430-8] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 04/11/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Chronic low back pain is pervasive, societally impactful, and current treatments only provide moderate relief. Exploring whether therapeutic elements, either unrecognised or perceived as implicit within clinical encounters, are acknowledged and deliberately targeted may improve treatment efficacy. Contextual factors (specifically, patient's and practitioner's beliefs/characteristics; patient-practitioner relationships; the therapeutic setting/environment; and treatment characteristics) could be important, but there is limited evidence regarding their influence. This research aims to review the impact of interventions modifying contextual factors during conservative care on patient's pain and physical functioning. DATABASES AND DATA TREATMENT Four electronic databases (Medline, CINAHL, PsycINFO and AMED) were searched from 2009 until 15th February 2022, using tailored search strategies, and resulted in 3476 unique citations. After initial screening, 170 full-text records were potentially eligible and assessed against the inclusion-exclusion criteria. Thereafter, studies were assessed for methodological quality using a modified Downs and Black scale, data extracted, and synthesised using a narrative approach. RESULTS Twenty-one primary studies (N = 3075 participants), were included in this review. Eight studies reported significant improvements in pain intensity, and seven in physical functioning, in favour of the contextual factor intervention(s). Notable contextual factors included: addressing maladaptive illness beliefs; verbal suggestions to influence symptom change expectations; visual or physical cues to suggest pain-relieving treatment properties; and positive communication such as empathy to enhance the therapeutic alliance. CONCLUSION This review identified influential contextual factors which may augment conservative chronic low back pain care. The heterogeneity of interventions suggests modifying more than one contextual factor may be more impactful on patients' clinical outcomes, although these findings require judicious interpretation.
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Affiliation(s)
- Bronwyn Sherriff
- Department of Rehabilitation and Sport Sciences, Faculty of Health and Social Sciences, Bournemouth University, Bournemouth, England.
- AECC University College, Bournemouth, England.
| | - Carol Clark
- Department of Rehabilitation and Sport Sciences, Faculty of Health and Social Sciences, Bournemouth University, Bournemouth, England
| | - Clare Killingback
- Department of Sport, Health and Exercise Sciences, Faculty of Health Sciences, University of Hull, Hull, England
| | - Dave Newell
- AECC University College, Bournemouth, England
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19
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Schnelle C, Clark J, Mascord R, Jones MA. Is There a Surgeons’ Effect on Patients’ Physical Health, Beyond the Intervention, That Requires Further Investigation? A Systematic Review. Ther Clin Risk Manag 2022; 18:467-490. [PMID: 35502434 PMCID: PMC9056050 DOI: 10.2147/tcrm.s357934] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 04/04/2022] [Indexed: 12/23/2022] Open
Abstract
Objective To find and review published papers researching surgeons’ effects on patients’ physical health. Clinical outcomes of surgery patients with similar prognoses cannot be fully explained by surgeon skill or experience. Just as there are “hospital” and “psychotherapist” effects, there may be “surgeons” effects that persist after controlling for known variables like patient health and operation riskiness. Methods Cohort studies and randomized controlled trials (RCTs) of any surgical intervention, which, after multivariate adjustment, either showed proportion of variance in patients’ physical health outcomes due to surgeons (random effects) or graded surgeons from best to worst (fixed effects). Studies with <15 surgeons or only ascribing surgeons’ effects to known variables excluded. Medline, PubMed, Embase, and PsycINFO were used for search until June 2020. Manual search for papers referring/referred by resulting studies. Risk of bias assessed by Cochrane risk-of-bias tool and Newcastle–Ottawa Scale. Results Included studies: 52 cohort studies and three RCTs of 52,436+ surgeons covering 102 outcomes (33 unique). Studies either graded surgeons from best to worst or calculated the intra-class correlation coefficient (ICC), the percentage of patients’ variation due to surgeons, in diverse ways. Sixteen studies showed exceptionally good and/or bad performers with confidence intervals wholly above or below the average performance. ICCs ranged from 0 to 47%, median 4.0%. There are no well-established reporting standards; highly heterogeneous reporting, therefore no meta-analysis. Discussion Interpretation: There is a surgeons' effect on patients’ physical health for many types of surgeries and outcomes, ranging from small to substantial. Surgeons with exceptional patient outcomes appear regularly even after accounting for all known confounding variables. Many existing cohort studies and RCTs could be reanalyzed for surgeons’ effects especially after methodological reporting guidelines are published. Conclusion In terms of patient outcomes, it can matter which surgeon is chosen. Surgeons with exceptional patient outcomes are worth studying further. ![]()
Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/pL-eGyAGhSk
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Affiliation(s)
- Christoph Schnelle
- Institute for Evidence-Based Healthcare, Bond University, Robina, Queensland, Australia
- Correspondence: Christoph Schnelle, Institute for Evidence-Based Healthcare, Bond University, Robina, Queensland, Australia, Email
| | - Justin Clark
- Institute for Evidence-Based Healthcare, Bond University, Robina, Queensland, Australia
| | - Rachel Mascord
- General Dentist, BMA House, Sydney, New South Wales, Australia
| | - Mark A Jones
- Institute for Evidence-Based Healthcare, Bond University, Robina, Queensland, Australia
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20
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De Ridder D, Vanneste S, Smith M, Adhia D. Pain and the Triple Network Model. Front Neurol 2022; 13:757241. [PMID: 35321511 PMCID: PMC8934778 DOI: 10.3389/fneur.2022.757241] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 01/28/2022] [Indexed: 12/15/2022] Open
Abstract
Acute pain is a physiological response that causes an unpleasant sensory and emotional experience in the presence of actual or potential tissue injury. Anatomically and symptomatically, chronic pathological pain can be divided into three distinct but interconnected pathways, a lateral “painfulness” pathway, a medial “suffering” pathway and a descending pain inhibitory circuit. Pain (fullness) can exist without suffering and suffering can exist without pain (fullness). The triple network model is offering a generic unifying framework that may be used to understand a variety of neuropsychiatric illnesses. It claims that brain disorders are caused by aberrant interactions within and between three cardinal brain networks: the self-representational default mode network, the behavioral relevance encoding salience network and the goal oriented central executive network. A painful stimulus usually leads to a negative cognitive, emotional, and autonomic response, phenomenologically expressed as pain related suffering, processed by the medial pathway. This anatomically overlaps with the salience network, which encodes behavioral relevance of the painful stimuli and the central sympathetic control network. When pain lasts longer than the healing time and becomes chronic, the pain- associated somatosensory cortex activity may become functionally connected to the self-representational default mode network, i.e., it becomes an intrinsic part of the self-percept. This is most likely an evolutionary adaptation to save energy, by separating pain from sympathetic energy-consuming action. By interacting with the frontoparietal central executive network, this can eventually lead to functional impairment. In conclusion, the three well-known pain pathways can be combined into the triple network model explaining the whole range of pain related co-morbidities. This paves the path for the creation of new customized and personalized treatment methods.
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Affiliation(s)
- Dirk De Ridder
- Section of Neurosurgery, Department of Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
- *Correspondence: Dirk De Ridder
| | - Sven Vanneste
- School of Psychology, Global Brain Health Institute, Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland
| | - Mark Smith
- Neurofeedbackservices of New York, New York, NY, United States
| | - Divya Adhia
- Section of Neurosurgery, Department of Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
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21
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Smith EA, Horan WP, Demolle D, Schueler P, Fu DJ, Anderson AE, Geraci J, Butlen-Ducuing F, Link J, Khin NA, Morlock R, Alphs LD. Using Artificial Intelligence-based Methods to Address the Placebo Response in Clinical Trials. INNOVATIONS IN CLINICAL NEUROSCIENCE 2022; 19:60-70. [PMID: 35382067 PMCID: PMC8970233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The placebo response is a highly complex psychosocial-biological phenomenon that has challenged drug development for decades, particularly in neurological and psychiatric disease. While decades of research have aimed to understand clinical trial factors that contribute to the placebo response, a comprehensive solution to manage the placebo response in drug development has yet to emerge. Advanced data analytic techniques, such as artificial intelligence (AI), might be needed to take the next leap forward in mitigating the negative consequences of high placebo-response rates. The objective of this review was to explore the use of techniques such as AI and the sub-discipline of machine learning (ML) to address placebo response in practical ways that can positively impact drug development. This examination focused on the critical factors that should be considered in applying AI and ML to the placebo response issue, examples of how these techniques can be used, and the regulatory considerations for integrating these approaches into clinical trials.
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Affiliation(s)
- Erica A Smith
- Drs. Smith and Demolle are with Cognivia in Mont St. Guibert, Belgium
- Dr. Horan is with VeraSci in Durham, North Carolina
- Drs. Horan and Anderson are with the University of California at Los Angeles in Los Angeles, California
- Dr. Schueler is with ICON Clinical Research in Langen, Germany
- Dr. Fu is with Janssen Reasearch and Development, LLC, in Titusville, New Jersey
- Dr. Geraci is with Nurosene Health, Inc. in Toronto, Ontario; Queen's University in Kingston, Ontario; and the Center for Biotechnology and Genomics Medicine, Medical College of Georgia, in Augusta, Georgia
- Dr. Butlen-Ducuing is with European Medicines Agency in Amsterdam, Netherlands
- Ms. Link is with Boehringer Ingelheim Pharma GmbH and Company KG in Baden Württenberg, Germany
- Dr. Khin is with Neurocrine Biosciences, Inc. in San Diego, California
- Dr. Morlock is with YourCareChoice in Ann Arbor, Michigan
- Dr. Alphs is with Denovo Biopharma, LLC in San Diego, California (at the time of writing, he was with Newron Pharmaceuticals in Morriston, New Jersey)
| | - William P Horan
- Drs. Smith and Demolle are with Cognivia in Mont St. Guibert, Belgium
- Dr. Horan is with VeraSci in Durham, North Carolina
- Drs. Horan and Anderson are with the University of California at Los Angeles in Los Angeles, California
- Dr. Schueler is with ICON Clinical Research in Langen, Germany
- Dr. Fu is with Janssen Reasearch and Development, LLC, in Titusville, New Jersey
- Dr. Geraci is with Nurosene Health, Inc. in Toronto, Ontario; Queen's University in Kingston, Ontario; and the Center for Biotechnology and Genomics Medicine, Medical College of Georgia, in Augusta, Georgia
- Dr. Butlen-Ducuing is with European Medicines Agency in Amsterdam, Netherlands
- Ms. Link is with Boehringer Ingelheim Pharma GmbH and Company KG in Baden Württenberg, Germany
- Dr. Khin is with Neurocrine Biosciences, Inc. in San Diego, California
- Dr. Morlock is with YourCareChoice in Ann Arbor, Michigan
- Dr. Alphs is with Denovo Biopharma, LLC in San Diego, California (at the time of writing, he was with Newron Pharmaceuticals in Morriston, New Jersey)
| | - Dominique Demolle
- Drs. Smith and Demolle are with Cognivia in Mont St. Guibert, Belgium
- Dr. Horan is with VeraSci in Durham, North Carolina
- Drs. Horan and Anderson are with the University of California at Los Angeles in Los Angeles, California
- Dr. Schueler is with ICON Clinical Research in Langen, Germany
- Dr. Fu is with Janssen Reasearch and Development, LLC, in Titusville, New Jersey
- Dr. Geraci is with Nurosene Health, Inc. in Toronto, Ontario; Queen's University in Kingston, Ontario; and the Center for Biotechnology and Genomics Medicine, Medical College of Georgia, in Augusta, Georgia
- Dr. Butlen-Ducuing is with European Medicines Agency in Amsterdam, Netherlands
- Ms. Link is with Boehringer Ingelheim Pharma GmbH and Company KG in Baden Württenberg, Germany
- Dr. Khin is with Neurocrine Biosciences, Inc. in San Diego, California
- Dr. Morlock is with YourCareChoice in Ann Arbor, Michigan
- Dr. Alphs is with Denovo Biopharma, LLC in San Diego, California (at the time of writing, he was with Newron Pharmaceuticals in Morriston, New Jersey)
| | - Peter Schueler
- Drs. Smith and Demolle are with Cognivia in Mont St. Guibert, Belgium
- Dr. Horan is with VeraSci in Durham, North Carolina
- Drs. Horan and Anderson are with the University of California at Los Angeles in Los Angeles, California
- Dr. Schueler is with ICON Clinical Research in Langen, Germany
- Dr. Fu is with Janssen Reasearch and Development, LLC, in Titusville, New Jersey
- Dr. Geraci is with Nurosene Health, Inc. in Toronto, Ontario; Queen's University in Kingston, Ontario; and the Center for Biotechnology and Genomics Medicine, Medical College of Georgia, in Augusta, Georgia
- Dr. Butlen-Ducuing is with European Medicines Agency in Amsterdam, Netherlands
- Ms. Link is with Boehringer Ingelheim Pharma GmbH and Company KG in Baden Württenberg, Germany
- Dr. Khin is with Neurocrine Biosciences, Inc. in San Diego, California
- Dr. Morlock is with YourCareChoice in Ann Arbor, Michigan
- Dr. Alphs is with Denovo Biopharma, LLC in San Diego, California (at the time of writing, he was with Newron Pharmaceuticals in Morriston, New Jersey)
| | - Dong-Jing Fu
- Drs. Smith and Demolle are with Cognivia in Mont St. Guibert, Belgium
- Dr. Horan is with VeraSci in Durham, North Carolina
- Drs. Horan and Anderson are with the University of California at Los Angeles in Los Angeles, California
- Dr. Schueler is with ICON Clinical Research in Langen, Germany
- Dr. Fu is with Janssen Reasearch and Development, LLC, in Titusville, New Jersey
- Dr. Geraci is with Nurosene Health, Inc. in Toronto, Ontario; Queen's University in Kingston, Ontario; and the Center for Biotechnology and Genomics Medicine, Medical College of Georgia, in Augusta, Georgia
- Dr. Butlen-Ducuing is with European Medicines Agency in Amsterdam, Netherlands
- Ms. Link is with Boehringer Ingelheim Pharma GmbH and Company KG in Baden Württenberg, Germany
- Dr. Khin is with Neurocrine Biosciences, Inc. in San Diego, California
- Dr. Morlock is with YourCareChoice in Ann Arbor, Michigan
- Dr. Alphs is with Denovo Biopharma, LLC in San Diego, California (at the time of writing, he was with Newron Pharmaceuticals in Morriston, New Jersey)
| | - Ariana E Anderson
- Drs. Smith and Demolle are with Cognivia in Mont St. Guibert, Belgium
- Dr. Horan is with VeraSci in Durham, North Carolina
- Drs. Horan and Anderson are with the University of California at Los Angeles in Los Angeles, California
- Dr. Schueler is with ICON Clinical Research in Langen, Germany
- Dr. Fu is with Janssen Reasearch and Development, LLC, in Titusville, New Jersey
- Dr. Geraci is with Nurosene Health, Inc. in Toronto, Ontario; Queen's University in Kingston, Ontario; and the Center for Biotechnology and Genomics Medicine, Medical College of Georgia, in Augusta, Georgia
- Dr. Butlen-Ducuing is with European Medicines Agency in Amsterdam, Netherlands
- Ms. Link is with Boehringer Ingelheim Pharma GmbH and Company KG in Baden Württenberg, Germany
- Dr. Khin is with Neurocrine Biosciences, Inc. in San Diego, California
- Dr. Morlock is with YourCareChoice in Ann Arbor, Michigan
- Dr. Alphs is with Denovo Biopharma, LLC in San Diego, California (at the time of writing, he was with Newron Pharmaceuticals in Morriston, New Jersey)
| | - Joseph Geraci
- Drs. Smith and Demolle are with Cognivia in Mont St. Guibert, Belgium
- Dr. Horan is with VeraSci in Durham, North Carolina
- Drs. Horan and Anderson are with the University of California at Los Angeles in Los Angeles, California
- Dr. Schueler is with ICON Clinical Research in Langen, Germany
- Dr. Fu is with Janssen Reasearch and Development, LLC, in Titusville, New Jersey
- Dr. Geraci is with Nurosene Health, Inc. in Toronto, Ontario; Queen's University in Kingston, Ontario; and the Center for Biotechnology and Genomics Medicine, Medical College of Georgia, in Augusta, Georgia
- Dr. Butlen-Ducuing is with European Medicines Agency in Amsterdam, Netherlands
- Ms. Link is with Boehringer Ingelheim Pharma GmbH and Company KG in Baden Württenberg, Germany
- Dr. Khin is with Neurocrine Biosciences, Inc. in San Diego, California
- Dr. Morlock is with YourCareChoice in Ann Arbor, Michigan
- Dr. Alphs is with Denovo Biopharma, LLC in San Diego, California (at the time of writing, he was with Newron Pharmaceuticals in Morriston, New Jersey)
| | - Florence Butlen-Ducuing
- Drs. Smith and Demolle are with Cognivia in Mont St. Guibert, Belgium
- Dr. Horan is with VeraSci in Durham, North Carolina
- Drs. Horan and Anderson are with the University of California at Los Angeles in Los Angeles, California
- Dr. Schueler is with ICON Clinical Research in Langen, Germany
- Dr. Fu is with Janssen Reasearch and Development, LLC, in Titusville, New Jersey
- Dr. Geraci is with Nurosene Health, Inc. in Toronto, Ontario; Queen's University in Kingston, Ontario; and the Center for Biotechnology and Genomics Medicine, Medical College of Georgia, in Augusta, Georgia
- Dr. Butlen-Ducuing is with European Medicines Agency in Amsterdam, Netherlands
- Ms. Link is with Boehringer Ingelheim Pharma GmbH and Company KG in Baden Württenberg, Germany
- Dr. Khin is with Neurocrine Biosciences, Inc. in San Diego, California
- Dr. Morlock is with YourCareChoice in Ann Arbor, Michigan
- Dr. Alphs is with Denovo Biopharma, LLC in San Diego, California (at the time of writing, he was with Newron Pharmaceuticals in Morriston, New Jersey)
| | - Jasmine Link
- Drs. Smith and Demolle are with Cognivia in Mont St. Guibert, Belgium
- Dr. Horan is with VeraSci in Durham, North Carolina
- Drs. Horan and Anderson are with the University of California at Los Angeles in Los Angeles, California
- Dr. Schueler is with ICON Clinical Research in Langen, Germany
- Dr. Fu is with Janssen Reasearch and Development, LLC, in Titusville, New Jersey
- Dr. Geraci is with Nurosene Health, Inc. in Toronto, Ontario; Queen's University in Kingston, Ontario; and the Center for Biotechnology and Genomics Medicine, Medical College of Georgia, in Augusta, Georgia
- Dr. Butlen-Ducuing is with European Medicines Agency in Amsterdam, Netherlands
- Ms. Link is with Boehringer Ingelheim Pharma GmbH and Company KG in Baden Württenberg, Germany
- Dr. Khin is with Neurocrine Biosciences, Inc. in San Diego, California
- Dr. Morlock is with YourCareChoice in Ann Arbor, Michigan
- Dr. Alphs is with Denovo Biopharma, LLC in San Diego, California (at the time of writing, he was with Newron Pharmaceuticals in Morriston, New Jersey)
| | - Ni A Khin
- Drs. Smith and Demolle are with Cognivia in Mont St. Guibert, Belgium
- Dr. Horan is with VeraSci in Durham, North Carolina
- Drs. Horan and Anderson are with the University of California at Los Angeles in Los Angeles, California
- Dr. Schueler is with ICON Clinical Research in Langen, Germany
- Dr. Fu is with Janssen Reasearch and Development, LLC, in Titusville, New Jersey
- Dr. Geraci is with Nurosene Health, Inc. in Toronto, Ontario; Queen's University in Kingston, Ontario; and the Center for Biotechnology and Genomics Medicine, Medical College of Georgia, in Augusta, Georgia
- Dr. Butlen-Ducuing is with European Medicines Agency in Amsterdam, Netherlands
- Ms. Link is with Boehringer Ingelheim Pharma GmbH and Company KG in Baden Württenberg, Germany
- Dr. Khin is with Neurocrine Biosciences, Inc. in San Diego, California
- Dr. Morlock is with YourCareChoice in Ann Arbor, Michigan
- Dr. Alphs is with Denovo Biopharma, LLC in San Diego, California (at the time of writing, he was with Newron Pharmaceuticals in Morriston, New Jersey)
| | - Robert Morlock
- Drs. Smith and Demolle are with Cognivia in Mont St. Guibert, Belgium
- Dr. Horan is with VeraSci in Durham, North Carolina
- Drs. Horan and Anderson are with the University of California at Los Angeles in Los Angeles, California
- Dr. Schueler is with ICON Clinical Research in Langen, Germany
- Dr. Fu is with Janssen Reasearch and Development, LLC, in Titusville, New Jersey
- Dr. Geraci is with Nurosene Health, Inc. in Toronto, Ontario; Queen's University in Kingston, Ontario; and the Center for Biotechnology and Genomics Medicine, Medical College of Georgia, in Augusta, Georgia
- Dr. Butlen-Ducuing is with European Medicines Agency in Amsterdam, Netherlands
- Ms. Link is with Boehringer Ingelheim Pharma GmbH and Company KG in Baden Württenberg, Germany
- Dr. Khin is with Neurocrine Biosciences, Inc. in San Diego, California
- Dr. Morlock is with YourCareChoice in Ann Arbor, Michigan
- Dr. Alphs is with Denovo Biopharma, LLC in San Diego, California (at the time of writing, he was with Newron Pharmaceuticals in Morriston, New Jersey)
| | - Larry D Alphs
- Drs. Smith and Demolle are with Cognivia in Mont St. Guibert, Belgium
- Dr. Horan is with VeraSci in Durham, North Carolina
- Drs. Horan and Anderson are with the University of California at Los Angeles in Los Angeles, California
- Dr. Schueler is with ICON Clinical Research in Langen, Germany
- Dr. Fu is with Janssen Reasearch and Development, LLC, in Titusville, New Jersey
- Dr. Geraci is with Nurosene Health, Inc. in Toronto, Ontario; Queen's University in Kingston, Ontario; and the Center for Biotechnology and Genomics Medicine, Medical College of Georgia, in Augusta, Georgia
- Dr. Butlen-Ducuing is with European Medicines Agency in Amsterdam, Netherlands
- Ms. Link is with Boehringer Ingelheim Pharma GmbH and Company KG in Baden Württenberg, Germany
- Dr. Khin is with Neurocrine Biosciences, Inc. in San Diego, California
- Dr. Morlock is with YourCareChoice in Ann Arbor, Michigan
- Dr. Alphs is with Denovo Biopharma, LLC in San Diego, California (at the time of writing, he was with Newron Pharmaceuticals in Morriston, New Jersey)
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22
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Abstract
A placebo is an inert substance normally used in clinical trials for comparison with an active substance. However, a placebo has been shown to have an effect on its own; commonly known as the placebo effect. A placebo is an essential component in the design of conclusive clinical trials but has itself become the focus of intense research. The placebo effect is partly the result of positive expectations of the recipient on the state of health. Conversely, a nocebo effect is when negative expectations from a substance lead to poor treatment outcomes and/or adverse events. Randomized controlled trials in functional urology have demonstrated the importance of the placebo and nocebo effects across different diseases such as overactive bladder, urinary incontinence, lower urinary tract symptoms and interstitial cystitis/painful bladder syndrome, as well as male and female sexual dysfunction. Understanding the true nature of the placebo-nocebo complex and the scope of its effect in functional urology could help urologists to maximize the positive effects of this phenomenon while minimizing its potentially negative effects.
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23
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D'Alessandro G, Ruffini N, Iacopini A, Annoni M, Kossowsky J, Cerritelli F. Overcoming placebo-related challenges in manual therapy trials: The ‘whats and hows’ and the ‘touch equality assumption’ proposals. INT J OSTEOPATH MED 2021. [DOI: 10.1016/j.ijosm.2021.10.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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24
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Siegel P, Peterson BS. What you don't know can help you: An activating placebo effect in spider phobia. Behav Res Ther 2021; 149:103994. [DOI: 10.1016/j.brat.2021.103994] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 09/03/2021] [Accepted: 11/03/2021] [Indexed: 12/18/2022]
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25
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Howick J. Unethical informed consent caused by overlooking poorly measured nocebo effects. JOURNAL OF MEDICAL ETHICS 2021; 47:590-594. [PMID: 32063581 DOI: 10.1136/medethics-2019-105903] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/04/2020] [Accepted: 01/13/2020] [Indexed: 06/10/2023]
Abstract
Unlike its friendly cousin the placebo effect, the nocebo effect (the effect of expecting a negative outcome) has been almost ignored. Epistemic and ethical confusions related to its existence have gone all but unnoticed. Contrary to what is often asserted, adverse events following from taking placebo interventions are not necessarily nocebo effects; they could have arisen due to natural history. Meanwhile, ethical informed consent (in clinical trials and clinical practice) has centred almost exclusively on the need to inform patients about intervention risks with patients to preserve their autonomy. Researchers have failed to consider the harm caused by the way in which the information is conveyed. In this paper, I argue that the magnitude of nocebo effects must be measured using control groups consisting of untreated patients. And, because the nocebo effect can produce harm, the principle of non-maleficence must be taken into account alongside autonomy when obtaining (ethical) informed consent and communicating intervention risks with patients.
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Affiliation(s)
- Jeremy Howick
- Faculty of Philosophy, University of Oxford, Oxford OX2 6GG, UK
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26
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Mostafaei H, Mori K, Quhal F, Miura N, Motlagh RS, Pradere B, Laukhtina E, Lysenko I, Ghaffari S, Hajebrahimi S, Shariat SF. Nocebo Response in the Pharmacological Management of Overactive Bladder: A Systematic Review and Meta-analysis. Eur Urol Focus 2021; 7:1143-1156. [PMID: 33153953 DOI: 10.1016/j.euf.2020.10.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 09/20/2020] [Accepted: 10/21/2020] [Indexed: 12/18/2022]
Abstract
CONTEXT The role of a nocebo response in managing urology patients is unclear. OBJECTIVE To assess the nocebo response in randomized placebo-controlled overactive bladder (OAB) trials of pharmacological treatment by investigating the adverse events in the placebo arms. EVIDENCE ACQUISITION PubMed, Scopus, Embase, and Cochrane Central Register of Controlled Trials were searched to identify potential randomized controlled trials published from 1998 to November 2019. After evaluating the risk of bias in the selected studies, all selected full-text articles were included due to their overall acceptable quality. We extracted the event rate of the most commonly reported adverse events in the placebo arms of OAB trials, and finally, we performed a meta-analysis to calculate the cumulative rate of certain adverse events. The primary outcomes were the event rate of adverse events in the placebo arms of OAB trials of pharmacological treatment, and differences in adverse events in the placebo groups based on drug type and routes of administration. EVIDENCE SYNTHESIS After a systematic search and risk of bias assessment, 57 trials comprising 15 446 patients were included in this systematic review. We selected 13 commonly reported adverse events for the meta-analysis. Owing to the possible differences in study samples and design, we used a random model for the analysis. The average age of the patients was 59.5 yr and 79.8% were female. Dry mouth was the most commonly evaluated adverse event reported in 57 studies comprising 15 324 patients; the mean event rate was 4.9% (95% confidence interval [CI] 0.042-0.057, p < 0.001). Constipation was the second most commonly reported adverse event in 49 studies comprising 14 556 patients; the mean event rate of constipation was 2.6% (95% CI 0.022-0.031, p < 0.001). The event rate of headache was evaluated in 33 studies comprising 10 202 patients, with a mean event rate of 3.1% (95% CI 0.026-0.037, p < 0.001). CONCLUSIONS Dry mouth, constipation, headache, and nasopharyngitis were the most prevalent events in the included studies. The nocebo response plays a statistically significant role in causing and/or facilitating adverse events. Health care providers should have a better understanding of the positive and negative expectations associated with therapies to achieve the best possible outcomes for each individual patient. Finally, identification of the real effect of nocebo requires studies that also include a no-treatment arm. Research could help us better understand and potentially modify the nocebo response. PATIENT SUMMARY In this meta-analysis of 57 studies comprising 15 446 patients, we reviewed the adverse events extracted from the placebo arms of randomized controlled trials studying therapies for overactive bladder. Dry mouth, constipation, headache, and urinary tract infection were the most common adverse events. Adverse events varied based on the drug type and the route of administration. Negative expectations from the therapy and giving verbal information to the patient can cause/alleviate adverse events.
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Affiliation(s)
- Hadi Mostafaei
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
| | - Keiichiro Mori
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Fahad Quhal
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Noriyoshi Miura
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Reza Sari Motlagh
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Benjamin Pradere
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, CHRU Tours, Francois Rabelais University, Tours, France
| | - Ekaterina Laukhtina
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Ivan Lysenko
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Sajjad Ghaffari
- Research Center for Evidence Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sakineh Hajebrahimi
- Research Center for Evidence Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahrokh F Shariat
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; Department of Urology, Weill Cornell Medicine, New York, NY, USA
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Verma N, Mudge JD, Kasole M, Chen RC, Blanz SL, Trevathan JK, Lovett EG, Williams JC, Ludwig KA. Auricular Vagus Neuromodulation-A Systematic Review on Quality of Evidence and Clinical Effects. Front Neurosci 2021; 15:664740. [PMID: 33994937 PMCID: PMC8120162 DOI: 10.3389/fnins.2021.664740] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 03/25/2021] [Indexed: 12/13/2022] Open
Abstract
Background: The auricular branch of the vagus nerve runs superficially, which makes it a favorable target for non-invasive stimulation techniques to modulate vagal activity. For this reason, there have been many early-stage clinical trials on a diverse range of conditions. These trials often report conflicting results for the same indication. Methods: Using the Cochrane Risk of Bias tool we conducted a systematic review of auricular vagus nerve stimulation (aVNS) randomized controlled trials (RCTs) to identify the factors that led to these conflicting results. The majority of aVNS studies were assessed as having "some" or "high" risk of bias, which makes it difficult to interpret their results in a broader context. Results: There is evidence of a modest decrease in heart rate during higher stimulation dosages, sometimes at above the level of sensory discomfort. Findings on heart rate variability conflict between studies and are hindered by trial design, including inappropriate washout periods, and multiple methods used to quantify heart rate variability. There is early-stage evidence to suggest aVNS may reduce circulating levels and endotoxin-induced levels of inflammatory markers. Studies on epilepsy reached primary endpoints similar to previous RCTs testing implantable vagus nerve stimulation therapy. Preliminary evidence shows that aVNS ameliorated pathological pain but not evoked pain. Discussion: Based on results of the Cochrane analysis we list common improvements for the reporting of results, which can be implemented immediately to improve the quality of evidence. In the long term, existing data from aVNS studies and salient lessons from drug development highlight the need for direct measures of local neural target engagement. Direct measures of neural activity around the electrode will provide data for the optimization of electrode design, placement, and stimulation waveform parameters to improve on-target engagement and minimize off-target activation. Furthermore, direct measures of target engagement, along with consistent evaluation of blinding success, must be used to improve the design of controls-a major source of concern identified in the Cochrane analysis. The need for direct measures of neural target engagement and consistent evaluation of blinding success is applicable to the development of other paresthesia-inducing neuromodulation therapies and their control designs.
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Affiliation(s)
- Nishant Verma
- Department of Biomedical Engineering, University of Wisconsin – Madison, Madison, WI, United States
- Wisconsin Institute for Translational Neuroengineering (WITNe) – Madison, Madison, WI, United States
| | - Jonah D. Mudge
- Department of Biomedical Engineering, University of Wisconsin – Madison, Madison, WI, United States
- Wisconsin Institute for Translational Neuroengineering (WITNe) – Madison, Madison, WI, United States
| | - Maïsha Kasole
- Department of Biomedical Engineering, University of Wisconsin – Madison, Madison, WI, United States
- Wisconsin Institute for Translational Neuroengineering (WITNe) – Madison, Madison, WI, United States
| | - Rex C. Chen
- Department of Biomedical Engineering, University of Wisconsin – Madison, Madison, WI, United States
- Wisconsin Institute for Translational Neuroengineering (WITNe) – Madison, Madison, WI, United States
| | - Stephan L. Blanz
- Department of Biomedical Engineering, University of Wisconsin – Madison, Madison, WI, United States
- Wisconsin Institute for Translational Neuroengineering (WITNe) – Madison, Madison, WI, United States
| | - James K. Trevathan
- Department of Biomedical Engineering, University of Wisconsin – Madison, Madison, WI, United States
- Wisconsin Institute for Translational Neuroengineering (WITNe) – Madison, Madison, WI, United States
| | | | - Justin C. Williams
- Department of Biomedical Engineering, University of Wisconsin – Madison, Madison, WI, United States
- Wisconsin Institute for Translational Neuroengineering (WITNe) – Madison, Madison, WI, United States
- Department of Neurosurgery, University of Wisconsin – Madison, Madison, WI, United States
| | - Kip A. Ludwig
- Department of Biomedical Engineering, University of Wisconsin – Madison, Madison, WI, United States
- Wisconsin Institute for Translational Neuroengineering (WITNe) – Madison, Madison, WI, United States
- Department of Neurosurgery, University of Wisconsin – Madison, Madison, WI, United States
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28
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Placebo Response in Patients with Oral Therapy for Overactive Bladder: A Systematic Review and Meta-analysis. Eur Urol Focus 2021; 8:239-252. [PMID: 33674256 DOI: 10.1016/j.euf.2021.02.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 01/10/2021] [Accepted: 02/05/2021] [Indexed: 12/28/2022]
Abstract
CONTEXT The role of a placebo response in the management of overactive bladder (OAB) remains unclear. OBJECTIVE The aim of this review is to methodically study the placebo response extracted from the control arms of randomized clinical trials assessing therapy in patients with OAB. EVIDENCE ACQUISITION Medline (PubMed), The Cochrane Library, EMBASE, and Scopus were searched to identify randomized controlled trials (RCTs) published until September 2019. Randomized placebo-controlled trials investigating oral drug therapy for OAB were included. The articles were critically appraised by two reviewers. The primary outcomes were the placebo response in the main patient-reported urinary outcomes together with assessing the impact of patient demographic factors on the placebo response. EVIDENCE SYNTHESIS The initial search resulted in 1982 records after reviewing the titles and abstracts, and reference lists of other systematic reviews; 57 studies with an overall estimated 12 901 patients were included in the meta-analysis. The included studies were of overall high/acceptable quality. The standardized mean difference was -0.45 (95% confidence interval [CI] -0.51 to -0.40; p<0.001) for daily micturition episodes, -0.33 (95% CI -0.42 to -0.24; p<0.001) for daily nocturia episodes, -0.46 (95% CI -0.55 to -0.37; p<0.001) for urgency urinary incontinence episodes, -0.50 (95% CI -0.61 to -0.39; p<0.001) for daily urgency episodes, -0.51 (95% CI -0.60 to -0.43; p<0.001) for daily incontinence episodes, and 0.25 (95% CI 0.211-0.290; p<0.001) for volume voided per micturition. The meta-regression of age-related impact of the placebo response on nocturia showed a slope of -0.02 (p<0.001). CONCLUSIONS Placebo has a statistically significant effect on improving symptoms and signs associated with OAB; this effect is age dependent. However, there is no consensus on what change of OAB symptoms and signs is clinically meaningful for the affected patient. Taken together, the placebo response seems to be non-negligible in OAB, supporting the need for placebo control in RCTs. PATIENT SUMMARY Placebo is an inert treatment method often used in clinical research for comparison with active treatment. However, studies show that placebo has an effect of its own. A placebo response means the total improvement resulting from receiving a placebo. In our study, placebo had a significant role in improving the symptoms of overactive bladder.
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29
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Shoffel-Havakuk H, Lava CX, Reuven Y, Moog D, Odell K, Reder LS, Hapner ER, Johns MM. Effect of Vitamin B12 Injection on the Vocal Performance of Professional Singers: A Randomized, Double-blind, Placebo-Controlled, Crossover Trial. JAMA Otolaryngol Head Neck Surg 2021; 147:9-15. [PMID: 33180098 PMCID: PMC7662483 DOI: 10.1001/jamaoto.2020.4026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 09/08/2020] [Indexed: 11/14/2022]
Abstract
Importance One-third of singers and vocal professionals report experiencing a benefit from empirical vitamin B12 injections for improvement of mild singing-related symptoms (eg, reduced stamina, vocal fatigue, and effort). However, there is no objective evidence to support or refute these claims. Objective To assess the presence and magnitude of the effect of empirical vitamin B12 injection on the vocal performance of singers. Design, Setting, and Participants A randomized, double-blind, placebo-controlled, crossover trial was conducted from November 7, 2017, to November 30, 2018, at an academic voice center among 20 active adult singers without dysphonia but with mild vocal symptoms. Individuals with known or suspected vitamin B12 deficiency or active or recent vitamin B12 treatment were excluded. Analysis was on a per-protocol basis. Interventions Participants were randomized to receive an intramuscular (deltoid) injection of either vitamin B12 (1000 μg of cyanocobalmin) or placebo (0.9% sodium chloride). After a washout period of at least 4 weeks, participants were crossed over to receive the opposite injection. Both the investigators and participants were blinded to the order of injections. Main Outcomes and Measures The participants completed the Singing Voice Handicap Index-10 (SVHI-10), the Voice Fatigue Index (VFI), and the Evaluation of the Ability to Sing Easily (EASE) before each injection and at intervals of 1 hour, 3 hours, 24 hours, 72 hours, and 1 week after the injection. The primary time point assessment was 72 hours after injection, and the SVHI-10 score was the primary outcome measure. Results Twenty singers (10 men; median age, 22 years [range, 19-42 years]) were enrolled. The improvements after either placebo or vitamin B12 injections were comparable to each other. At 72 hours after the vitamin B12 injection, the median difference in the SVHI-10 score was 1 (95% CI, -1 to 2) compared with 3 (95% CI, 0-4) after placebo. The median difference between differences at 72 hours between placebo and vitamin B12 injections were 1.5 (95% CI, -2 to 5) for the SVHI-10, 1 (95% CI, -9 to 9) for the VFI, and -1 (95% CI, -3 to 2) for the EASE. The improvements after both injections failed to reach the estimated minimal clinically important difference. Of the 20 participants, 4 (20%) reached the estimated minimal clinically important difference in their SVHI-10 score after 72 hours for both vitamin B12 and placebo injections. Conclusions and Relevance This randomized, double-blind, placebo-controlled, crossover trial found that after empirical vitamin B12 injection to improve mild voice-related symptoms, the improvement in self-reported voice measures in singers shows no meaningful difference compared with placebo. Trial Registration ClinicalTrials.gov Identifier: NCT03437824.
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Affiliation(s)
- Hagit Shoffel-Havakuk
- Department of Otolaryngology–Head and Neck Surgery, Rabin Medical Center, Petach Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Christian X. Lava
- USC Voice Center, Department of Otolaryngology–Head and Neck Surgery, University of Southern California, Los Angeles
| | - Yonatan Reuven
- Department of Otolaryngology–Head and Neck Surgery, Rabin Medical Center, Petach Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Dominic Moog
- USC Voice Center, Department of Otolaryngology–Head and Neck Surgery, University of Southern California, Los Angeles
| | - Karla Odell
- USC Voice Center, Department of Otolaryngology–Head and Neck Surgery, University of Southern California, Los Angeles
| | - Lindsay S. Reder
- USC Voice Center, Department of Otolaryngology–Head and Neck Surgery, University of Southern California, Los Angeles
| | - Edie R. Hapner
- UAB Voice Center, Otolaryngology, University of Alabama, Birmingham
| | - Michael M. Johns
- USC Voice Center, Department of Otolaryngology–Head and Neck Surgery, University of Southern California, Los Angeles
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30
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Coninx S. Strong representationalism and bodily sensations: Reliable causal covariance and biological function. PHILOSOPHICAL PSYCHOLOGY 2020. [DOI: 10.1080/09515089.2020.1858476] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Sabrina Coninx
- Institute for Philosophy II, Ruhr University Bochum, Bochum, Germany
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31
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Morphine-Conditioned Placebo Analgesia in Female and Male Rats with Chronic Neuropathic Pain: c-Fos Expression in the Rostral Ventromedial Medulla. Neuroscience 2020; 457:51-73. [PMID: 33285237 DOI: 10.1016/j.neuroscience.2020.11.038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/19/2020] [Accepted: 11/23/2020] [Indexed: 12/17/2022]
Abstract
Placebo analgesia has great potential to overcome the inadequacies of current drug therapies to treat conditions of chronic pain. The rostral ventromedial medulla (RVM) has been implicated as a critical relay in the antinociceptive pathway underpinning placebo analgesia in humans. We developed a model of opiate-conditioned placebo analgesia in rats with neuropathic injury to identify medullary nuclei active during placebo analgesia. Using female and male rats the degree of thermal allodynia was first determined following nerve injury, and a pharmacological conditioning procedure, pairing contextual cues with the experience of morphine-induced analgesia, was used to elicit placebo analgesic reactions. This protocol revealed clear subpopulations of placebo reactors (36% of males, 25% of females) and non-reactors in proportions similar to those reported in human studies. We detected injury-specific c-Fos expression in the gracile nucleus and morphine-specific c-Fos expression in the serotonergic midline raphe nuclei and the caudal nuclei of the solitary tract. However, c-Fos expression did not differ between placebo reactors and non-reactors in either serotonergic or non-serotonergic neurons of the RVM. Despite a subpopulation of rats demonstrating placebo reactions, we found no evidence for enhanced activity in the nuclei from which the classical RVM → spinal cord descending analgesic pathways emerge.
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32
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Acosta-Olivo CA, Millán-Alanís JM, Simental-Mendía LE, Álvarez-Villalobos N, Vilchez-Cavazos F, Peña-Martínez VM, Simental-Mendía M. Effect of Normal Saline Injections on Lateral Epicondylitis Symptoms: A Systematic Review and Meta-analysis of Randomized Clinical Trials. Am J Sports Med 2020; 48:3094-3102. [PMID: 32045280 DOI: 10.1177/0363546519899644] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Lateral epicondylitis, or tennis elbow, is a painful degenerative disorder that commonly occurs in adults between 40 and 60 years of age. Normal saline (NS) injections have been used as placebo through a large number of randomized controlled trials (RCTs) focused on the treatment of lateral epicondylitis. PURPOSE This meta-analysis of RCTs aimed to assess the therapeutic effect of NS injections on lateral epicondylitis symptoms and compare results with established minimal clinically important difference criteria. STUDY DESIGN Systematic review and meta-analysis. METHODS MEDLINE, Embase, Web of Science, and Scopus databases were searched for clinical trials reporting pain and joint function with the visual analog scale, Patient-Rated Tennis Elbow Evaluation, and Disabilities of the Arm, Shoulder and Hand in patients with lateral epicondylitis. The meta-analysis was conducted with a random effects model and generic inverse variance method. Heterogeneity was tested with the I2 statistic index. RESULTS A total of 15 RCTs included in this meta-analysis revealed a significant improvement in pain (mean difference, 3.61 cm [95% CI, 2.29-4.92 cm]; P < .00001; I2 = 88%; visual analog scale) and function (mean difference, 25.65 [95% CI, 13.30-37.99]; P < .0001; I2 = 82%; Patient-Rated Tennis Elbow Evaluation / Disabilities of the Arm, Shoulder and Hand) after NS injection (≥6 months). CONCLUSION NS injections yielded a statistically significant and clinically meaningful improvement in pain and functional outcomes in patients with lateral epicondylitis. New research should focus on better methods to diminish the potential confounders that could lead to this effect because NS injections could mask the real effect of an active therapeutic intervention in RCT. REGISTRATION CRD42019127547 (PROSPERO).
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Affiliation(s)
- Carlos Alberto Acosta-Olivo
- Universidad Autonoma de Nuevo Leon, Orthopedics and Traumatology Service, Facultad de Medicina y Hospital Universitario Dr José Eleuterio González, Monterrey, Mexico
| | - Juan Manuel Millán-Alanís
- Universidad Autonoma de Nuevo Leon, Plataforma Invest-KER Unit Mexico, Facultad de Medicina, Monterrey, Mexico
| | | | - Neri Álvarez-Villalobos
- Universidad Autonoma de Nuevo Leon, Plataforma Invest-KER Unit Mexico, Facultad de Medicina, Monterrey, Mexico
- Universidad Autonoma de Nuevo Leon, Clinical Research Unit, Facultad de Medicina y Hospital Universitario Dr José Eleuterio González, Monterrey, Mexico
- Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, Minnesota, USA
| | - Félix Vilchez-Cavazos
- Universidad Autonoma de Nuevo Leon, Orthopedics and Traumatology Service, Facultad de Medicina y Hospital Universitario Dr José Eleuterio González, Monterrey, Mexico
| | - Víctor Manuel Peña-Martínez
- Universidad Autonoma de Nuevo Leon, Orthopedics and Traumatology Service, Facultad de Medicina y Hospital Universitario Dr José Eleuterio González, Monterrey, Mexico
| | - Mario Simental-Mendía
- Universidad Autonoma de Nuevo Leon, Orthopedics and Traumatology Service, Facultad de Medicina y Hospital Universitario Dr José Eleuterio González, Monterrey, Mexico
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Annoni M. Better than nothing: A historical account of placebos and placebo effects from modern to contemporary medicine. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2020; 153:3-26. [PMID: 32563292 DOI: 10.1016/bs.irn.2020.03.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Throughout the history of medicine, multiple conceptions of "placebo" and "placebo effect" have often co-existed across different domains, and today the meaning of these concepts is still disputed. Against this background, this chapter provides a succinct account of the key events in the history of the concepts of "placebo," "placebo control," and "placebo effect." The first section reconstructs the etymology of the term "placebo" and its first introduction in medicine. The next sections provide an account of how placebos have been employed in both medical practice and scientific research in modern medicine. Later sections trace the emergence of the concepts of "placebo control" and "placebo effect" in the first half of the 20th century, from the first empirical studies investigating the effects of placebos up to the publication of Beecher's landmark article "The Powerful Placebo." Finally, the last two sections review the varieties of randomized, placebo-controlled trials (RCTs) in the second half of the 20th century, and the subsequent wave of empirical studies that, starting from the 1970s, have investigated the psychological, pharmacological and neurobiological mechanisms of placebo effects.
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Affiliation(s)
- Marco Annoni
- National Research Council of Italy (CNR), Institute of Biomedical Technologies (ITB), Fondazione Umberto Veronesi, Rome, Italy.
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Hutchinson P. The “placebo” paradox and the emotion paradox: Challenges to psychological explanation. THEORY & PSYCHOLOGY 2020. [DOI: 10.1177/0959354320928139] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Philosophical debates about how best to explain emotion or placebo are debates about how best to characterise and explain the distinctive form of human responsiveness to the world that is the object of interest for each of those domains of inquiry. In emotion research, the cognitive theory of emotion faces several intractable problems. I discuss two of these: the problem of epistemic deficit and the problem of recalcitrant emotions. Cognitive explanations in Placebo Studies, such as response-expectancy and belief-based explanations, also face the problem of epistemic deficit in addition to the problem of logically self-destructive true belief. While such considerations might motivate a retreat to affect, this brings its own problems. I argue that it is a particular version of cognitivism, representational cognitivism (Rep-Cog), that generates the paradoxes we encounter in emotion and placebo research. I propose that turning to nonrepresentational accounts of cognition will dissolve these paradoxes. As I move toward conclusion, I propose drawing on the ethnomethodological tradition to respecify human responsiveness to loci of significance in the lifeworld by undertaking ethnographies of members’ own situated methods for making intelligible and accountable their attitudinal and nonattitudinal responsiveness to loci of significance in their environment.
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Schmacke N. [Homeopathy: insubstantial doctrine of salvation]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2020; 63:541-547. [PMID: 32246158 DOI: 10.1007/s00103-020-03125-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Homeopathy is one of the frequently used alternative healing methods in Germany. This article is intended to discuss and analyze why homeopathy should not be part of medicine and should rather be understood as a concept of belief that lies outside of scientific methods. The clinical, legal, and political dimensions of the homeopathy debate are explained. Finally, the question of the legitimacy of placebo applications is discussed in light of the demand for patient-centered medicine.
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Affiliation(s)
- Norbert Schmacke
- Institut für Public Health und Pflegeforschung, Universität Bremen, Bremen, Deutschland. .,, Bibliothekstrasse 1, 28359, Bremen, Deutschland.
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Frumkin K. Behavioral Conditioning, the Placebo Effect, and Emergency Department Pain Management. J Emerg Med 2020; 59:303-310. [PMID: 32451185 DOI: 10.1016/j.jemermed.2020.04.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 03/26/2020] [Accepted: 04/08/2020] [Indexed: 10/24/2022]
Abstract
Animals and humans can be readily conditioned to associate a novel stimulus (often a unique taste) by pairing it with the effects of a drug or other agent. When later presented with the stimulus alone, their body's systems respond as if the drug or agent were given. The earliest clinical applications demonstrated both conditioned suppression and enhancement of immune processes. Unique benign stimuli, paired with chemotherapy, come to elicit T-cell suppression when administered alone. The beneficial immune responses to an antigen can be conditioned in the same manner. Further study of what came to be called "psychoneuroimmunology" led to the understanding that the familiar placebo effect, previously attributed to suggestion and expectation, is at least equally dependent on the same sorts of behavioral conditioning. The demonstrated ability to manipulate the immune system by a conditioned taste stimulus is, by definition, a placebo: a therapeutic effect caused by an inactive agent. The purpose of this analysis was to stimulate research in, and the application of, placebo-response conditioning to emergency medicine. Clinical and experimental studies confirm the usefulness of conditioned placebos in analgesia and in placebo-controlled dose reduction. Such conditioning paradigms demonstrate "one-trial learning," making them potentially useful in pain and addiction management within a single emergency department encounter.
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Affiliation(s)
- Kenneth Frumkin
- Emergency Medicine Department, Naval Medical Center, Portsmouth, Virginia
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Ho RS, Wong CH, Wu JC, Wong SY, Chung VC. Non-specific effects of acupuncture and sham acupuncture in clinical trials from the patient's perspective: a systematic review of qualitative evidence. Acupunct Med 2020; 39:3-19. [PMID: 32375500 DOI: 10.1177/0964528420920299] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Previous clinical trials have demonstrated that both acupuncture and sham acupuncture exert significant, non-specific effects on treatment outcomes when compared to no-treatment controls. A recently developed framework (mechanisms in orthodox and complementary and alternative medicine-MOCAM) suggests that the non-specific effects of acupuncture originate from multiple domains (e.g. patient characteristics, acupuncturist skill/technique, the patient-acupuncturist relationship, and the acupuncture environment). However, it remains to be determined precisely how these domains influence the non-specific effects of treatment among patients receiving acupuncture and sham acupuncture in clinical trials. Therefore, we conducted a systematic review to synthesize existing qualitative evidence on how trial participants randomized to acupuncture and sham acupuncture groups experience non-specific effects, regardless of the types of medical condition investigated. METHODS This systematic review included primary qualitative studies embedded in randomized controlled trials designed to investigate acupuncture or sham acupuncture interventions. Eligible studies published in English were derived from a search of five international databases. The methodological quality of included studies was evaluated using the Critical Appraisal Skills Programme (CASP) tool. Using a framework synthesis approach, the identified MOCAM framework was adapted based on the synthesis of the available qualitative evidence. RESULTS A total of 20 studies of high methodological quality were included. Our proposed model indicated that the effects of acupuncture may be increased by maintaining a professional status, applying a holistic treatment approach, practicing empathy, and providing patients with an appropriate explanation of the theory behind acupuncture and sham acupuncture. From the patient's perspective, the efficacy of treatment can be increased by following the lifestyle modification advice provided by acupuncturists, maintaining a positive attitude toward treatment efficacy, actively engaging with acupuncturists during consultation, and making behavioral changes based on experience gained during the trial. CONCLUSION The results of this study may provide a basis for improving and standardizing key components of non-specific effects in acupuncture treatment, and for improving the isolation of specific effects in future clinical trials involving acupuncture and sham acupuncture.
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Affiliation(s)
- Robin St Ho
- Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Charlene Hl Wong
- Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Justin Cy Wu
- Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Samuel Ys Wong
- Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Vincent Ch Chung
- Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, Hong Kong.,School of Chinese Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
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Walach H. [Comment on the article by Norbert Schmacke: Homeopathy: "insubstantial doctrine of salvation"]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2020; 63:548-552. [PMID: 32246160 DOI: 10.1007/s00103-020-03136-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Affiliation(s)
- Harald Walach
- Dept. Pädiatrische Gastroenterologie, Medizinische Universität Poznan, Poznan, Polen. .,Dept. Psychologie, Universität Witten-Herdecke, Witten, Deutschland. .,Change Health Science Institut, Schönwalder Str. 17, 13347, Berlin, Deutschland.
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Rogowska AM. The Sensational Past and Present: How We Use Our Senses Today. AMERICAN JOURNAL OF PSYCHOLOGY 2020. [DOI: 10.5406/amerjpsyc.133.1.0138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Aleksandra M. Rogowska
- University of Opole, Faculty of Social Sciences, Institute of Psychology, Pl. Staszica 1, p. 312, 45-052 Opole, Poland, E-mail:
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Ratnapalan M, Coghlan B, Tan M, Everitt H, Geraghty AWA, Little P, Lewith G, Bishop FL. Placebos in primary care? a nominal group study explicating UK GP and patient views of six theoretically plausible models of placebo practice. BMJ Open 2020; 10:e032524. [PMID: 32075826 PMCID: PMC7044897 DOI: 10.1136/bmjopen-2019-032524] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVES To better understand which theoretically plausible placebogenic techniques might be acceptable in UK primary care. DESIGN A qualitative study using nominal group technique and thematic analysis. Participants took part in audio-recorded face-to-face nominal groups in which the researcher presented six scenarios describing the application in primary care of theoretically plausible placebogenic techniques: (1) Withholding side effects information, (2) Monitoring, (3) General practitioner (GP) endorsement, (4) Idealised consultation, (5) Deceptive placebo pills and (6) Open-label placebo pills. Participants voted on whether they thought each scenario was acceptable in practice and discussed their reasoning. Votes were tallied and discussions transcribed verbatim. SETTING Primary care in England. PARTICIPANTS 21 GPs in four nominal groups and 20 'expert patients' in five nominal groups. RESULTS Participants found it hard to decide which practices were acceptable and spoke about needing to weigh potential symptomatic benefits against the potential harms of lost trust eroding the therapeutic relationship. Primary care patients and doctors felt it was acceptable to harness placebo effects in practice by patient self-monitoring (scenario 2), by the GP expressing a strongly positive belief in a therapy (scenario 3) and by conducting patient-centred, empathic consultations (scenario 4). Deceptive placebogenic practices (scenarios 1 and 5) were unacceptable to most groups. Patient and GP groups expressed a diverse range of opinions about open-label placebo pills. CONCLUSIONS Attempts to harness placebo effects in UK primary care are more likely to be accepted and implemented if they focus on enhancing positive patient-centred communication and empathic relationships. Using placebos deceptively is likely to be unacceptable to both GPs and patients. Open-label placebos also do not have clear support; they might be acceptable to some doctors and patients in very limited circumstances-but further evidence, clear information and guidance would be needed.
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Affiliation(s)
- Mohana Ratnapalan
- Primary Care and Population Sciences, University of Southampton, Southampton, UK
| | | | - Mengxin Tan
- Centre of Global Mental Health, London School of Hygiene and Tropical Medicine, London, London, UK
- Institute of Psychiatry, Psychology and Neuroscience, London, London, UK
| | - Hazel Everitt
- Primary Care and Population Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Adam W A Geraghty
- Primary Care and Population Sciences, University of Southampton, Southampton, UK
| | - Paul Little
- Primary Care and Population Sciences, University of Southampton, Southampton, UK
| | - George Lewith
- Primary Care and Population Sciences, University of Southampton, Southampton, UK
| | - Felicity L Bishop
- Primary Care and Population Sciences, University of Southampton, Southampton, UK
- Centre for Clinical and Community Applications of Health Psychology, University of Southampton, Southampton, UK
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Nagai K, Matsubayashi K, Ide K, Seto K, Kawasaki Y, Kawakami K. Factors Influencing Placebo Responses in Rheumatoid Arthritis Clinical Trials: A Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Studies. Clin Drug Investig 2020; 40:197-209. [PMID: 31953723 DOI: 10.1007/s40261-020-00887-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND OBJECTIVE A better understanding of placebo responses and the specific factors influencing these outcomes is important for clinical trial design. We investigated the magnitude of placebo responses at 3 months and the potential factors influencing these outcomes in rheumatoid arthritis (RA) clinical trials. METHODS We conducted a systematic review of randomized placebo-controlled trials of pharmacological agents for RA identified from PubMed, Embase, and Cochrane Central Register of Controlled Trials databases. The primary placebo outcome was American College of Rheumatology 20% response rate (ACR20). Data were pooled with a random-effects model. Factors influencing placebo response were assessed by meta-regression analyses. Subgroup analyses were performed for studies conducted in non-Western countries only versus in Western countries (North America and/or Europe) only or both. RESULTS The meta-analysis included 88 studies comprising 8406 patients receiving a placebo. The pooled estimate of placebo ACR20 was 29.0% (range 10.0-46.2; 95% confidence interval 27.2-30.9). Placebo ACR20 was negatively associated with trials in non-Western (Asian) countries and patient populations showing an inadequate response to biological disease-modifying antirheumatic drugs (DMARDs) in the multivariable analysis, whereas it was positively associated with the year of publication. No background DMARD treatment was also a negative predictor (albeit statistically non-significant). In subgroup analyses of Western and multiregional studies, study population and publication year were significant factors. CONCLUSIONS Our meta-analysis suggests that study location, patient population, and a background DMARD treatment influence placebo ACR20. These along with placebo response temporal profiles have important implications for designing and interpreting RA clinical trials.
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Affiliation(s)
- Kota Nagai
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
- Eisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo, 112-8088, Japan
| | - Keisuke Matsubayashi
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Kazuki Ide
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
- Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, 606-8501, Japan
| | - Kahori Seto
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Yohei Kawasaki
- Biostatistics Section, Clinical Research Center, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8677, Japan
| | - Koji Kawakami
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
- Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, 606-8501, Japan.
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The effect of lid hygiene on the tear film and ocular surface, and the prevalence of Demodex blepharitis in university students. Cont Lens Anterior Eye 2019; 43:159-168. [PMID: 31548151 DOI: 10.1016/j.clae.2019.09.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 08/26/2019] [Accepted: 09/10/2019] [Indexed: 01/10/2023]
Abstract
AIM To evaluate the effect blepharitis lid cleansers have on the tear film and ocular surface, and to examine the prevalence of Demodex folliculorum in a young population. METHODS Forty-eight university students completed a randomised, controlled, investigator-masked, eight-week clinical trial. Three eyelid hygiene products were investigated: blepharitis eyelid cleanser (OCuSOFT® Lid Scrub® PLUS foam), diluted baby shampoo (10% Johnson's® No More Tears ®) and a tea-tree based face wash (dr.organic®). Cooled boiled water was used as a control. Subjects attended for four visits: baseline, two weeks, four weeks and eight weeks. At each visit, subjective symptoms, non-invasive tear break up time, ocular surface staining and Demodex folliculorum investigation were assessed to evaluate any positive or negative effect on the tear film and ocular surface. Osmolarity was also measured at baseline and week eight only. RESULTS The overall prevalence of Demodex folliculorum found at baseline was 15%. Subjective symptoms improved in all groups, including control. There was no significant difference in mean osmolarity between the groups or within each group after eight weeks. There was a significant increase in osmolarity inter-eye variability in the baby shampoo group (5.5 ± 5.4 vs 15.2 ± 9.5; p = 0.03). There was no significant change in non-invasive tear break up time or ocular surface staining demonstrated after eight weeks of eyelid hygiene. CONCLUSION A low prevalence of Demodex folliculorum can be found in a young population. All blepharitis lid cleansers used demonstrated subjective improvement in symptoms, with no negative effects on tear break-up time or ocular surface staining. The blepharitis eyelid cleanser and tea-tree based face wash revealed no adverse effect on mean osmolarity or inter-eye variability. Similarly, baby shampoo did not cause a significant increase in mean osmolarity, however, a significant increase in inter-eye variability was found; suggesting a possible increase in ocular surface inflammation.
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Nelson DH, Perchaluk JM, Logan AC, Katzman MA. The Bell Tolls for Homeopathy: Time for Change in the Training and Practice of North American Naturopathic Physicians. J Evid Based Integr Med 2019; 24:2515690X18823696. [PMID: 30789055 PMCID: PMC6343431 DOI: 10.1177/2515690x18823696] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
North American naturopathic medicine is a distinct form of practice that is woven into the larger fabric of integrative medicine; in a number of US states and Canadian provinces, naturopathic doctors enjoy a wide scope of practice, including the ability to make diagnoses, order tests, use medical technology, write prescription drugs, and perform minor surgeries. However, the basic premise of naturopathic medicine and its guiding principles-considering the whole person and supporting healthy lifestyle behaviors-is the unifying approach in clinical practice. In the 1970s, homeopathy-considered in many circles to be a hypothesis-driven, fringe form of alternative medicine-became embedded into the training and practice of North American naturopathic doctors. Since the earliest days of its theory (circa 1800), homeopathy has escaped, and continues to escape, biological plausibility; however, the persistence of this modality (and the insistence by both its consumers and practitioners that it provides benefit) speaks to the role of expectations, beliefs, values, agency, context effects, and the placebo-at-large. It is our contention that the progression of professional naturopathic medicine in the 21st century requires a major transition in how it approaches the subject of homeopathy. We propose that students should be encouraged to critically analyze the tenets of homeopathy, its lesser known history, and the idea of homeopathy as a biomedicine that simply awaits untold chemicophysical mechanisms. Furthermore, the modality of homeopathy should be incorporated into the larger context of placebo studies, narrative medicine, ethics, and psychotherapeutic techniques.
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Affiliation(s)
- David H Nelson
- 1 Canadian College of Naturopathic Medicine, Toronto, Ontario, Canada
| | | | - Alan C Logan
- 3 inVIVO Planetary Health, Research Group of the Worldwide Universities Network (WUN), West New York, NJ, USA
| | - Martin A Katzman
- 4 The Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada
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Antonelli M, Donelli D. Reinterpreting homoeopathy in the light of placebo effects to manage patients who seek homoeopathic care: A systematic review. HEALTH & SOCIAL CARE IN THE COMMUNITY 2019; 27:824-847. [PMID: 30456773 DOI: 10.1111/hsc.12681] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 10/10/2018] [Accepted: 10/12/2018] [Indexed: 06/09/2023]
Abstract
Homoeopathy is widespread, and users claim to benefit from it. However, clear evidence of its efficacy over placebo is not available to date. As a consequence, a social separation between homoeopathy users and mainstream medicine exists, exposing these patients to many risks. Our primary objective is to assess homoeopathy efficacy by systematically reviewing existing systematic reviews and meta-analyses and to systematically review trials on open-label placebo (OLP) treatments. A secondary objective is to understand if homoeopathy as a whole may be considered as a placebo treatment. PubMed/Medline, Embase, Google Scholar, and Cochrane Library were systematically searched for systematic reviews and meta-analyses on homoeopathy efficacy, and 61 studies were included. Same databases plus Journal of Interdisciplinary Placebo Studies (JIPS) were also systematically searched for randomised controlled trials (RCTs) on OLP treatments, and 10 studies were included. Databases were searched up to 24 February 2018. Two authors independently screened all retrieved articles and selected studies eligible for inclusion. The quality of reviews of included studies was evaluated with a dedicated NIH tool in the first review, whereas the risk of bias of trials of included studies was assessed with the specific Cochrane tool in the second review. Qualitative syntheses show that homoeopathy efficacy can be considered comparable to placebo, and that OLP treatments may be effective in some health conditions. Placebo effects like placebo itself, treatment context, physician-patient relationship, and other nonspecific factors can define the idea of placebo treatments, which may be effective in some conditions. If homoeopathy efficacy is comparable to placebo, and if placebo treatments can be effective in some conditions, then homoeopathy as a whole may be considered as a placebo treatment. Reinterpreting homoeopathy as a placebo treatment would define limits and possibilities of this practice. This perspective shift suggests a strategy to manage patients who seek homoeopathic care and to reconcile them with mainstream medicine in a sustainable way.
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Affiliation(s)
- Michele Antonelli
- Department of Medicine and Surgery, Institute of Public Health, University of Parma, Parma, Italy
- Terme di Monticelli, Parma, Italy
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Bishop FL, Greville-Harris M, Bostock J, Din A, Graham CA, Lewith G, Liossi C, O'Riordan T, White P, Yardley L. Informing Adults With Back Pain About Placebo Effects: Randomized Controlled Evaluation of a New Website With Potential to Improve Informed Consent in Clinical Research. J Med Internet Res 2019; 21:e9955. [PMID: 30664462 PMCID: PMC6354200 DOI: 10.2196/jmir.9955] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 08/28/2018] [Accepted: 10/04/2018] [Indexed: 12/12/2022] Open
Abstract
Background Placebo effects and their underpinning mechanisms are increasingly well understood. However, this is poorly communicated to participants in placebo-controlled trials. For valid informed consent, participants should be informed about the potential benefits and risks of participating in placebo-controlled trials. Existing information leaflets often fail to describe the potential benefits and adverse effects associated with placebo allocation. This study tested the effects of a new website designed to inform patients about placebo effects (The Power of Placebos, PoP). PoP was designed using qualitative methods in combination with theory- and evidence-based approaches to ensure it was engaging, informative, and addressed patients’ concerns. Objective This study aimed to test the effects of PoP, compared with a control website, on people’s knowledge about placebo and the ability to make an informed choice about taking part in a placebo-controlled trial. Methods A total of 350 adults with back pain recruited from 26 general practices in Southern England participated in this Web-based study. Participants were randomly assigned to PoP (which presented scientifically accurate information about placebo effects in an engaging way) or a control website (based on existing information leaflets from UK trials). Participants self-completed Web-based pre- and postintervention questionnaire measures of knowledge about placebo effects and preintervention questionnaire measures of attitudes toward and intentions to participate in a placebo-controlled trial. The 2 primary outcomes were (1) knowledge and (2) informed choice to take part in a placebo-controlled trial (computed from knowledge, attitudes, and intentions). Results After viewing PoP, participants had significantly greater knowledge about placebos (mean 8.28 [SD 1.76]; n=158) than participants who viewed the control (mean 5.60 [SD 2.24]; n=174; F1,329=173.821; P<.001; η2=.346). Participants who viewed PoP were 3.16 times more likely than those who viewed the control to make an informed choice about placebos (χ21=36.5; P<.001). Conclusions In a sample of adults with back pain, PoP increased knowledge and rates of informed choice about placebos compared with a control website. PoP could be used to improve knowledge about placebo effects in back pain. After essential further development and testing in clinical trial settings, it could support informed consent in placebo-controlled trials.
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Affiliation(s)
- Felicity L Bishop
- Department of Psychology, University of Southampton, Southampton, United Kingdom
| | | | - Jennifer Bostock
- Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
| | - Amy Din
- Centre for Innovation & Leadership in Health Sciences, School of Health Sciences, University of Southampton, Southampton, United Kingdom
| | - Cynthia A Graham
- Department of Psychology, University of Southampton, Southampton, United Kingdom
| | - George Lewith
- Primary Care and Population Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Christina Liossi
- Department of Psychology, University of Southampton, Southampton, United Kingdom
| | | | - Peter White
- Centre for Innovation & Leadership in Health Sciences, School of Health Sciences, University of Southampton, Southampton, United Kingdom
| | - Lucy Yardley
- Department of Psychology, University of Southampton, Southampton, United Kingdom.,School of Psychological Science, Faculty of Life Sciences, University of Bristol, Bristol, United Kingdom
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Hamberger J, Meissner K, Hinterberger T, Loew T, Weimer K. Placebo Economics: A Systematic Review About the Economic Potential of Utilizing the Placebo Effect. Front Psychiatry 2019; 10:653. [PMID: 31572237 PMCID: PMC6751772 DOI: 10.3389/fpsyt.2019.00653] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 08/13/2019] [Indexed: 12/12/2022] Open
Abstract
Background: Recent research shows that placebo mechanisms can be utilized in ethical and legal ways such as in open-label conditions, when patients know that they receive placebos, and through psychological interventions aiming to optimize patients' expectations. Showing that placebo interventions are also cost-efficient could improve their acceptability. Objective: To review studies that performed health economic evaluations (HEEs) of intentional placebo interventions and to review studies that intentionally applied placebo interventions and reported outcomes eligible for HEEs. Methods: Two systematic reviews of the literature were performed. For the first review, we searched MEDLINE using "placebo" and Medical Subject Headings (MeSH) terms associated with HEEs such as "costs," "cost-benefit analyses," and "economics." Studies were eligible if they employed patients, applied placebo interventions, included an appropriate control group, and reported results of cost analyses. For the second review, we searched the Journal of Interdisciplinary Placebo Studies (JIPS) database and MEDLINE using search terms for outcomes eligible for cost-utility analyses, such as "quality of life" or "quality-adjusted life years" ("QALYs"). Risk of bias of all studies found was assessed according to the Cochrane Handbook, and a narrative synthesis of the results is provided. Results: The first search resulted in 1,853 articles, which were screened for eligibility. Two studies were found only in which costs or cost-effectiveness analysis were reported, but with medium to high risks of biases. The second search yielded 164 articles particularly from the JIPS database of which 11 studies met our search criteria: in six studies, patients received placebo pills in open-label conditions; three studies investigated effects of patient-physician relationships; and two studies used psychological interventions to optimize treatment expectations, in patients with various diseases and disorders. These studies report outcomes potentially eligible for HEEs when costs of interventions were known. Risks of biases were low to medium, but patients were not blinded to the conditions in most studies. Conclusions: The state of knowledge about HEEs of placebo interventions is scarce. To gain more visibility and acceptability for placebo interventions, future studies should measure outcomes usable for HEEs and costs of interventions, and HEEs should be performed for existing studies if data are available.
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Affiliation(s)
- Jens Hamberger
- Department of Psychosomatic Medicine, University Clinic Regensburg, Regensburg, Germany.,Division of Health Promotion, University of Applied Sciences Coburg, Coburg, Germany
| | - Karin Meissner
- Division of Health Promotion, University of Applied Sciences Coburg, Coburg, Germany.,Institute of Medical Psychology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Thilo Hinterberger
- Department of Psychosomatic Medicine, University Clinic Regensburg, Regensburg, Germany
| | - Thomas Loew
- Department of Psychosomatic Medicine, University Clinic Regensburg, Regensburg, Germany
| | - Katja Weimer
- Department of Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, Ulm, Germany
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Tuchina OD, Agibalova TV, Shustov DI, Shustova SA, Buzik ОG, Petrosyan YE. [The practical use of placebo effect in psychotherapeutic treatment of patients with substance use disorders: therapeutic and ethic consequences]. Zh Nevrol Psikhiatr Im S S Korsakova 2018; 116:61-68. [PMID: 28300816 DOI: 10.17116/jnevro201611611261-68] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The article discusses therapeutic potential of placebo and nocebo effects in treatment of substance use disorders. The authors review the background of the issue, describe neurobiological and psychological mechanisms of placebo effects and demonstrate their impact on psychotherapy of patients with substance use disorders. Attention is drawn to the clinical and ethical issues of practical use of placebo effects including that in terms of placebo-therapy, indirect suggestion psychotherapy, motivational interventions and cognitive-behavioral psychotherapy, psychotherapy with the use of disulfiram, psychopharmacotherapy with opioid antagonists. The authors conclude that the ethical use of placebo-effects in treatment of substance use disorders may improve its overall efficiency.
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Affiliation(s)
- O D Tuchina
- Peoples' Friendship University of Russia, Moscow, Russia
| | - T V Agibalova
- Peoples' Friendship University of Russia, Moscow, Russia; Serbsky Federal Medical Research Center for Psychiatry and Narcology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - D I Shustov
- Academician Pavlov Ryazan State Medical University, Ryazan, Russia
| | - S A Shustova
- Academician Pavlov Ryazan State Medical University, Ryazan, Russia
| | - О G Buzik
- Peoples' Friendship University of Russia, Moscow, Russia
| | - Yu E Petrosyan
- Peoples' Friendship University of Russia, Moscow, Russia
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48
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Placebos Without Deception: Outcomes, Mechanisms, and Ethics. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2018; 138:219-240. [PMID: 29681327 DOI: 10.1016/bs.irn.2018.01.005] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Scientific research indicates that open-label and dose-extending placebos (that patients know are placebos) can elicit behavioral, biological, and clinical outcome changes. In this chapter, we present the state-of-the-art evidence and ethical considerations about open-label and dose-extending placebos, discussing the perspective of giving placebos with a rational, as dose extension of active drugs, or expectancy boosters. Previous comprehensive reviews of placebo use have considered how to harness placebo effects in medicine and the need to focus on elements of the clinical encounter as well as patient-clinician relations. Here, we illustrate the similarities and differences between standard (deceptive) placebos, open-label placebos and dose-extending placebos. We conclude that placebos without deception would override ethical barriers to their clinical use. This paves the way to future large-scale, pragmatic randomized trials that investigate the potential of ethical open-label and dose-extending placebos to improve patients' outcomes, and reduce side effects.
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Carlino E, Vase L. Can knowledge of Placebo and Nocebo Mechanisms Help Improve Randomized Clinical Trials? INTERNATIONAL REVIEW OF NEUROBIOLOGY 2018; 138:329-357. [PMID: 29681333 DOI: 10.1016/bs.irn.2018.01.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Over the last decade, there has been a substantial increase in negative results from randomized controlled trials (RCTs), which may be due to an increasing placebo response among other factors. Currently, identification and exclusion of placebo responders from trials are attempted to overcome this problem, but so far the success of these approaches has been limited. At the same time, the placebo-mechanism literature has highlighted how contextual factors, such as patients' expectations, interfere with the effect of drug administration, leading to a certain degree of uncertainty in RCTs. In this chapter, we review the current challenges of RCTs including the uncertainties of the active arm, the placebo arm, the additivity assumption, and the double-blind procedure. We use the placebo-mechanism literature to debate the strengths and weaknesses of attempts to identify and exclude placebo responders from trials. Finally, we illustrate how insights from the placebo-mechanism literature may point to new ways of improving RCTs.
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Affiliation(s)
| | - Lene Vase
- School of Business and Social Sciences, Aarhus University, Aarhus, Denmark.
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McCullough RW. Practice insights on patient care-management overview for chemoradiation toxic mucositis-guidelines, guideline-supported therapies and high potency polymerized cross-linked sucralfate (ProThelial). J Oncol Pharm Pract 2018; 25:409-422. [PMID: 29460703 DOI: 10.1177/1078155218758864] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
AIM To offer a practice insight for the management of chemoradiation toxic mucositis. METHOD Review chemoradiation toxic mucositis, its pathobiology and breadth of symptom presentation. Review mucositis guidelines and guideline-supported anti-mucositis therapies. Offer guidance on guidelines and an abbreviated review of high potency cross-linked sucralfate for management of chemoradiation toxic mucositis. RESULT There are six major mucositis guidelines but only one that is current and regularly updated. Guidelines from the Multinational Association Supportive Cancer Care suggest 14 interventions gleaned from controlled trials, 12 of which are off-label uses of therapies that offer statistically significant but incrementally beneficial outcomes. Several evidence-based limitations of guidelines are discussed. Data on high potency polymerized cross-linked sucralfate confirming complete prevention and rapid (2-3 days) elimination, sustained throughout cancer treatment is verified as high quality evidence in accordance to standards adopted by Agency for Healthcare Research and Quality. A 96-97% reduction in mucositis duration qualifies as a positive Glasziou treatment effect, which is discussed as an additional measure of evidence-based medicine. CONCLUSION Statistically significant but fractional treatment effects of guideline-supported interventions are not likely to substantially alter the course of mucositis when it occurs nor completely prevent its onset. Complete prevention and rapid sustained elimination should be the goal, therefore high potency polymerized cross-linked sucralfate may be useful. Where guidelines fail, institution-based protocols led by oncology pharmacists could succeed. In an effort to eliminate toxic mucositis, enhance compliance to chemoradiation regimens, and improve survival, such protocols for practice may verify pharmacoeconomic benefits, if any, in using high potency polymerized cross-linked sucralfate to manage toxic mucositis.
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Affiliation(s)
- Ricky W McCullough
- 1 Medical Research, Translational Medicine Clinic & Research Center, Storrs, CT, USA.,2 Veterans Administration Medical Center, Department of Medicine, Emergency Division, Brown University School of Medicine, Providence, RI, USA
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