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Raghuraman N, White JN, Watson L, Belleï-Rodriguez CÉ, Shafir R, Wang Y, Colloca L. Neuropsychological mechanisms of observational learning in human placebo effects. Psychopharmacology (Berl) 2025; 242:889-900. [PMID: 38743108 PMCID: PMC11561162 DOI: 10.1007/s00213-024-06608-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 05/02/2024] [Indexed: 05/16/2024]
Abstract
Scientific evidence indicates that placebo effects are psychoneurobiological events involving the contribution of distinct central nervous systems and peripheral physiological mechanisms that influence pain perception and other symptoms. Placebo effects can occur without formal conditioning and direct prior experience because crucial information can be acquired through observational learning. Observation of benefits in another person results in placebo effects of a magnitude like those induced by directly experiencing an analgesic benefit. Understanding the psychological mechanisms of observationally induced placebo effects is a complex and multifaceted endeavor. While previous reviews have highlighted various frameworks and models to understand these phenomena, the underlying biological mechanisms have been overlooked. We summarize critically current understanding of its behavioral and neural mechanisms. Understanding the neural mechanisms of hypoalgesia driven by observation can serve as a foundation for future development of novel theoretical and methodological approaches and ultimately, applications.
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Affiliation(s)
- Nandini Raghuraman
- Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, MD, USA
- Graduate Program in Life Sciences, Program in Epidemiology and Human Genetics, University of Maryland School of Medicine, Baltimore, MD, USA
- Placebo Beyond Opinions Center, University of Maryland School of Nursing, Baltimore, USA
| | - Jewel N White
- Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, MD, USA
- Placebo Beyond Opinions Center, University of Maryland School of Nursing, Baltimore, USA
- Graduate Program in Life Sciences, Program in Neuroscience, University of Maryland School of Medicine, Baltimore, USA
| | - Lakota Watson
- Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, MD, USA
- Graduate Program in Life Sciences, Program in Neuroscience, University of Maryland School of Medicine, Baltimore, USA
| | | | - Roni Shafir
- Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, MD, USA
- Placebo Beyond Opinions Center, University of Maryland School of Nursing, Baltimore, USA
| | - Yang Wang
- Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, MD, USA
- Placebo Beyond Opinions Center, University of Maryland School of Nursing, Baltimore, USA
- Center to Advance Chronic Pain Research, University of Maryland, Baltimore, USA
| | - Luana Colloca
- Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, MD, USA.
- Placebo Beyond Opinions Center, University of Maryland School of Nursing, Baltimore, USA.
- Center to Advance Chronic Pain Research, University of Maryland, Baltimore, USA.
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Krywuczky F, Kokkoris M, Kleijnen M, Millet K. A laypeople's typology of cosmetic surgeries using cluster analysis. Sci Rep 2025; 15:13415. [PMID: 40251284 PMCID: PMC12008185 DOI: 10.1038/s41598-025-96727-8] [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: 10/07/2024] [Accepted: 03/31/2025] [Indexed: 04/20/2025] Open
Abstract
Interest in cosmetic surgery has been steadily growing, with the term "cosmetic surgery" now serving as a broad label for a diverse array of aesthetic procedures. However, major differences exist between these treatments, raising questions about the validity of grouping them under a single, uniform category. Going beyond prior research that has typically treated cosmetic surgery as a rather homogeneous construct, we examine how people perceive cosmetic procedures and highlight the distinctions they may recognize between them. Using a cluster analysis methodology, we present the first systematic typology of cosmetic surgeries based on the perspective of laypeople. By considering key treatment characteristics such as invasiveness, visibility, and degree of transformation, we identify six distinct types of cosmetic procedures: (1) surgical augmentations, (2) surgical adjustments, (3) surgical reductions, (4) minimally invasive reductions, (5) minimally invasive augmentations, and (6) concealed surgical reductions. This new typology paves the path for future research to explore specific motives and expectations tied to each category, offering more fine-grained insights into the decision-making processes behind cosmetic surgery and a more nuanced understanding of public opinion about these procedures.
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Affiliation(s)
| | - Michail Kokkoris
- Vrije Universiteit Amsterdam, Amsterdam, 1081 HV, The Netherlands
| | - Mirella Kleijnen
- Vrije Universiteit Amsterdam, Amsterdam, 1081 HV, The Netherlands
| | - Kobe Millet
- Vrije Universiteit Amsterdam, Amsterdam, 1081 HV, The Netherlands
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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. A scoping review of placebo and nocebo responses and effects: insights for clinical trials and practice. Health Psychol Rev 2025:1-39. [PMID: 40028813 DOI: 10.1080/17437199.2025.2471792] [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: 11/07/2024] [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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Mulvaney SW, Dineen KJ, Mahadevan S, Desronvilles R, Rae Olmsted KL. Three-Month Durability of Bilateral Two-Level Stellate Ganglion Blocks in Patients with Generalized Anxiety Disorder: A Retrospective Analysis. Brain Sci 2025; 15:188. [PMID: 40002521 PMCID: PMC11853295 DOI: 10.3390/brainsci15020188] [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: 12/11/2024] [Revised: 02/10/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
Purpose: Determine if performing ultrasound-guided, bilateral, two-level cervical sympathetic chain blocks (2LCSB) (performed on subsequent days) provides durable improvement in symptoms associated with anxiety. Methods: A retrospective chart review was conducted between January 2022 and November 2024. We identified 114 patients who received bilateral, 2LCSB for anxiety symptoms. Generalized Anxiety Disorder 7-Item Scale (GAD-7) outcome measure scores were collected at baseline and three-months post procedure in 71 males and 43 females. Results: Out of 114 patients, 99 patients (86.8%) showed a long-lasting improvement in their GAD-7 scores. Collected GAD-7 forms had a baseline average of 15.52 (14.99 for males and 16.40 for females), which decreased after three months to an average of 7.28 (6.96 for males and 7.81 for females). This represents a 52% average improvement in anxiety symptoms. Conclusions: In individuals treated with bilateral, 2LCSB, GAD-related symptoms were improved by 52% for at least 3 months regardless of initial anxiety severity.
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Affiliation(s)
- Sean W. Mulvaney
- Department of Military and Emergency Medicine, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA;
| | - Kyle J. Dineen
- Orthobiologics Research Initiative Inc., 11200 Rockville Pike #230, North Bethesda, MD 20852, USA; (S.M.); (R.D.J.)
| | - Sanjay Mahadevan
- Orthobiologics Research Initiative Inc., 11200 Rockville Pike #230, North Bethesda, MD 20852, USA; (S.M.); (R.D.J.)
| | - Roosevelt Desronvilles
- Orthobiologics Research Initiative Inc., 11200 Rockville Pike #230, North Bethesda, MD 20852, USA; (S.M.); (R.D.J.)
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Shani A, Granot M, Agostinho MR, Rahamimov N, Treister R. The prediction of the analgesic placebo response is moderated by outward-focused attention: A sham, randomized clinical trial of chronic back pain patients. THE JOURNAL OF PAIN 2025; 27:104761. [PMID: 39725051 DOI: 10.1016/j.jpain.2024.104761] [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: 08/01/2024] [Revised: 11/23/2024] [Accepted: 12/17/2024] [Indexed: 12/28/2024]
Abstract
The within-subject variability (WSV) of pain-intensity reports has gained attention as a predictor of the placebo response but has demonstrated mixed results. We hypothesized that participants' inward- and outward-directed attention will moderate WSV's prediction of the analgesic placebo response. In this sham randomized clinical trial (protocol number NCT05994118); placebo response was induced in chronic back-pain patients (n=113) through a saline injection plus verbal suggestion. The WSV assessed by the focused analgesia selection test (FAST) served as a predictor. The revised Self-Consciousness Scale (SCS-R), evaluating a person's tendency to focus attention inward or outward was used to moderate the prediction. The placebo response prediction was significantly moderated by 2 SCS-R subscales: public self-consciousness (b = 46.36, SE = 23.08, t = 2.0, p = 0.047) and social anxiety (b = 44.01, SE = 18.02, t = 2.44, p = 0.016). The prediction was significant at low levels of both moderators (p < 0.01), but not at high levels of these traits. Prediction of the placebo response is of value and could promote personalized medical care. Better understanding of factors shaping the placebo response could further contribute to both clinical practice and clinical trials. PERSPECTIVE: The current study demonstrates that the prediction of the analgesic placebo response could be improved if relevant personal characteristics are included as moderators of the prediction. Better predictions of the placebo response could contribute to improve both clinical research and clinical care.
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Affiliation(s)
- Adi Shani
- The Cheryl Spencer Department of Nursing, Faculty of Social Welfare and Health Sciences, University of Haifa, Mount Carmel, Haifa, Israel; Department of Orthopedics B and Spine Surgery, Galilee Medical Center, Nahariya, Israel; Oncologic Day Care Unit, Galilee Medical Center, Nahariya, Israel
| | - Michal Granot
- The Cheryl Spencer Department of Nursing, Faculty of Social Welfare and Health Sciences, University of Haifa, Mount Carmel, Haifa, Israel
| | - Mariana Ribolhos Agostinho
- The Cheryl Spencer Department of Nursing, Faculty of Social Welfare and Health Sciences, University of Haifa, Mount Carmel, Haifa, Israel; CIIS, Centre for Interdisciplinary Health Research, Faculty of Health Sciences and Nursing, Universidade Católica Portuguesa, Lisbon, Portugal
| | - Nimrod Rahamimov
- Department of Orthopedics B and Spine Surgery, Galilee Medical Center, Nahariya, Israel; Faculty of Medicine, Bar Ilan Medical School, Tsfat, Israel
| | - Roi Treister
- The Cheryl Spencer Department of Nursing, Faculty of Social Welfare and Health Sciences, University of Haifa, Mount Carmel, Haifa, Israel.
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Busl KM, Smith CR, Troxel AB, Fava M, Illenberger N, Pop R, Yang W, Frota LM, Gao H, Shan G, Hoh BL, Maciel CB. Rationale and Design for the BLOCK-SAH Study (Pterygopalatine Fossa Block as an Opioid-Sparing Treatment for Acute Headache in Aneurysmal Subarachnoid Hemorrhage): A Phase II, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial with a Sequential Parallel Comparison Design. Neurocrit Care 2025; 42:290-300. [PMID: 39138719 PMCID: PMC11810580 DOI: 10.1007/s12028-024-02078-z] [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: 05/10/2024] [Accepted: 07/09/2024] [Indexed: 08/15/2024]
Abstract
BACKGROUND Acute post-subarachnoid hemorrhage (SAH) headaches are common and severe. Management strategies for post-SAH headaches are limited, with heavy reliance on opioids, and pain control is overall poor. Pterygopalatine fossa (PPF) nerve blocks have shown promising results in treatment of acute headache, including our preliminary and published experience with PPF-blocks for refractory post-SAH headache during hospitalization. The BLOCK-SAH trial was designed to assess the efficacy and safety of bilateral PPF-blocks in awake patients with severe headaches from aneurysmal SAH who require opioids for pain control and are able to verbalize pain scores. METHODS BLOCK-SAH is a phase II, multicenter, randomized, double-blinded, placebo-controlled clinical trial using the sequential parallel comparison design (SPCD), followed by an open-label phase. RESULTS Across 12 sites in the United States, 195 eligible study participants will be randomized into three groups to receive bilateral active or placebo PPF-injections for 2 consecutive days with periprocedural monitoring of intracranial arterial mean flow velocities with transcranial Doppler, according to SPCD (group 1: active block followed by placebo; group 2: placebo followed by active block; group 3: placebo followed by placebo). PPF-injections will be delivered under ultrasound guidance and will comprise 5-mL injectates of 20 mg of ropivacaine plus 4 mg of dexamethasone (active PPF-block) or saline solution (placebo PPF-injection). CONCLUSIONS The trial has a primary efficacy end point (oral morphine equivalent/day use within 24 h after each PPF-injection), a primary safety end point (incidence of radiographic vasospasm at 48 h from first PPF-injection), and a primary tolerability end point (rate of acceptance of second PPF-injection following the first PPF-injection). BLOCK-SAH will inform the design of a phase III trial to establish the efficacy of PPF-block, accounting for different headache phenotypes.
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Affiliation(s)
- Katharina M Busl
- Department of Neurology, College of Medicine, University of Florida, McKnight Brain Institute, L3-100, 1149 Newell Drive, Gainesville, FL, 32608, USA.
- Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, FL, USA.
| | - Cameron R Smith
- Department of Anesthesiology, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Andrea B Troxel
- Department of Population Health, New York University Grossman School of Medicine, New York, NY, USA
| | - Maurizio Fava
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
| | - Nicholas Illenberger
- Department of Population Health, New York University Grossman School of Medicine, New York, NY, USA
| | - Ralisa Pop
- Department of Neurology, College of Medicine, University of Florida, McKnight Brain Institute, L3-100, 1149 Newell Drive, Gainesville, FL, 32608, USA
| | - Wenqing Yang
- Department of Population Health, New York University Grossman School of Medicine, New York, NY, USA
| | - Luciola Martins Frota
- Department of Neurology, College of Medicine, University of Florida, McKnight Brain Institute, L3-100, 1149 Newell Drive, Gainesville, FL, 32608, USA
| | - Hanzhi Gao
- Department of Biostatistics, University of Florida, Gainesville, FL, USA
| | - Guogen Shan
- Department of Biostatistics, University of Florida, Gainesville, FL, USA
| | - Brian L Hoh
- Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Carolina B Maciel
- Department of Neurology, College of Medicine, University of Florida, McKnight Brain Institute, L3-100, 1149 Newell Drive, Gainesville, FL, 32608, USA
- Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, FL, USA
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Sawang S, Kimpee P, Itthichaikulthol W, Tontisirin N, Limpoon S, Seangrung R, Pasutharnchat K, Cohen SP. Analgesic effectiveness of methoxyflurane inhaler during genicular nerve block in knee osteoarthritis: a randomized controlled trial. Reg Anesth Pain Med 2024:rapm-2024-105777. [PMID: 39174051 DOI: 10.1136/rapm-2024-105777] [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: 06/17/2024] [Accepted: 08/07/2024] [Indexed: 08/24/2024]
Abstract
BACKGROUND Up to 30% of patients with knee osteoarthritis (KOA) have evidence of sensitization, with a similar proportion experiencing severe pain during procedures. Most patients with KOA are elderly and often develop side effects from intravenous sedation. Our study investigated the effectiveness of a methoxyflurane inhaler combined with local anesthesia in reducing procedural pain from genicular nerve block compared with local anesthesia alone. METHODS 42 adults with refractory KOA were randomized into two groups. Methoxyflurane group received a self-titrated methoxyflurane inhaler with local anesthesia whereas lidocaine group received local anesthesia only. The primary outcome was pain score on a 0-10 verbal numerical rating scale (VNRS) during the procedure. Secondary outcomes included changes in VNRS and behavioral pain scale (critical care pain observational tool) during the procedure, hemodynamic changes, anxiety level, sedation score, and adverse events. RESULTS 42 patients with a mean age of 66±12 years participated in this study. There were no significant baseline differences. During the procedure, the methoxyflurane group experienced a significantly greater VNRS pain reduction from baseline (2 (1, 4) vs -1 (-2, 0); p<0.01) and greater VNRS reduction over time (p=0.01) compared with the lidocaine group, with a higher sedation score (p<0.01). Immediately postprocedure, anxiety levels were lower in the methoxyflurane group compared with the lidocaine group (median State-Trait Anxiety Inventory score 21 (IQR 20, 24) vs 27 (23, 29); p=0.02), but the median reduction in anxiety level was not significant (6 (1, 12) vs 5 (0, 14); p=0.61). There were no differences in behavioral pain scores, hemodynamic parameters, recovery or discharge times, and adverse effects between the two groups. CONCLUSION A methoxyflurane inhaler combined with local anesthesia provided better procedural pain control than local anesthesia alone with no observable differences in adverse effects. Future studies evaluating the impact of a methoxyflurane inhaler on different types of painful procedures are warranted.
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Affiliation(s)
- Saowanee Sawang
- Department of Anesthesiology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Pretimon Kimpee
- Chakri Naruebodindra Medical Institute (CNMI), Mahidol University, Bang Phli, Samut Prakan, Thailand
| | - Wichai Itthichaikulthol
- Department of Anesthesiology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Nuj Tontisirin
- Department of Anesthesiology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Suwimon Limpoon
- Department of Anesthesiology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Rattaphol Seangrung
- Department of Anesthesiology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Koravee Pasutharnchat
- Department of Anesthesiology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Steven Paul Cohen
- Department of Anesthesiology, Physical Medicine & Rehabilitation, Neurology, Psychiatry and Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
- Physical Medicine & Rehabilitation and Anesthesiology, Uniformed Services University, Bethesda, Maryland, USA
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Huang YB, Yuan L, Xiao XY, Wang XY, Feng SJ, Zheng H. Effect of different non-pharmacologic placebo treatments on migraine prevention: a network meta-analysis of randomized controlled trials. Acta Neurol Belg 2024; 124:1125-1139. [PMID: 38245660 DOI: 10.1007/s13760-023-02460-2] [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: 09/05/2023] [Accepted: 12/08/2023] [Indexed: 01/22/2024]
Abstract
BACKGROUND Placebo control plays an important role in evaluating the effectiveness of interventions. Specifying differential effects of various placebo controls on migraine prevention would be essential in the explanation of preventive treatment for migraine and the indirect comparison between different prophylactic therapeutics. OBJECTIVES To access the impact of different non-pharmacologic placebo types on different outcomes in migraine patients. METHODS We searched PubMed, Cochrane Controlled Register of Trials, Embase, and Web of Science databases from the date of creation to June 19, 2023. Randomized controlled trials of migraine that included sham intervention of acupuncture or cognitive behavioural therapy (CBT) or non-invasive Vagus Nerve Stimulation (nVNS) or repetitive Transcranial Magnetic Stimulation (rTMS) or transcranial Direct Current Stimulation (tDCS) were conducted. The primary outcome was the migraine days, and the secondary outcomes were the number of migraine attacks, headache days, headache frequency, and responder's rate. Placebo effects were assessed using five individual placebos for network meta-analysis, using mean differences to measure the relative effect of pair-wise comparisons between interventions. RESULT A total of 50 trials with 4880 subjects were included. Twenty-seven trials were evaluated for low risk of bias. The results of indirect comparisons show that sham rTMS and sham tDCS had optimal and similar effects in reducing migraine days; sham acupuncture has the greatest effect on reducing the number of migraine attacks and relieving headache frequency; sham rTMS had a highly significant advantage in reducing headache days compared with the other placebo controls. CONCLUSION Based on the network meta-analysis results, we found that sham acupuncture had the greatest effect on migraine prophylaxis. The strong placebo effect of sham acupuncture should be considered when assessing the therapeutic effect.
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Affiliation(s)
- Yan-Bing Huang
- The Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, No. 1166 Liutai Avenue, Wenjiang District, Chengdu, 611100, China
| | - Lu Yuan
- The Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, No. 1166 Liutai Avenue, Wenjiang District, Chengdu, 611100, China
| | - Xin-Yu Xiao
- The Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, No. 1166 Liutai Avenue, Wenjiang District, Chengdu, 611100, China
| | - Xiao-Ying Wang
- The Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, No. 1166 Liutai Avenue, Wenjiang District, Chengdu, 611100, China
| | - Si-Jia Feng
- The Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, No. 1166 Liutai Avenue, Wenjiang District, Chengdu, 611100, China
| | - Hui Zheng
- The Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, No. 1166 Liutai Avenue, Wenjiang District, Chengdu, 611100, China.
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Pozo-Rosich P, Dolezil D, Paemeleire K, Stepien A, Stude P, Snellman J, Arkuszewski M, Stites T, Ritter S, Lopez Lopez C, Maca J, Ferraris M, Gil-Gouveia R. Early Use of Erenumab vs Nonspecific Oral Migraine Preventives: The APPRAISE Randomized Clinical Trial. JAMA Neurol 2024; 81:461-470. [PMID: 38526461 PMCID: PMC10964163 DOI: 10.1001/jamaneurol.2024.0368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 12/13/2023] [Indexed: 03/26/2024]
Abstract
Importance Patients with migraine often cycle through multiple nonspecific preventive medications due to poor tolerability and/or inadequate efficacy leading to low adherence and increased disease burden. Objective To compare the efficacy, tolerability, patient adherence, and patient satisfaction between erenumab and nonspecific oral migraine preventive medications (OMPMs) in patients with episodic migraine (EM) who had previously failed 1 or 2 preventive treatments. Design, Setting, and Participants The 12-month prospective, interventional, global, multicenter, active-controlled, randomized clinical trial comparing sustained benefit of 2 treatment paradigms (erenumab qm vs oral prophylactics) in adult episodic migraine patients (APPRAISE) trial was a 12-month open-label, multicenter, active-controlled, phase 4 randomized clinical trial conducted from May 15, 2019, to October 1, 2021. This pragmatic trial was conducted at 84 centers across 17 countries. Overall, participants 18 years or older with a 12-month or longer history of migraine, and 4 or more but fewer than 15 monthly migraine days (MMDs) were included. Interventions Patients were randomized (2:1) to receive erenumab or OMPMs. Dose adjustment was permitted (label dependent). Main Outcomes and Measures The primary end point was the proportion of patients completing 1 year of the initially assigned treatment and achieving a reduction of 50% or greater from baseline in MMDs at month 12. Secondary end points included the cumulative mean change from baseline in MMDs during the treatment period and the proportion of responders according to the Patients' Global Impression of Change (PGIC) scale at month 12 for patients taking the initially assigned treatment. Results A total of 866 patients were screened, of whom 245 failed the screening and 621 completed the screening and baseline period. Of the 621 randomized patients (mean [SD] age, 41.3 [11.2] years; 545 female [87.8%]; 413 [66.5%] in the erenumab group; 208 [33.5%] in the OMPM group), 523 (84.2%) completed the treatment phase, and 98 (15.8%) discontinued the study. At month 12, significantly more patients assigned to erenumab vs OMPM achieved the primary end point (232 of 413 [56.2%] vs 35 of 208 [16.8%]; odds ratio [OR], 6.48; 95% CI, 4.28-9.82; P <.001). Compared with OMPMs, treatment with erenumab showed higher responder rate (314 of 413 [76.0%] vs 39 of 208 [18.8%]; OR, 13.75; 95% CI, 9.08-20.83; P <.001) on the PGIC scale (≥5 at month 12). Significant reduction in cumulative average MMDs was reported with erenumab treatment vs OMPM treatment (-4.32 vs -2.65; treatment difference [SE]: -1.67 [0.35] days; P < .001). Substantially fewer patients in the erenumab arm compared with the OMPM arm switched medication (9 of 413 [2.2%] vs 72 of 208 [34.6%]) and discontinued treatment due to adverse events (12 of 408 [2.9%] vs 48 of 206 [23.3%]). No new safety signals were identified. Conclusions and Relevance Results of this randomized clinical trial demonstrated that earlier use of erenumab in patients with EM who failed 1 or 2 previous preventive treatments provided greater and sustained efficacy, safety, and adherence than continuous OMPM. Trial Registration ClinicalTrials.gov Identifier: NCT03927144.
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Affiliation(s)
- Patricia Pozo-Rosich
- Headache and Neurological Pain Research Group, Vall d’Hebron Institute of Research (VHIR), Department of Medicine, Universitat Autònoma de Barcelona, Spain
- Headache Unit, Neurology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain
| | - David Dolezil
- Headache Center, Dado Medical sro, Prague, Czech Republic
| | - Koen Paemeleire
- Department of Neurology, Ghent University Hospital, Ghent, Belgium
| | - Adam Stepien
- Department of Neurology, Military Institute of Medicine-National Research Institute, Warsaw, Poland
| | | | | | | | - Tracy Stites
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey
| | - Shannon Ritter
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey
| | | | - Jeff Maca
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey
| | | | - Raquel Gil-Gouveia
- Hospital da Luz Headache Center, Neurology Department, Hospital da Luz, Lisboa, Portugal
- Center for Interdisciplinary Research in Health, Universidade Católica Portuguesa, Lisboa, Portugal
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Reis G, Savassi LCM, Ferreira TS, Reis LLF, Simplicio MIC, Ribeiro LB, Silva EADSM, Lat PK, Harari O, Forrest JI, Dron L, Park JJH, Thorlund K, Mills EJ. Matched vs Nonmatched Placebos in a Randomized Trial of COVID-19 Treatments. JAMA Netw Open 2024; 7:e2410335. [PMID: 38767921 PMCID: PMC11107303 DOI: 10.1001/jamanetworkopen.2024.10335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 03/07/2024] [Indexed: 05/22/2024] Open
Abstract
Importance Matched placebo interventions are complex and resource intensive. Recent evidence suggests matched placebos may not always be necessary. Previous studies have predominantly evaluated potential bias of nonmatched placebos (ie, differing on dose, frequency of administration, or formulation) in pain and mental health, but to date no systematic examination has been conducted in infectious disease. Objective To test for differences between nonmatched and matched placebo arms with respect to clinical outcome measures across multiple therapeutics for COVID-19. Design, Setting, and Participants In a comparative effectiveness research study, a post hoc analysis was conducted of data on individual patients enrolled in a large, multiarm, platform randomized clinical trial in symptomatic adult outpatients with COVID-19 between January 15, 2021, to September 28, 2023, in which the outcomes of both matched and nonmatched placebo groups were reported. Bayesian and frequentist covariate-adjusted techniques were compared with 7 intervention-placebo pairs. Exposures Seven matched and nonmatched placebo pairs (for a total of 7 comparisons) were evaluated throughout the primary platform trial. Comparisons were made between treatment and its associated matched (concurrent) placebo, as well as with nonmatched placebo (alone and in combination) assessed at a similar time point. Main Outcomes and Measures Outcomes assessed included hospitalizations, EuroQol 5-Dimension 5-level scores, and PROMIS Global-10 scores. Results A total of 7 intervention-control pairs (N = 2684) were assessed, including 1620 (60.4%) women, with mean (SD) age, 47 (15.2) years; the most common comorbidities were obesity (41.9%) and hypertension (37.9%). In a meta-analysis with decoupled SEs, accounting for overlapping placebo patients, the overall odds ratio (OR) of nonmatched compared with matched placebo was 1.01 (95% credible interval, 0.77-1.32), with posterior probability of equivalence, defined as 0.8 ≤ OR ≤ 1.2 (a deviation from perfect equivalence ie, OR = 1, by no more than 0.2) of 85.4%, implying no significant difference. Unadjusted analysis of the event rate difference between all nonmatched and matched placebo groups did not identify any notable differences across all 7 treatment-placebo combinations assessed. Similar analysis that was conducted for patient-reported quality of life outcomes did not yield statistically significant differences. Conclusions and Relevance In this post hoc study of a randomized clinical platform trial, pooling matched and nonmatched placebo patient data did not lead to inconsistencies in treatment effect estimation for any of the investigational drugs. These findings may have significant implications for future platform trials, as the use of nonmatched placebo may improve statistical power, or reduce barriers to placebo implementation.
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Affiliation(s)
- Gilmar Reis
- Research Division, Cardresearch-Cardiologia Assistencial e de Pesquisa, Belo Horizonte, Brazil
- Department of Medicine, Pontifícia Universidade Católica de Minas Gerais, Belo Horizonte, Brazil
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- David Sackett Research Institute, Belo Horizonte, Brazil
| | - Leonardo Cançado Monteiro Savassi
- Research Division, Cardresearch-Cardiologia Assistencial e de Pesquisa, Belo Horizonte, Brazil
- David Sackett Research Institute, Belo Horizonte, Brazil
- Public Health, Mental and Family Medicine Department, Ouro Preto Federal University, Ouro Preto, Brazil
| | - Thiago Santiago Ferreira
- Research Division, Cardresearch-Cardiologia Assistencial e de Pesquisa, Belo Horizonte, Brazil
- David Sackett Research Institute, Belo Horizonte, Brazil
| | - Luiza Lanna França Reis
- Research Division, Cardresearch-Cardiologia Assistencial e de Pesquisa, Belo Horizonte, Brazil
- David Sackett Research Institute, Belo Horizonte, Brazil
| | - Maria Izabel Campos Simplicio
- Research Division, Cardresearch-Cardiologia Assistencial e de Pesquisa, Belo Horizonte, Brazil
- David Sackett Research Institute, Belo Horizonte, Brazil
| | - Luciene Barra Ribeiro
- Research Division, Cardresearch-Cardiologia Assistencial e de Pesquisa, Belo Horizonte, Brazil
- David Sackett Research Institute, Belo Horizonte, Brazil
| | | | | | - Ofir Harari
- Core Clinical Sciences, Vancouver, British Columbia, Canada
| | | | - Louis Dron
- Cascade Outcomes Research, Vancouver, British Columbia, Canada
| | - Jay J. H. Park
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- Core Clinical Sciences, Vancouver, British Columbia, Canada
| | - Kristian Thorlund
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Edward J. Mills
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- Purpose Life Sciences, Vancouver, British Columbia, Canada
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11
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Nikolakopoulou A, Chaimani A, Furukawa TA, Papakonstantinou T, Rücker G, Schwarzer G. When does the placebo effect have an impact on network meta-analysis results? BMJ Evid Based Med 2024; 29:127-134. [PMID: 37385716 PMCID: PMC10982636 DOI: 10.1136/bmjebm-2022-112197] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/13/2023] [Indexed: 07/01/2023]
Abstract
The placebo effect is the 'effect of the simulation of treatment that occurs due to a participant's belief or expectation that a treatment is effective'. Although the effect might be of little importance for some conditions, it can have a great role in others, mostly when the evaluated symptoms are subjective. Several characteristics that include informed consent, number of arms in a study, the occurrence of adverse events and quality of blinding may influence response to placebo and possibly bias the results of randomised controlled trials. Such a bias is inherited in systematic reviews of evidence and their quantitative components, pairwise meta-analysis (when two treatments are compared) and network meta-analysis (when more than two treatments are compared). In this paper, we aim to provide red flags as to when a placebo effect is likely to bias pairwise and network meta-analysis treatment effects. The classic paradigm has been that placebo-controlled randomised trials are focused on estimating the treatment effect. However, the magnitude of placebo effect itself may also in some instances be of interest and has also lately received attention. We use component network meta-analysis to estimate placebo effects. We apply these methods to a published network meta-analysis, examining the relative effectiveness of four psychotherapies and four control treatments for depression in 123 studies.
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Affiliation(s)
- Adriani Nikolakopoulou
- Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
| | - Anna Chaimani
- Centre of Research in Epidemiology and Statistics (CRESS-U1153), Inserm, Université Paris Cité, Paris, France
| | - Toshi A Furukawa
- Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan
| | - Theodoros Papakonstantinou
- Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
| | - Gerta Rücker
- Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
| | - Guido Schwarzer
- Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
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12
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Yavropoulou MP, Kasdagli MI, Makras P, Diomatari KM, Anastasilakis AD, Mitsikostas DD, Kassi E, Sfikakis PP, Kravvariti E. Nocebo-associated treatment discontinuation with subcutaneous anti-osteoporotic drugs. A systematic review and meta-analysis of placebo-arm dropouts in randomized-controlled trials. Maturitas 2024; 179:107874. [PMID: 37976923 DOI: 10.1016/j.maturitas.2023.107874] [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: 05/29/2023] [Revised: 09/22/2023] [Accepted: 10/24/2023] [Indexed: 11/19/2023]
Abstract
OBJECTIVE Nocebo is a concept of therapeutics referring to unpleasant symptoms attributed by a patient to a drug, due to negative anticipation. Patients receiving oral anti-osteoporotic drugs in randomized controlled trials (RCT) can experience adverse events leading to dropout, implying that nocebo contributes to treatment discontinuation for these drugs. In this study we aim to investigate the nocebo effect of subcutaneous anti-osteoporotic drugs with a higher compliance rate than orally administered drugs. STUDY DESIGN We searched MEDLINE, EMBASE, SCOPUS, and Cochrane databases for double-blind trials investigating subcutaneous anti-osteoporotic drugs for osteoporosis (namely, denosumab, teriparatide, abaloparatide and romosozumab) published up to May 2023. MAIN OUTCOME MEASURE Dropouts due to reported adverse events in the placebo arms ("nocebo dropouts"). RESULTS Data from 17 trials were extracted. Among 10,529 placebo-treated patients the pooled nocebo-dropout percentage was 3 % for denosumab (average: 0.03; 95 % CI: 0.01-0.05), 1 % for romosozumab (average: 0.01; 95 % CI: 0.00-0.03) and 6 % for teriparatide and abaloparatide (average: 0.06; 95 % CI: 0.05-0.07). Nocebo-dropouts were significantly higher in men than women (6 % vs. 3 %, respectively, p = 0.012), in older (mean age >68 years) than in younger patients (5 % vs. 1 %, respectively, p = 0.017) and in those with more severe osteoporosis (based on the percentage of participants with prior fragility-related fractures in the study cohort) compared with patients with no prior fracture history (4 % vs. 1 %, respectively, p = 0.046). CONCLUSION Nocebo responses may contribute to treatment discontinuation with subcutaneous anti-osteoporotic drugs in clinical practice. Higher nocebo-related dropout rates in the higher-risk RCT population (older patients, males, those with prior fractures) show that nocebo mechanisms have the potential to hinder therapeutic efforts to specific populations who would benefit most. Prospero registration number CRD42020212843.
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Affiliation(s)
- Maria P Yavropoulou
- Endocrinology Unit, 1st Department of Propaedeutic and Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Laikon University Hospital of Athens, 11527 Athens, Greece.
| | - Maria-Iosifina Kasdagli
- Department of Hygiene and Epidemiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Polyzois Makras
- Department of Medical Research, 251 Hellenic Air Force & VA General Hospital, Athens, Greece
| | - Konstantina-Maria Diomatari
- Postgraduate Medical Studies in the Physiology of Aging and Geriatric Syndromes, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | | | - Dimos D Mitsikostas
- 1st Neurology Department, Aeginition Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
| | - Eva Kassi
- Endocrinology Unit, 1st Department of Propaedeutic and Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Laikon University Hospital of Athens, 11527 Athens, Greece
| | - Petros P Sfikakis
- Endocrinology Unit, 1st Department of Propaedeutic and Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Laikon University Hospital of Athens, 11527 Athens, Greece; 1st Department of Propaedeutic and Internal Medicine, Joint Academic Rheumatology Program, School of Medicine, National and Kapodistrian University of Athens, Laikon University Hospital of Athens, 11527 Athens, Greece
| | - Evrydiki Kravvariti
- Endocrinology Unit, 1st Department of Propaedeutic and Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Laikon University Hospital of Athens, 11527 Athens, Greece; 1st Department of Propaedeutic and Internal Medicine, Joint Academic Rheumatology Program, School of Medicine, National and Kapodistrian University of Athens, Laikon University Hospital of Athens, 11527 Athens, Greece
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13
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Basedau H, Ornello R, Matteis ED, Davaasuren B, Kadyrova B, Vuralli D, Bozhenko M, Azizova I, Bitsadze N, Eralieva E, Ashina M, Mitsikostas D, Puledda F. Placebo and nocebo in the treatment of migraine: How much does real world effectiveness depend on contextual effects? Cephalalgia 2023; 43:3331024231218392. [PMID: 38041833 DOI: 10.1177/03331024231218392] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2023]
Abstract
PURPOSE Treatments in medicine impact individuals beyond their intended effects, due to phenomena such as the placebo and nocebo effects. The placebo effect arises from the positive expectation of a treatment being beneficial, while the nocebo effect stems from the negative expectation of a treatment causing harm. Both in real-world practice and clinical trials, treatments can lead to outcomes unrelated to their intended mechanism of action, which we categorize as placebo and nocebo responses. These responses, combined with the inherent fluctuation in a condition's natural progression, regression to the mean, and random comorbidities, make up a significant part of the therapeutic experience. Particularly in pain management, placebo and nocebo effects play a substantial role. By addressing modifiable contextual factors such as patient expectations, lifestyle choices, and the therapeutic relationship, healthcare providers can enhance the effectiveness of migraine treatments, paving the way for a more comprehensive, individualized approach to patient care. We must also consider non-modifiable factors like personal experiences, beliefs, and information from social media and the internet. CONCLUSION This review offers a summary of our current understanding of the placebo and nocebo effects in migraine management.
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Affiliation(s)
- Hauke Basedau
- Department of Systems Neuroscience, University Medical Center Hamburg- Eppendorf, Hamburg, Germany
| | - Raffaele Ornello
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Eleonora De Matteis
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | | | - Begimai Kadyrova
- Department of Special Clinical Disciplines, International School of Medicine of International University of Kyrgyzstan, Bishkek, Kyrgyzstan
| | - Doga Vuralli
- Department of Neurology and Algology, Neuropsychiatry Center, Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara, Turkey
| | - Myroslav Bozhenko
- Department of Neurology, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
| | - Ilaha Azizova
- Neurological Clinic "New Medical Technologies", Baku, Azerbaijan
| | | | | | - Messoud Ashina
- Danish Headache Center, Department of Neurology, Rigshospitalet-Glostrup, University of Copenhagen, Copenhagen, Denmark
| | - Dimos Mitsikostas
- Department of Neurology Α, Aegintion Hospital, National and Kapidistrian University of Athens, Athens, Greece
| | - Francesca Puledda
- Headache Group, Wolfson SPaRC, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
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14
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Sollie M, Thomsen JB, Sørensen JA. Autologous Fat Grafting Is Not Superior to Placebo as Treatment of Postherpetic Neuralgia: A Double-Blind Randomized Clinical Trial. Plast Reconstr Surg 2023; 152:1053e-1062e. [PMID: 36988642 DOI: 10.1097/prs.0000000000010462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2023]
Abstract
BACKGROUND Postherpetic neuralgia (PHN) is a chronic pain syndrome occurring after a herpes zoster outbreak. While there is no effective treatment available today, autologous fat grafting has shown promise. This randomized controlled trial investigated the effectiveness of fat grafting as treatment for PHN compared with a sham treatment. METHODS A total of 46 participants with PHN were included. After liposuction under general anesthesia, participants were randomly assigned to receive either autologous fat grafting or saline injection to the area of pain. The primary outcomes were the average and maximum degree of pain measured on an 11-point numeric rating scale. Secondary outcomes were quality and degree of neuropathic pain (Neuropathic Pain Symptom Inventory) and quality of life (36-Item Short-Form Health Survey). RESULTS Forty-two participants completed follow-up of 6 months. For maximal degree of pain, a reduction of -1.1 ± 0.6 and -1.0 ± 0.5 mean change (±SE) on the numeric rating scale was observed in the intervention and control groups, respectively. For average degree of pain, the reduction was -1.2 ± 0.5 and -1.3 ± 0.4 in the intervention and control groups, respectively. The authors did not observe any significant changes in the neuropathic pain and quality-of-life parameters. For all measured outcomes, the differences between the groups were not statistically significant. CONCLUSIONS The authors did not find autologous fat grafting superior to a placebo when treating PHN of the skin. Given their results, they cannot recommend the routine use of this method to treat these pains. CLINICAL RELEVANCE STATEMENT Since autologous fat grafting was not proven to be more effective than a placebo in treating PHN, alternative treatment options should be explored. It is also essential to emphasize the importance of prophylactic vaccination against herpes zoster. CLINICAL QUESTION/LEVEL OF EVIDENCE Therapeutic, I.
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Affiliation(s)
- Martin Sollie
- From the Research Unit for Plastic Surgery
- Open Patient Data Explorative Network, Odense University Hospital
- Department of Clinical Research, University of Southern Denmark
| | - Jørn B Thomsen
- From the Research Unit for Plastic Surgery
- Department of Clinical Research, University of Southern Denmark
| | - Jens A Sørensen
- From the Research Unit for Plastic Surgery
- Department of Clinical Research, University of Southern Denmark
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15
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Sun C, Xiong Z, Sun C, Liu T, Liu X, Zhang Q, Liu B, Yan S, Liu C. Placebo response in sham-acupuncture-controlled trials for migraine: A systematic review and meta-analysis. Complement Ther Clin Pract 2023; 53:101800. [PMID: 37793307 DOI: 10.1016/j.ctcp.2023.101800] [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: 05/03/2023] [Revised: 09/09/2023] [Accepted: 09/21/2023] [Indexed: 10/06/2023]
Abstract
AIM To understand the placebo response of acupuncture and its effect on migraine and optimize the design of future acupuncture clinical trials on migraine treatment. METHODS Randomized controlled trials with sham acupuncture as a control in migraine treatment were searched in four English databases from inception to September 1, 2022. The primary outcome was placebo response rate. Secondary outcomes were migraine symptoms, emotional condition, and quality of life. Factors associated with placebo response were also explored. Results were combined using risk difference (RD) or standardized mean difference (SMD) and 95% confidence interval (CI) with a random effects model. RESULTS The final analysis included 21 studies involving 1177 patients. The pooled response rate of sham acupuncture was 0.34 (RD, 95% CI 0.23-0.45, I2 89.8%). The results (SMD [95% CI]) showed significant improvements in migraine symptoms (pain intensity -0.56 [-0.73 to -0.38], and episode conditions -0.55 [-0.75 to -0.35]); emotional condition (anxiety scale -0.49 [-0.90 to -0.08] and depression scale -0.21 [-0.40 to -0.03]); and quality of life on the Migraine-Specific Quality-of-Life Questionnaire (restrictive 0.78 [0.61-0.95]; preventive 0.52 [0.35-0.68]; and emotional 0.45 [0.28-0.62]) and on the Medical Outcomes Study Short-Form (physical 0.48 [0.34-0.62] and mental 0.21 [0.02-0.41]). Only acupuncture treatment frequency had a significant impact on the placebo response rate (RD 0.49 vs. 0.14; p = 0.00). CONCLUSIONS The effect sizes for placebo response of sham acupuncture varied across migraine treatment trials. Further studies should routinely consider adjusting for a more complete set of treatment factors.
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Affiliation(s)
- Chengyi Sun
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Zhiyi Xiong
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Chongyang Sun
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Tinglan Liu
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoyu Liu
- School of Acupuncture-Moxibustion and Tuina, Tianjin University of Chinese Medicine, Tianjin, China
| | - Qinhong Zhang
- Department of Tuina, Acupuncture and Moxibustion, Shenzhen Jiuwei Chinese Medicine Clinic, Shenzhen, China
| | - Baoyan Liu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Shiyan Yan
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China; International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine, Beijing, China.
| | - Cunzhi Liu
- International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine, Beijing, China
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16
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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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17
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Jones CMP, Lin CWC, Blease C, Lawson J, Abdel Shaheed C, Maher CG. Time to reflect on open-label placebos and their value for clinical practice. Pain 2023; 164:2139-2142. [PMID: 37713359 DOI: 10.1097/j.pain.0000000000003017] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 06/24/2023] [Indexed: 09/17/2023]
Affiliation(s)
- Caitlin M P Jones
- Sydney Musculoskeletal Health, The University of Sydney, Sydney, Australia
- The Institute for Musculoskeletal Health, The University of Sydney and Sydney Local Health District, Sydney, Australia
| | - Chung-Wei Christine Lin
- Sydney Musculoskeletal Health, The University of Sydney, Sydney, Australia
- The Institute for Musculoskeletal Health, The University of Sydney and Sydney Local Health District, Sydney, Australia
| | - Charlotte Blease
- Department of Women's and Children's Health, Uppsala University Sweden
- Digital Psychiatry, Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
| | - Jen Lawson
- Patient Advocate, Kalamazoo, Michigan, United States
| | - Christina Abdel Shaheed
- Sydney Musculoskeletal Health, The University of Sydney, Sydney, Australia
- The Institute for Musculoskeletal Health, The University of Sydney and Sydney Local Health District, Sydney, Australia
- The University of Sydney, School of Public Health, Sydney, Australia
| | - Christopher G Maher
- Sydney Musculoskeletal Health, The University of Sydney, Sydney, Australia
- The Institute for Musculoskeletal Health, The University of Sydney and Sydney Local Health District, Sydney, Australia
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18
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Buergler S, Sezer D, Gaab J, Locher C. The roles of expectation, comparator, administration route, and population in open-label placebo effects: a network meta-analysis. Sci Rep 2023; 13:11827. [PMID: 37481686 PMCID: PMC10363169 DOI: 10.1038/s41598-023-39123-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 07/20/2023] [Indexed: 07/24/2023] Open
Abstract
Three meta-analyses have demonstrated the clinical potential of open-label placebos (OLPs). However, there is a need to synthesize the existing evidence through more complex analyses that would make it possible to answer questions beyond mere efficacy. Such analyses would serve to improve the understanding of why and under what circumstances OLPs work (e.g., depending on induced expectations or across different control groups). To answer these questions, we conducted the first network meta-analyses in the field of OLPs. Our analyses revealed that OLPs could be beneficial in comparison to no treatment in nonclinical (12 trials; 1015 participants) and clinical populations (25 trials; 2006 participants). Positive treatment expectations were found to be important for OLPs to work. Also, OLP effects can vary depending on the comparator used. While the kind of administration route had no substantial impact on the OLP effects, effects were found to be larger in clinical populations than in nonclinical populations. These results suggest that the expectation, comparator, administration route, and population should be considered when designing and interpreting OLP studies.
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Affiliation(s)
- Sarah Buergler
- Division of Clinical Psychology and Psychotherapy, Faculty of Psychology, University of Basel, Basel, Switzerland.
| | - Dilan Sezer
- Division of Clinical Psychology and Psychotherapy, Faculty of Psychology, University of Basel, Basel, Switzerland
| | - Jens Gaab
- Division of Clinical Psychology and Psychotherapy, Faculty of Psychology, University of Basel, Basel, Switzerland
| | - Cosima Locher
- Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Faculty of Health, University of Plymouth, Plymouth, UK
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19
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Fawsitt CG, Thom H, Regnier SA, Lee XY, Kymes S, Vase L. Comparison of indirect treatment methods in migraine prevention to address differences in mode of administration. J Comp Eff Res 2023; 12:e230021. [PMID: 37222593 PMCID: PMC10508308 DOI: 10.57264/cer-2023-0021] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 05/02/2023] [Indexed: 05/25/2023] Open
Abstract
Aim: Indirect treatment comparisons (ITCs) are anchored on a placebo comparator, and the placebo response may vary according to drug administration route. Migraine preventive treatment studies were used to evaluate ITCs and determine whether mode of administration influences placebo response and the overall study findings. Materials & methods: Change from baseline in monthly migraine days produced by monoclonal antibody treatments (subcutaneous, intravenous) was compared using fixed-effects Bayesian network meta-analysis (NMA), network meta-regression (NMR), and unanchored simulated treatment comparison (STC). Results: NMA and NMR provide mixed, rarely differentiated results between treatments, whereas unanchored STC strongly favors eptinezumab over other preventive treatments. Conclusion: Further investigations are needed to determine which ITC best reflects the impact of mode of administration on placebo.
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Affiliation(s)
| | - Howard Thom
- Clifton Insight, Bristol, United Kingdom
- University of Bristol, Bristol, United Kingdom
| | | | | | | | - Lene Vase
- Department of Psychology & Behavioural Sciences, Aarhus University, Aarhus, Denmark
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20
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Gossenheimer AN, de Freitas MB, Pádua Borges RD, Pohlmann L, Dalzochio M, Todendi P, Ziegelmann PK, Telo GH, Schaan EBD. The power of the placebo effect in diabetes: A systematic review and meta-analysis. Prim Care Diabetes 2023; 17:221-228. [PMID: 37003927 DOI: 10.1016/j.pcd.2023.03.006] [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: 11/30/2022] [Revised: 02/16/2023] [Accepted: 03/22/2023] [Indexed: 04/03/2023]
Abstract
This review aims to identify the magnitude of the placebo effect in people with type 2 diabetes mellitus. Literature research was conducted Medline, Embase and Virtual Health Library for studies published between the date of inception and June 2021. The eligibility criteria included randomized controlled trials, showing comparison to placebo, having participants with type 2 diabetes mellitus, and having glycated hemoglobin (HbA1c) as the primary outcome. Meta-analysis was conducted with the effect of changing HbA1c in relation to the baseline. Exploration of heterogeneity was performed.The meta-analysis showed an increase in the average of HbA1c compared to the baseline of 0.14% (95% CI: 0.07-0.21). There was a significant difference between follow-up times (p = 0.03) and between administration routes (p = 0.01), with an increase in HbA1c in the oral route [0.15% (95% CI: 0.07-0.23)]. The meta-regression of the year of publication showed a significant downward trend (p = 0.01) of the increase in HbA1c compared to the baseline.In this study, the expected placebo effect of Hba1c reduction was not found; instead, higher Hba1c levels were observed in the control groups, although this effect was reduced over the years. Registration: PROSPERO ID CRD42020172797.
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Affiliation(s)
- Agnes Nogueira Gossenheimer
- Department of Internal Medicine, Faculty of Medicine, Graduate Program in Medical Sciences: Endocrinology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
| | | | | | | | | | - Pâmela Todendi
- Department of Internal Medicine, Faculty of Medicine, Graduate Program in Medical Sciences: Endocrinology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Patrícia Klarmann Ziegelmann
- Department of Statistics and the Postgraduate Program in Cardiology and Cardiovascular Sciences at Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Gabriela H Telo
- School of Medicine, Graduate Program in Medicine and Health Sciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil
| | - E Beatriz D Schaan
- Department of Internal Medicine, Faculty of Medicine, Graduate Program in Medical Sciences: Endocrinology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil; Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
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21
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Xie Y, Liu X, Liu T, Sun C, Xin Z, Hu Y, Wang Y, Zhang C, Yan S. Descriptions of sham acupuncture in randomised controlled trials: a critical review of the literature. BMC Complement Med Ther 2023; 23:173. [PMID: 37254178 PMCID: PMC10227975 DOI: 10.1186/s12906-023-04007-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 05/22/2023] [Indexed: 06/01/2023] Open
Abstract
BACKGROUND Sham acupuncture is usually used to assess the specific effects of acupuncture. However, the reporting quality of sham acupuncture remains unclear despite its critical importance in understanding and analyzing the effects of acupuncture. This paper presents a literature review aimed at assessing the quality of reporting of sham acupuncture in randomized controlled trials (RCTs) based on STRICTA 2010 and TIDieR-Placebo. METHODS Three electronic English-language databases (PubMed, MEDLINE and Embase) were searched from inception to March 7, 2022, and RCTs of sham acupuncture were identified. The reporting quality of sham acupuncture was assessed in accordance with the items recommended in STRICTA 2010 and TIDieR-Placebo. The reporting quality of other items related to sham acupuncture apart from items from these two checklists was also captured to further assess the reporting quality of sham acupuncture. RESULTS A total of 609 eligible studies were included. For all of the items recommended in STRICTA 2010 and TIDieR-Placebo, 100% of the studies reported a brief name that described the sham acupuncture, 93.9% studies reported the needle type, and 90.0% reported the names of the points used. Other items for which the reporting rates were above 50% included the number, frequency and duration of treatment sessions; needle retention time; and number of needle insertions per subject per session. Overall, 49.4% of the studies revealed the rationale why sham acupuncture was chosen, 39.7% of the studies involving insertion processes reported the depth of insertion, and 37.9% of the studies reported the needle manufacturer. Other items for which the reporting rates were below 30% included practitioner-related information, response sought, evaluation of blinding, intervention mode and environment, assisting tools, and the extent to which the treatment was varied. The items "Modifications", "How well (planned)" and "How well (actual)" were not reported in any of the analyzed studies. CONCLUSIONS The overall reporting quality of sham acupuncture in RCTs was suboptimal. Although STRICTA 2010 and TIDieR-Placebo could be beneficial for describing sham acupuncture, neither can offer recommendations specifically for sham acupuncture. There is thus an urgent need to develop specialized guidelines for reporting sham acupuncture in clinical trials.
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Affiliation(s)
- Yixuan Xie
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoyu Liu
- School of Acupuncture-Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Tinglan Liu
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Chiyun Sun
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Zeyin Xin
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Yuzhi Hu
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Yue Wang
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Cheng Zhang
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Shiyan Yan
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China.
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22
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Tepper SJ, Cirillo J, Kim E, L'Italien G, Tweedie JM, Lodaya K, Riley D, Pathan F, Antaki N, Nathanson BH, McAllister P. The temporal trend of placebo response in migraine prevention from 1990 to 2021: a systematic literature review and meta-analysis with regression. J Headache Pain 2023; 24:54. [PMID: 37193973 DOI: 10.1186/s10194-023-01587-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 04/26/2023] [Indexed: 05/18/2023] Open
Abstract
BACKGROUND Migraine affects 1.1 billion people globally and is the second leading cause of disability worldwide. In clinical trials, treatment efficacy is evaluated by comparing the differential responses in the treatment and placebo arms. Although placebo response in preventive migraine trials has been studied, there is limited research examining temporal trends. This study evaluates the trend of placebo response over thirty years in migraine prevention trials and investigates the association of potential confounders, such as patient, treatment, and study characteristics on placebo response using meta-analysis with regression. METHODS We conducted literature searches from January 1990 to August 2021 in bibliographical databases (PubMed, Cochrane Library, and EMBASE). Studies were selected according to PICOS criteria and included randomized, double-blind, placebo-controlled trials evaluating preventive migraine treatments in adult patients diagnosed with episodic or chronic migraine, with or without aura. The protocol was registered with PROSPERO (CRD42021271732). Migraine efficacy outcomes included were either continuous (e.g., monthly migraine days) or dichotomous (e.g., ≥ 50% responder rate (yes/no)). We assessed the correlation of the change in outcome from baseline in the placebo arm, with the year of publication. The relationship between placebo response and year of publication was also assessed after accounting to confounders. RESULTS A total of 907 studies were identified, and 83 were found eligible. For the continuous outcomes, the change from baseline in mean placebo response showed an increase over the years (rho = 0.32, p = 0.006). The multivariable regression analysis also showed an overall increase in placebo response over the years. The correlation analysis of dichotomous responses showed no significant linear trend between publication year and mean placebo response (rho = 0.08, p = 0.596). Placebo response also varied by route of administration. CONCLUSION Placebo response increased over the past 30 years in migraine preventive trials. This phenomenon should be considered when designing clinical trials and conducting meta-analyses.
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Affiliation(s)
- Stewart J Tepper
- Geisel School of Medicine at Dartmouth, Dartmouth Headache Clinic, Hanover, NH, USA.
| | | | - Edward Kim
- Biohaven Pharmaceuticals, New Haven, CT, USA
| | | | | | - Kunal Lodaya
- Boston Strategic Partners Inc, 4 Wellington St., Suite 3, Boston, MA, USA
| | - Dushon Riley
- Boston Strategic Partners Inc, 4 Wellington St., Suite 3, Boston, MA, USA
| | - Farah Pathan
- Boston Strategic Partners Inc, 4 Wellington St., Suite 3, Boston, MA, USA
| | - Nicholas Antaki
- Boston Strategic Partners Inc, 4 Wellington St., Suite 3, Boston, MA, USA
| | | | - Peter McAllister
- New England Institute for Neurology and Headache, Stamford, CT, USA
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23
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Haghdoost F, Puledda F, Garcia-Azorin D, Huessler EM, Messina R, Pozo-Rosich P. Evaluating the efficacy of CGRP mAbs and gepants for the preventive treatment of migraine: A systematic review and network meta-analysis of phase 3 randomised controlled trials. Cephalalgia 2023; 43:3331024231159366. [PMID: 36855951 DOI: 10.1177/03331024231159366] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
BACKGROUND Several novel treatments targeting the calcitonin gene-related peptide pathway have been developed for migraine. We evaluated the efficacy of these medications, including atogepant, rimegepant, erenumab, eptinezumab, fremanezumab, and galcanezumab, for the prevention of migraine via network meta-analysis. METHODS Databases, including MEDLINE via PubMed, EMBASE, and Cochrane central, were systematically reviewed, and all eligible phase 3 randomised controlled trials were included. RESULTS Nineteen studies (n = 14,584 participants) were included. Studies included episodic (n = 11) and chronic (n = 4) migraine or both (n = 4). All interventions, except for eptinzumab 30 mg, significantly reduced mean monthly migraine days compared to placebo. All medications had a higher ≥50% responder rate than placebo and results were statistically significant in those with the subcutaneous or intravenous route of administrations, but not with the oral one. All medications significantly reduced mean monthly headache days, although no data for this outcome was available for rimegepant, and mean monthly acute medication days, with no data for eptinezumab. CONCLUSION The results show that medications targeting calcitonin gene-related peptide were effective in preventing migraine compared to placebo. Considering limitations of single studies, different populations such as episodic and chronic migraine, and the absence of head-to-head trials, all novel treatments decreased mean monthly migraine and headache days, and showed higher 50%, 75% and 100% responder rates than placebo.Trial registration: PROSPERO registration: CRD42022310579.
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Affiliation(s)
- Faraidoon Haghdoost
- The George Institute for Global Health, University of New South Wales, Sydney, Australia
| | - Francesca Puledda
- Headache Group, Wolfson CARD, SLaM Biomedical Research Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, National Institute for Health Research-Wellcome Trust King's Clinical Research Facility, King's College Hospital, London, United Kingdom
| | - David Garcia-Azorin
- Headache Unit, Department of Neurology, Hospital Clínico Universitario de Valladolid, Gerencia Regional de Salud de Castilla y Leon, Valladolid, Spain
| | - Eva-Maria Huessler
- Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Germany
| | - Roberta Messina
- Neuroimaging Research Unit and Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Patricia Pozo-Rosich
- Headache Unit and Headache and Neurological Pain Research Group, Neurology Department, Hospital Universitari Vall d'Hebron and VHIR, Barcelona, Spain
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24
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Lee YS, Kim SY, Lee H, Chae Y, Lee MS. ACURATE: A guide for reporting sham controls in trials using acupuncture. J Evid Based Med 2023; 16:82-90. [PMID: 36959765 DOI: 10.1111/jebm.12524] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 03/06/2023] [Indexed: 03/25/2023]
Abstract
OBJECTIVE To promote better reporting quality regarding sham acupuncture in clinical trials for a precise appraisal of the adequacy of the sham acupuncture procedure. METHODS A three-stage online Delphi survey was conducted to a group of experts. Items with higher than 80% consensus from the initial checklist were selected as the final candidates. Further discussion among the working group was convened to preclude potential redundancy among the items. RESULTS A total of 23 experts out of 35 (66%) responded to the Delphi process. The final checklist consists of 23 items in six categories: type of sham acupuncture, details of sham acupuncture manipulation, location of sham acupuncture, treatment regimen, practitioner, and protocol and settings. CONCLUSION This paper presents the Acupuncture Controls gUideline for Reporting humAn Trials and Experiments (ACURATE) checklist, an extension of The Consolidated Standards for Reporting of Trials (CONSORT) and to be used along with STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) when sham acupuncture needles are used in the study. This checklist focuses on a clear depiction of sham needling procedures to enhance replicability and enable a precise appraisal. We encourage researchers to use ACURATE in trials and reviews involving sham acupuncture to assist reporting sham acupuncture procedures and the related components.
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Affiliation(s)
- Ye-Seul Lee
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, Republic of Korea
| | - Song-Yi Kim
- Department of Anatomy and Acupoint, College of Korean Medicine, Gachon University, Seongnam, Republic of Korea
| | - Hyangsook Lee
- Department of Science in Korean Medicine, College of Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Younbyoung Chae
- Acupuncture and Meridian Science Research Center, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Myeong Soo Lee
- KM Science Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
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25
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Yoo Y, Oh JH, Lee H, Choi H, Joo S, Han AH, Moon JY. Myth and Truth in Opioid Consumption with Intrathecal Morphine Pump Implantation in Chronic Pain: A Retrospective Cohort Study with Claims Database in South Korea. PAIN MEDICINE 2023; 24:79-88. [PMID: 35881702 DOI: 10.1093/pm/pnac110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 06/22/2022] [Accepted: 07/18/2022] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To investigate the opioid consumption and the healthcare resource utilization in patients with the intrathecal drug delivery system (IDDS) therapy and the comprehensive medical management (CMM) alone. DESIGN A retrospective cohort study with a customized claims database. SETTING In a university-based hospital. SUBJECTS Patients with complex regional pain syndrome, post-laminectomy syndrome, and fibromyalgia. METHODS Using propensity score matching (1:3), we selected patients with morphine infusion through IDDS (IDDS group) and CMM alone (CMM group). The primary endpoints were comparisons of average morphine equivalents daily dosages (MEDD, mg/day) for 6 and 12 months from an index date. The number of emergency room (ER) visits and hospitalizations and the total medical expenditures were compared as secondary outcomes. RESULTS In total, 82 patients (N = 23 in the IDDS group and N = 59 in the CMM group) were analyzed. Although a 6-month average MEDD did not reach statistical significance, a 12-month average MEDD was significantly decreased in the IDDS group compared to the CMM group (53.2 ± 46.3 vs 123.9 ± 176.4, respectively; P = 0.008). ER visits were more frequent in the IDDS group than the CMM group at baseline (5.4 vs 0.5, respectively; P = .002), which was maintained for 12 months (P < 0.001). Otherwise, the number of hospitalization and the medical expenditures for pain management were not different between the groups for 12 months. CONCLUSIONS The combined IDDS therapy had some benefits in reducing opioid consumption for 1-year follow-up compared to the CMM alone in chronic noncancer pain patients.
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Affiliation(s)
- Yongjae Yoo
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Joo Hyeon Oh
- Department of Anesthesiology and Pain Medicine, Boramae Medical Center, Seoul, Republic of Korea
| | - Haine Lee
- Healthcare Economics and Government Affairs, Medtronic Korea, Inc., Seoul, Republic of Korea
| | - Hyunsook Choi
- Healthcare Economics and Government Affairs, Medtronic Korea, Inc., Seoul, Republic of Korea.,Department of Health Convergence, Ewha Womans University, Seoul, Republic of Korea
| | - Somin Joo
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | | | - Jee Youn Moon
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
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26
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Abstract
The placebo effect can be defined as any improvement of illnesses or reduction of subjective symptoms that result from interventions possessing no known physical effects. By contrast, the nocebo effect refers to undesirable symptoms or illnesses that follow interventions also lacking known physical effects. It may also play a role in chronic illnesses that lack objective confirmation. Both placebo and nocebo effects can be potent and must be understood by both practitioners and researchers for proper application in clinical medicine. Individual caregivers can apply these principles to modify results in the daily care of patients.
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Affiliation(s)
- Morton E Tavel
- Clinical Professor Emeritus, Indiana University School of Medicine, Indianapolis.
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27
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Cowan RP, Marmura MJ, Diener HC, Starling AJ, Schim J, Hirman J, Brevig T, Cady R. Quantity changes in acute headache medication use among patients with chronic migraine treated with eptinezumab: subanalysis of the PROMISE-2 study. J Headache Pain 2022; 23:115. [PMID: 36068494 PMCID: PMC9446734 DOI: 10.1186/s10194-022-01482-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/09/2022] [Indexed: 11/10/2022] Open
Abstract
Background Patients with chronic migraine (CM) treated with eptinezumab in the PROMISE-2 trial achieved greater reductions in migraine and headache frequency, impact, and acute headache medication (AHM) use than did patients who received placebo. This post hoc analysis examines relationships between headache frequency reductions and changes in AHM use in patients in PROMISE-2. Methods PROMISE-2 was a double-blind, placebo-controlled trial conducted in adults with CM. Patients were randomized to eptinezumab 100 mg, 300 mg, or placebo, administered intravenously once every 12 weeks for up to two doses. Patients recorded headache/AHM information daily and for each event in an electronic diary; data from all days with daily reports were included. Shifts in headache frequency and AHM use were assessed in the three populations: total CM population, patients with CM and medication-overuse headache (MOH), and patients with CM and MOH who were ≥ 50% responders during treatment (response over weeks 1–24). Results A total of 1072 adults with CM received treatment (eptinezumab, n = 706; placebo, n = 366). Mean baseline headache frequency was 20.5 days; mean baseline AHM days was 13.4; 431 patients had MOH, of which 225 (52.2%) experienced ≥50% response over weeks 1–24. Relative to baseline, the proportion of days with both headache and AHM use decreased 25.1% (eptinezumab) versus 17.0% (placebo) in the total population (N = 1072), 29.2% versus 18.4% in the MOH subpopulation (n = 431), and 38.3% versus 31.5% in the CM with MOH population with ≥50% response subgroup (n = 225) during weeks 1–24. The proportion of days with headache and triptan use decreased 9.1% (eptinezumab) versus 5.8% (placebo), 11.8% versus 7.2%, and 14.5% versus 12.6%, respectively. Reductions in other AHM types were smaller. Conclusions In this post hoc analysis, eptinezumab use in patients with CM was associated with greater decreases in days with headache with AHM overall and with triptans in particular. The magnitude of effect was greater in the subgroup of CM patients with MOH and ≥ 50% response. Trial registration ClinicalTrials.gov Identifier: NCT02974153. Graphical abstract Eptinezumab reduces headache frequency and acute medication use in patients with chronic migraine.![]()
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Affiliation(s)
| | | | - Hans-Christoph Diener
- Medical Faculty of the University Duisburg-Essen, Institute for Medical Informatics, Biometry and Epidemiology, Essen, Germany
| | | | - Jack Schim
- The Neurology Center of Southern California, Carlsbad, CA, USA
| | - Joe Hirman
- Pacific Northwest Statistical Consulting, Inc., Woodinville, WA, USA
| | | | - Roger Cady
- Lundbeck LLC, Deerfield, IL, USA. .,RK Consults, Ozark, MO, USA. .,Missouri State University, Springfield, MO, USA.
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28
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Schim JD, Anderson C, Brunner E, Hirman J, Ogbru A, Cady R, McGill L. Likelihood of response with subsequent dosing for patients with migraine and initial suboptimal response with eptinezumab: A post hoc analysis of two placebo‐controlled randomized clinical trials. Headache 2022; 62:558-565. [PMID: 35524405 PMCID: PMC9321567 DOI: 10.1111/head.14302] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 02/16/2022] [Accepted: 03/21/2022] [Indexed: 11/30/2022]
Affiliation(s)
- Jack D. Schim
- Headache Center of Southern California Carlsbad California USA
| | | | | | - Joe Hirman
- Pacific Northwest Statistical Consulting Woodinville Washington USA
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29
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Medrea I, Christie S, Tepper SJ, Thavorn K, Hutton B. Network meta-analysis of therapies for cluster headache: Effects of acute therapies for episodic and chronic cluster. Headache 2022; 62:482-511. [PMID: 35343597 DOI: 10.1111/head.14283] [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: 09/09/2021] [Revised: 01/19/2022] [Accepted: 02/01/2022] [Indexed: 11/27/2022]
Abstract
OBJECTIVE We used network meta-analysis (NMA) to characterize the relative effectiveness and harms of acute treatment options for cluster headache. BACKGROUND There are few evidence-based acute treatments available for cluster headache. As most treatments were compared only against placebos in clinical trials, few head-to-head comparisons of treatments are available. METHODS An a priori registered scoping review was performed to identify randomized controlled trials evaluating treatments in adult patients (>18 years old) with cluster headache per accepted diagnostic criteria. Bayesian NMAs were performed to compare treatments in terms of headache relief at 15 or 30 min, and also the occurrence of adverse events. We report odds ratios (ORs) of relative treatment effects along with corresponding 95% credible intervals (CrIs), as well as measures of treatment ranking. RESULTS A total of 13 randomized controlled trials informed NMAs. We found high flow oxygen to be the most effective therapy for headache response at 15 and 30 min (OR 9.0, 95% CrI 5.3 to 15.9 vs. placebo), with injectable sumatriptan demonstrating the next highest effect (OR 6.4, 95% CrI 3.75 to 11.1 vs. placebo). High flow oxygen was also more effective than low flow oxygen (OR 2.55, 95% CrI 1.13 to 5.8), nasal spray zolmitriptan (OR 3.75, 95% CrI 1.72 to 8.4), octreotide (OR 4.5, 95% CrI 1.64 to 12.5), and non-invasive vagal nerve stimulation (nVNS; OR 5.2, 95% CrI 2.29 to 11.9). Sumatriptan injectable was also effective for headache relief and was found to be better than nasal spray zolmitriptan (OR 2.67, 95% CrI 1.21 to 5.9), octreotide (OR 3.20, 95% CrI 1.17 to 8.8), and nVNS (OR 3.69, 95% CrI 1.63 to 8.4). Octreotide (OR 4.1, 95% CrI 1.71 to 10.5) and sumatriptan (OR 2.40, 95% CrI 1.39 to 4.2) were associated with greater risk of adverse events compared to placebo, while other treatments did not demonstrate increased risk. When focusing on patients with episodic cluster headache, nVNS was significantly better than placebo (OR 4.9, 95% CrI 1.89 to 14.1). CONCLUSIONS Our findings suggest that high flow oxygen is more efficacious when compared to low flow oxygen for headache relief. When low flow oxygen fails in patients who can tolerate oxygen, increased flow rates should be tried. Additionally, high flow oxygen is likely more effective than zolmitriptan nasal spray, nVNS, and octreotide. Sumatriptan injectable is more likely to be effective when compared to zolmitriptan nasal spray, octreotide, and nVNS.
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Affiliation(s)
- Ioana Medrea
- University of Ottawa, Ottawa, Ontario, Canada
- SUNY Upstate Medical University, Syracuse, New York, USA
| | - Suzanne Christie
- University of Ottawa, Ottawa, Ontario, Canada
- Ottawa Headache Centre, Ottawa, Ontario, Canada
| | - Stewart J Tepper
- Geisel School of Medicine at Dartmouth, Dartmouth, New Hampshire, USA
| | - Kednapa Thavorn
- University of Ottawa, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, Ontario, Canada
| | - Brian Hutton
- University of Ottawa, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, Ontario, Canada
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30
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Curran JG, Waters J, Yuan H. Parenteral NSAIDs for acute treatment of migraine: Adherence to the IHS guidelines for controlled trials. CEPHALALGIA REPORTS 2022. [DOI: 10.1177/25158163221114465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: Parenteral non-steroidal anti-inflammatory drugs (NSAIDs) are important alternatives to oral NSAIDs, especially in patients with severe migraine who have emesis or gastroparesis. With increasing research on using parenteral NSAIDs for acute migraine, it is critical to examine the quality of these studies. Our goal was to assess the adherence of these trials to the International Headache Society (IHS) controlled trial guidelines for acute treatment of migraine. Methods: We queried PubMed for clinical trials investigating parenteral NSAIDs for acute treatment of migraine in adult patients. We developed a 14-point scoring system based on the essential components of the IHS guidelines. To date, four versions of the IHS’s Guidelines for controlled trials of acute treatment of migraine attacks have been published. Each trial was evaluated with the appropriate edition of the guidelines. Results: We identified 216 studies and assessed 27 eligible clinical trials. The mean score was 6.7 ± 2.1 (2–11). Most trials followed the IHS migraine diagnosis criteria (85.2%), but only six (22.2%) selected patients based on the recommended headache frequency. Most trials were randomized (88.8%), but fewer were double-blinded (74.1%) or placebo-controlled (11.1%). Almost every trial clearly explained the pain scale (96.3%), and three-quarters (77.8%) assessed headache-associated symptoms. However, no trial utilized the recommended primary endpoint: pain-freedom at 2-hours. Conclusions: Most clinical trials on parenteral NSAIDs for acute migraine did not fully adhere to the IHS recommendations. Future studies should pay special attention to the IHS guideline to improve the quality of clinical trials for the acute treatment of migraine.
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Affiliation(s)
- John G Curran
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | - John Waters
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | - Hsiangkuo Yuan
- Jefferson Headache Center, Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA
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31
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Gorantla S, Gopireddy MMR, Bhat A, Ayyasamy L, Jaishankar SKJ, Kherallah B, Nersesyan H. Placebo response with subcutaneous injections in calcitonin gene-related peptide receptor monoclonal antibody migraine preventative trials – A systematic review and meta-analysis. CEPHALALGIA REPORTS 2022. [DOI: 10.1177/25158163221120103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: The majority of CGRP monoclonal antibodies for migraine prevention are administered subcutaneously. Therefore, we attempted to calculate the pooled placebo response with subcutaneous placebo injections in this systematic review and meta-analysis. Methods: We identified 16 randomized controlled trials that met our inclusion and exclusion criteria through a comprehensive search in five electronic databases (PubMed Central, EMBASE, MEDLINE, Cochrane library and clinicaltrials.gov ). The risk of bias was assessed for all included studies. Random effects model was used to calculate pooled mean monthly migraine days and 50% response rates. Results: A total of 4240 subjects were included from 16 studies in this meta-analysis. The pooled mean monthly migraine day reduction with subcutaneous placebo injections was 2.15 (95% CI: 1.60–2.69). The pooled proportion of patients achieving a 50% reduction in mean monthly headache days was 26% (95% CI: 20%–31%). Placebo response accounted for more than 50% of therapeutic gain in our study. Conclusion: A substantial placebo response was noted with subcutaneous injections in migraine CGRP monoclonal antibody clinical trials. This meta-analysis may serve as a reference point to calculate sample size in clinical trials using subcutaneous interventions for migraine prevention. We registered our study at PROSPERO (CRD42020185300).
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Affiliation(s)
- Sasikanth Gorantla
- University of Illinois College of Medicine at Peoria and Illinois Neurological Institute, OSF Healthcare, Peoria, IL, USA
| | | | - Archana Bhat
- Evidencian Research Associates, Bangalore, India
| | | | | | - Bassil Kherallah
- University of Illinois College of Medicine at Peoria and Illinois Neurological Institute, OSF Healthcare, Peoria, IL, USA
| | - Hrachya Nersesyan
- University of Illinois College of Medicine at Peoria and Illinois Neurological Institute, OSF Healthcare, Peoria, IL, USA
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Hurley RW, Adams MCB, Barad M, Bhaskar A, Bhatia A, Chadwick A, Deer TR, Hah J, Hooten WM, Kissoon NR, Lee DW, Mccormick Z, Moon JY, Narouze S, Provenzano DA, Schneider BJ, van Eerd M, Van Zundert J, Wallace MS, Wilson SM, Zhao Z, Cohen SP. Consensus practice guidelines on interventions for cervical spine (facet) joint pain from a multispecialty international working group. Reg Anesth Pain Med 2022; 47:3-59. [PMID: 34764220 PMCID: PMC8639967 DOI: 10.1136/rapm-2021-103031] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 08/02/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND The past two decades have witnessed a surge in the use of cervical spine joint procedures including joint injections, nerve blocks and radiofrequency ablation to treat chronic neck pain, yet many aspects of the procedures remain controversial. METHODS In August 2020, the American Society of Regional Anesthesia and Pain Medicine and the American Academy of Pain Medicine approved and charged the Cervical Joint Working Group to develop neck pain guidelines. Eighteen stakeholder societies were identified, and formal request-for-participation and member nomination letters were sent to those organizations. Participating entities selected panel members and an ad hoc steering committee selected preliminary questions, which were then revised by the full committee. Each question was assigned to a module composed of 4-5 members, who worked with the Subcommittee Lead and the Committee Chairs on preliminary versions, which were sent to the full committee after revisions. We used a modified Delphi method whereby the questions were sent to the committee en bloc and comments were returned in a non-blinded fashion to the Chairs, who incorporated the comments and sent out revised versions until consensus was reached. Before commencing, it was agreed that a recommendation would be noted with >50% agreement among committee members, but a consensus recommendation would require ≥75% agreement. RESULTS Twenty questions were selected, with 100% consensus achieved in committee on 17 topics. Among participating organizations, 14 of 15 that voted approved or supported the guidelines en bloc, with 14 questions being approved with no dissensions or abstentions. Specific questions addressed included the value of clinical presentation and imaging in selecting patients for procedures, whether conservative treatment should be used before injections, whether imaging is necessary for blocks, diagnostic and prognostic value of medial branch blocks and intra-articular joint injections, the effects of sedation and injectate volume on validity, whether facet blocks have therapeutic value, what the ideal cut-off value is for designating a block as positive, how many blocks should be performed before radiofrequency ablation, the orientation of electrodes, whether larger lesions translate into higher success rates, whether stimulation should be used before radiofrequency ablation, how best to mitigate complication risks, if different standards should be applied to clinical practice and trials, and the indications for repeating radiofrequency ablation. CONCLUSIONS Cervical medial branch radiofrequency ablation may provide benefit to well-selected individuals, with medial branch blocks being more predictive than intra-articular injections. More stringent selection criteria are likely to improve denervation outcomes, but at the expense of false-negatives (ie, lower overall success rate). Clinical trials should be tailored based on objectives, and selection criteria for some may be more stringent than what is ideal in clinical practice.
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Affiliation(s)
- Robert W Hurley
- Anesthesiology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Meredith C B Adams
- Anesthesiology, Wake Forest Baptist Health, Winston-Salem, North Carolina, USA
| | - Meredith Barad
- Anesthesiology, Perioperative and Pain Medicine, Stanford Hospital and Clinics, Redwood City, California, USA
| | - Arun Bhaskar
- Anesthesiology, Imperial College Healthcare NHS Trust Haemodialysis Clinic, Hayes Satellite Unit, Hayes, UK
| | - Anuj Bhatia
- Anesthesia and Pain Management, University of Toronto and University Health Network - Toronto Western Hospital, Toronto, Ontario, Canada
| | - Andrea Chadwick
- Anesthesiology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Timothy R Deer
- Spine and Nerve Center of the Virginias, West Virginia University - Health Sciences Campus, Morgantown, West Virginia, USA
| | - Jennifer Hah
- Stanford University School of Medicine, Palo Alto, California, USA
| | | | | | - David Wonhee Lee
- Fullerton Orthopaedic Surgery Medical Group, Fullerton, California, USA
| | - Zachary Mccormick
- Physical Medicine and Rehabilitation, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Jee Youn Moon
- Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Anesthesiology and Pain Medicine, Seoul National University Hospital, Jongno-gu, South Korea
| | - Samer Narouze
- Center for Pain Medicine, Summa Western Reserve Hospital, Cuyahoga Falls, Ohio, USA
| | - David A Provenzano
- Pain Diagnostics and Interventional Care, Sewickley, Pennsylvania, USA
- Pain Diagnostics and Interventional Care, Edgeworth, Pennsylvania, USA
| | - Byron J Schneider
- Physical Medicine and Rehabilitation, Vanderbilt University, Nashville, Tennessee, USA
| | - Maarten van Eerd
- Anesthesiology, Maastricht University Medical Centre, Maastricht, Limburg, The Netherlands
| | - Jan Van Zundert
- Anesthesiology, Maastricht University Medical Centre, Maastricht, Limburg, The Netherlands
| | - Mark S Wallace
- Anesthesiology, UCSD Medical Center - Thornton Hospital, San Diego, California, USA
| | | | - Zirong Zhao
- Neurology, VA Healthcare Center District of Columbia, Washington, District of Columbia, USA
| | - Steven P Cohen
- Anesthesiology, Neurology, Physical Medicine and Rehabilitation and Psychiatry, Pain Medicine Division, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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33
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Hurley RW, Adams MCB, Barad M, Bhaskar A, Bhatia A, Chadwick A, Deer TR, Hah J, Hooten WM, Kissoon NR, Lee DW, Mccormick Z, Moon JY, Narouze S, Provenzano DA, Schneider BJ, van Eerd M, Van Zundert J, Wallace MS, Wilson SM, Zhao Z, Cohen SP. Consensus practice guidelines on interventions for cervical spine (facet) joint pain from a multispecialty international working group. PAIN MEDICINE (MALDEN, MASS.) 2021; 22:2443-2524. [PMID: 34788462 PMCID: PMC8633772 DOI: 10.1093/pm/pnab281] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 09/15/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND The past two decades have witnessed a surge in the use of cervical spine joint procedures including joint injections, nerve blocks and radiofrequency ablation to treat chronic neck pain, yet many aspects of the procedures remain controversial. METHODS In August 2020, the American Society of Regional Anesthesia and Pain Medicine and the American Academy of Pain Medicine approved and charged the Cervical Joint Working Group to develop neck pain guidelines. Eighteen stakeholder societies were identified, and formal request-for-participation and member nomination letters were sent to those organizations. Participating entities selected panel members and an ad hoc steering committee selected preliminary questions, which were then revised by the full committee. Each question was assigned to a module composed of 4-5 members, who worked with the Subcommittee Lead and the Committee Chairs on preliminary versions, which were sent to the full committee after revisions. We used a modified Delphi method whereby the questions were sent to the committee en bloc and comments were returned in a non-blinded fashion to the Chairs, who incorporated the comments and sent out revised versions until consensus was reached. Before commencing, it was agreed that a recommendation would be noted with >50% agreement among committee members, but a consensus recommendation would require ≥75% agreement. RESULTS Twenty questions were selected, with 100% consensus achieved in committee on 17 topics. Among participating organizations, 14 of 15 that voted approved or supported the guidelines en bloc, with 14 questions being approved with no dissensions or abstentions. Specific questions addressed included the value of clinical presentation and imaging in selecting patients for procedures, whether conservative treatment should be used before injections, whether imaging is necessary for blocks, diagnostic and prognostic value of medial branch blocks and intra-articular joint injections, the effects of sedation and injectate volume on validity, whether facet blocks have therapeutic value, what the ideal cut-off value is for designating a block as positive, how many blocks should be performed before radiofrequency ablation, the orientation of electrodes, whether larger lesions translate into higher success rates, whether stimulation should be used before radiofrequency ablation, how best to mitigate complication risks, if different standards should be applied to clinical practice and trials, and the indications for repeating radiofrequency ablation. CONCLUSIONS Cervical medial branch radiofrequency ablation may provide benefit to well-selected individuals, with medial branch blocks being more predictive than intra-articular injections. More stringent selection criteria are likely to improve denervation outcomes, but at the expense of false-negatives (ie, lower overall success rate). Clinical trials should be tailored based on objectives, and selection criteria for some may be more stringent than what is ideal in clinical practice.
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Affiliation(s)
- Robert W Hurley
- Anesthesiology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Meredith C B Adams
- Anesthesiology, Wake Forest Baptist Health, Winston-Salem, North Carolina, USA
| | - Meredith Barad
- Anesthesiology, Perioperative and Pain Medicine, Stanford Hospital and Clinics, Redwood City, California, USA
| | - Arun Bhaskar
- Anesthesiology, Imperial College Healthcare NHS Trust Haemodialysis Clinic, Hayes Satellite Unit, Hayes, UK
| | - Anuj Bhatia
- Anesthesia and Pain Management, University of Toronto and University Health Network - Toronto Western Hospital, Toronto, Ontario, Canada
| | - Andrea Chadwick
- Anesthesiology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Timothy R Deer
- Spine and Nerve Center of the Virginias, West Virginia University - Health Sciences Campus, Morgantown, West Virginia, USA
| | - Jennifer Hah
- Anesthesiology, Stanford University School of Medicine, Palo Alto, California, USA
| | | | | | - David Wonhee Lee
- Fullerton Orthopaedic Surgery Medical Group, Fullerton, California, USA
| | - Zachary Mccormick
- Physical Medicine and Rehabilitation, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Jee Youn Moon
- Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Anesthesiology and Pain Medicine, Seoul National University Hospital, Jongno-gu, South Korea
| | - Samer Narouze
- Center for Pain Medicine, Summa Western Reserve Hospital, Cuyahoga Falls, Ohio, USA
| | - David A Provenzano
- Pain Diagnostics and Interventional Care, Sewickley, Pennsylvania, USA
- Pain Diagnostics and Interventional Care, Edgeworth, Pennsylvania, USA
| | - Byron J Schneider
- Physical Medicine and Rehabilitation, Vanderbilt University, Nashville, Tennessee, USA
| | - Maarten van Eerd
- Anesthesiology, Maastricht University Medical Centre, Maastricht, Limburg, The Netherlands
| | - Jan Van Zundert
- Anesthesiology, Maastricht University Medical Centre, Maastricht, Limburg, The Netherlands
| | - Mark S Wallace
- Anesthesiology, UCSD Medical Center - Thornton Hospital, San Diego, California, USA
| | | | - Zirong Zhao
- Neurology, VA Healthcare Center District of Columbia, Washington, District of Columbia, USA
| | - Steven P Cohen
- Anesthesia, WRNMMC, Bethesda, Maryland, USA
- Physical Medicine and Rehabilitation, WRNMMC, Bethesda, Maryland, USA
- Anesthesiology, Neurology, Physical Medicine and Rehabilitation and Psychiatry, Pain Medicine Division, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Sezer D, de Leeuw M, Netzer C, Dieterle M, Meyer A, Buergler S, Locher C, Ruppen W, Gaab J, Schneider T. Open-Label Placebo Treatment for Acute Postoperative Pain (OLP-POP Study): Study Protocol of a Randomized Controlled Trial. Front Med (Lausanne) 2021; 8:687398. [PMID: 34805194 PMCID: PMC8602681 DOI: 10.3389/fmed.2021.687398] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 10/07/2021] [Indexed: 11/13/2022] Open
Abstract
Introduction: Open-label placebos have been proposed as way of using long recognized analgesic placebo effects in an ethical manner. Recent evidence shows efficacy of open-label placebos for clinical conditions, but there is need for more research on open-label placebos in acute pain. In the treatment of acute postoperative pain, minimization of opioid related side effects remains one of the key challenges. Therefore, this study aims at investigating the potential of adding unconditioned open-label placebos to treatment as usual as a means of reducing opioid consumption and its related side effects in patients with acute postoperative pain. Methods and Analysis: This is the protocol of an ongoing single site randomized controlled trial. The first patient was enrolled in May 2020. In total, 70 patients suffering from acute postoperative pain following dorsal lumbar interbody fusion are randomized to either a treatment as usual group or an experimental intervention group. The treatment as usual group consists of participants receiving a patient-controlled morphine pump. On day 1 and 2 post-surgery, patients in the intervention group receive, in addition to treatment as usual, two open-label placebo injections per day along with an evidence-based treatment rationale explaining the mechanisms of placebos. The primary outcome is measured by means of self-administered morphine during day 1 and 2 post-surgery. Several other outcome measures including pain intensity and adverse events as well as potential predictors of placebo response are assessed. Analysis of covariance will be used to answer the primary research question and additional statistical techniques such as generalized linear mixed models will be applied to model the temporal course of morphine consumption. Discussion: This study will provide valuable insights into the efficacy of open-label placebos in acute pain and will potentially constitute an important step toward the implementation of open-label placebos in the clinical management of acute postoperative pain. In addition, it will shed light on a cost-efficient and patient-centered strategy to reduce opioid consumption and its related side effects, without any loss in pain management efficacy. Ethics and Dissemination: The "Ethikkommission Nordwest- und Zentralschweiz" (BASEC2020-00099) approved the study protocol. Results of the analysis will be submitted for publication in a peer-reviewed journal. Clinical Trial Registration: The study is registered at ClinicalTrials.gov (NCT04339023) and is listed in the Swiss national registry at kofam.ch (SNCTP000003720).
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Affiliation(s)
- Dilan Sezer
- Division of Clinical Psychology and Psychotherapy, Faculty of Psychology, University of Basel, Basel, Switzerland
| | - Matthijs de Leeuw
- Pain Unit, Department of Anesthesiology, University Hospital of Basel, Basel, Switzerland
| | - Cordula Netzer
- Department of Spine Surgery, University Hospital of Basel, Basel, Switzerland
| | - Markus Dieterle
- Pain Unit, Department of Anesthesiology, University Hospital of Basel, Basel, Switzerland
| | - Andrea Meyer
- Division of Clinical Psychology and Epidemiology, Faculty of Psychology, University of Basel, Basel, Switzerland
| | - Sarah Buergler
- Division of Clinical Psychology and Psychotherapy, Faculty of Psychology, University of Basel, Basel, Switzerland
| | - Cosima Locher
- Division of Clinical Psychology and Psychotherapy, Faculty of Psychology, University of Basel, Basel, Switzerland.,Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine, University Hospital Zurich, Zurich, Switzerland
| | - Wilhelm Ruppen
- Pain Unit, Department of Anesthesiology, University Hospital of Basel, Basel, Switzerland
| | - Jens Gaab
- Division of Clinical Psychology and Psychotherapy, Faculty of Psychology, University of Basel, Basel, Switzerland
| | - Tobias Schneider
- Pain Unit, Department of Anesthesiology, University Hospital of Basel, Basel, Switzerland
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35
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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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Miller CT, Owen PJ, Than CA, Ball J, Sadler K, Piedimonte A, Benedetti F, Belavy DL. Attempting to Separate Placebo Effects from Exercise in Chronic Pain: A Systematic Review and Meta-analysis. Sports Med 2021; 52:789-816. [PMID: 34453277 DOI: 10.1007/s40279-021-01526-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/20/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND Pain is the most disabling characteristic of musculoskeletal disorders, and while exercise is promoted as an important treatment modality for chronic musculoskeletal conditions, the relative contribution of the specific effects of exercise training, placebo effects and non-specific effects such as natural history are not clear. The aim of this systematic review and meta-analysis was to determine the relative contribution of these factors to better understand the true effect of exercise training for reducing pain in chronic primary musculoskeletal pain conditions. DESIGN Systematic review with meta-analysis DATA SOURCES: MEDLINE, CINAHL, SPORTDiscus, EMBASE and CENTRAL from inception to February 2021. Reference lists of prior systematic reviews. ELIGIBILITY CRITERIA Randomised controlled trials of interventions that used exercise training compared to placebo, true control or usual care in adults with chronic primary musculoskeletal pain. The review was registered prospectively with PROSPERO (CRD42019141096). RESULTS We identified 79 eligible trials for quantitative analysis. Pairwise meta-analysis showed very low-quality evidence (GRADE criteria) that exercise training was not more effective than placebo (g [95% CI]: 0.94 [- 0.17, 2.06], P = 0.098, I2 = 92.46%, studies: n = 4). Exercise training was more effective than true, no intervention controls (g [95% CI]: 0.99 [0.66, 1.32], P < 0.001, I2 = 92.43%, studies: n = 42), usual care controls (g [95% CI]: 0.64 [0.44, 0.83], P < 0.001, I2 = 76.52%, studies: n = 33), and when all controls combined (g [95% CI]: 0.84 [0.64, 1.04], P < 0.001, I2 = 90.02%, studies: n = 79). CONCLUSIONS There is very low-quality evidence that exercise training is not more effective than non-exercise placebo treatments in chronic pain. Exercise training and the associated clinical encounter are more effective than true control or standard medical care for reductions in pain for adults with chronic musculoskeletal pain, with very low quality of evidence based on GRADE criteria.
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Affiliation(s)
- Clint T Miller
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, VIC, Australia.
| | - Patrick J Owen
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, VIC, Australia
| | - Christian A Than
- School of Biomedical Sciences, The University of Queensland, St. Lucia, Brisbane, Australia
| | - Jake Ball
- School of Medicine and Public Health, University of Newcastle, Callaghan, Newcastle, Australia
| | - Kate Sadler
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, VIC, Australia
| | - Alessandro Piedimonte
- Department of Neuroscience "Rita Levi Montalcini", University of Turin, Turin, Italy
| | - Fabrizio Benedetti
- Department of Neuroscience "Rita Levi Montalcini", University of Turin, Turin, Italy.,Medicine and Physiology of Hypoxia, Plateau Rosà, Zermatt, Switzerland
| | - Daniel L Belavy
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, VIC, Australia.,Department of Applied Health Sciences, Division of Physiotherapy, Hochschule für Gesundheit (University of Applied Sciences), Bochum, Germany
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Marticorena FM, Carvalho A, Oliveira LFDE, Dolan E, Gualano B, Swinton P, Saunders B. Nonplacebo Controls to Determine the Magnitude of Ergogenic Interventions: A Systematic Review and Meta-analysis. Med Sci Sports Exerc 2021; 53:1766-1777. [PMID: 33587551 DOI: 10.1249/mss.0000000000002635] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Placebos are used as a control treatment that is meant to be indistinguishable from the active intervention. However, where substantive placebo effects may occur, studies that do not include a nonplacebo control arm may underestimate the overall effect of the intervention (active plus placebo components). This study aimed to determine the relative magnitude of the placebo effect associated with nutritional supplements (caffeine and extracellular buffers) by meta-analyzing data from studies containing both placebo and nonplacebo control sessions. METHODS Bayesian multilevel meta-analysis models were used to estimate pooled effects and express the placebo effect as a percentage of the overall intervention effect. RESULTS Thirty-four studies were included, with the median pooled effect size (ES0.5) indicating a very small (ES0.5 = 0.09 (95% credible interval (CrI), 0.01-0.17)) improvement in the performance of placebo compared with control. There was no moderating effect of exercise type (capacity or performance), exercise duration, or training status. The comparison between active intervention and control indicated a small to medium effect (ES0.5 = 0.37 (95% CrI, 0.20-0.56)). Expressed in relative terms, the placebo effect was equivalent to 25% (75% CrI, 16%-35%) and 59% (75% CrI, 34%-94%) of the total intervention effect for buffers and caffeine. CONCLUSIONS These results demonstrate a very small but potentially important placebo effect with nutritional supplementation studies. A substantive proportion of supplement effects may be due to placebo effects, with the relative proportion influenced by the magnitude of the overall ergogenic effect. Where feasible, intervention studies should use nonplacebo control-arm comparators to identify the proportion of the effect estimated to come from placebo effects and avoid underestimating the overall benefits that the physiological plus psychobiological aspects associated with an intervention provide in the real world.
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Affiliation(s)
- Felipe Miguel Marticorena
- Applied Physiology and Nutrition Research Group, School of Physical Education and Sport, Rheumatology Division, Faculdade de Medicina FMUSP, Universidade de Sao Paulo (University of São Paulo), São Paulo, BRAZIL
| | - Arthur Carvalho
- Applied Physiology and Nutrition Research Group, School of Physical Education and Sport, Rheumatology Division, Faculdade de Medicina FMUSP, Universidade de Sao Paulo (University of São Paulo), São Paulo, BRAZIL
| | - Luana Farias DE Oliveira
- Applied Physiology and Nutrition Research Group, School of Physical Education and Sport, Rheumatology Division, Faculdade de Medicina FMUSP, Universidade de Sao Paulo (University of São Paulo), São Paulo, BRAZIL
| | - Eimear Dolan
- Applied Physiology and Nutrition Research Group, School of Physical Education and Sport, Rheumatology Division, Faculdade de Medicina FMUSP, Universidade de Sao Paulo (University of São Paulo), São Paulo, BRAZIL
| | | | - Paul Swinton
- School of Health Sciences, Robert Gordon University, Aberdeen, UNITED KINGDOM
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Different routes of administration in chronic migraine prevention lead to different placebo responses: a meta-analysis. Pain 2021; 163:415-424. [PMID: 34252914 DOI: 10.1097/j.pain.0000000000002365] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 06/01/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT Placebo response is a powerful determinant of health outcomes in several disorders. Meta-analysis of clinical trials in pain conditions shows that it can contribute up to 75% of the overall treatment effect. Placebo response deriving from different routes of administration is poorly understood in primary headaches' pharmacological prevention. Thus, this meta-analysis aims to analyze how different routes of administration affect the placebo response in chronic migraine (CM). We conducted a meta-analysis with 7 randomized, double-blind, placebo-controlled clinical trials, with 5672 patients older than 18 years who suffer from CM without associated comorbidities. We compared those who received a placebo-administered agent for the preventive treatment of CM subcutaneous, endovenous, or oral against those who received multiple head injections. The primary outcome was reduction in the number of days with migraine in the month assessed at 12, 16, and 24 weeks of treatment compared with baseline. Our study shows that placebo responses were greater when botulinum toxin was applied to the head, followed by intravenous injection of the anti-calcitonin gene-related peptide monoclonal antibody eptinezumab. Oral topiramate and subcutaneous monoclonal showed no difference, being inferior to head injection. Administration route affects placebo responses in CM preventive treatment. Elucidating the underlying mechanisms that mediate a placebo response in migraine treatment is beneficial to clinical practice and drug development, especially when comparing drugs with different routes of administration, with the effect of application to the head being superior to the other routes in this study. In our study the placebo response accounted for approximately 75% of the therapeutic gain in the treatment of CM.
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Wilhelm M, Euteneuer F. Does Health Literacy Make a Difference? Comparing the Effect of Conventional Medicine Versus Homeopathic Prescribing on Treatment Credibility and Expectancy. Front Psychol 2021; 12:581255. [PMID: 34140910 PMCID: PMC8204743 DOI: 10.3389/fpsyg.2021.581255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 04/27/2021] [Indexed: 11/13/2022] Open
Abstract
Objective While homeopathic remedies are often used to treat non-specific complaints such as headaches, empirical evidence suggests their treatment effect is due to the placebo effect. Low health literacy seems to be connected to higher use of complementary and alternative medicine (CAM). The aim of this study was to examine what people with occasional headaches expect from conventional medicine or homeopathic remedies and if health literacy interacts with this expectation. Methods In this experimental study, n = 582 participants with occasional headaches were randomized to read one of two vignettes, which described the prescription of either conventional medicine or a homeopathic remedy. Subsequently, the participants were asked to rate treatment credibility and expectancy with regard to their assigned vignette. Health literacy was assessed as a potential moderator. Results Participants in the conventional medicine group rated treatment credibility and expectancy higher than in the homeopathic remedy group. Moderation analysis revealed that when being offered conventional medicine, participant reports of treatment credibility and expectancy decreased with lower health literacy, while these outcomes increased with lower health literacy for homeopathic remedies. Discussion People with occasional headaches estimate the effectiveness of conventional medication properly. However, health care professionals should pay special attention to patients with low health literacy, as they might need more time and information to give their informed consent.
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Affiliation(s)
- Marcel Wilhelm
- Department of Clinical Psychology and Psychotherapy, Philipps University of Marburg, Marburg, Germany
| | - Frank Euteneuer
- Department of Clinical Psychology and Psychotherapy, Philipps University of Marburg, Marburg, Germany.,Department of Psychology, Clinical Psychology and Psychotherapy, Medical School Berlin, Berlin, Germany
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He J, Perez DG, Le-Rademacher JL, Dodge A, Enck P, Loprinzi CL, Zahrieh D. Does the placebo effect on hot flashes depend on the placebo dose? Support Care Cancer 2021; 29:6741-6749. [PMID: 33973082 DOI: 10.1007/s00520-021-06244-3] [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: 11/30/2020] [Accepted: 04/20/2021] [Indexed: 11/29/2022]
Abstract
PURPOSE To investigate the presence of a placebo dose-response effect in four randomized, double-blind, placebo-controlled, multi-dose hot flash clinical trials conducted at Mayo Clinic. METHODS Hot flash score, frequency, and hot flash-related distress for each placebo dose level were summarized at each time point by mean and standard deviation and changes from baseline were plotted to visualize a possible placebo dose-effect response. Furthermore, a meta-analysis was conducted for each endpoint in the highest and lowest dosage arms across the four trials. RESULTS Longitudinal plots of mean hot flash scores, frequencies, and hot flash-related distress scores in patients taking placebo in each study showed a decline in hot flash scores over time without any clinically meaningful differences between the lowest and highest dosage arms in each study. The meta-analysis for each endpoint in the highest and lowest dosage arms across the four trials revealed no clinically important differences either. CONCLUSION While the current study cannot rule out the existence of a placebo dose-response effect in multi-dose placebo-controlled trials in patients with hot flashes or other conditions, it suggests, along with the available data in the placebo literature, that, at least in well-conducted multi-dose clinical trials in which the placebo was used as control, such an effect, if it exists at all, should be very small. Therefore, pooling data from different placebo subgroups is unlikely to compromise the validity of comparisons between the combined placebo arms and each treatment arm.
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Affiliation(s)
- Jun He
- Biomedical Statistics and Informatics - Cancer Statistics, Mayo Clinic, MN, Rochester, USA
| | - Domingo G Perez
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | | | - Andrew Dodge
- Biomedical Statistics and Informatics - Kern Center HSA, Mayo Clinic, MN, Rochester, USA
| | - Paul Enck
- Department of Internal Medicine VI: Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany
| | | | - David Zahrieh
- Biomedical Statistics and Informatics - Cancer Statistics, Mayo Clinic, MN, Rochester, USA
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41
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The Influence of Verbal Suggestion on Post-Needling Soreness and Pain Processing after Dry Needling Treatment: An Experimental Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18084206. [PMID: 33921101 PMCID: PMC8071378 DOI: 10.3390/ijerph18084206] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/08/2021] [Accepted: 04/08/2021] [Indexed: 11/17/2022]
Abstract
BACKGROUND It remains unclear as to whether verbal suggestions and expectancies can influence the perception of post-needling soreness. The aim of this study was to analyze the effects of verbal suggestions on post-needling soreness after dry needling of the trapezius muscle. METHODS This study is a randomized controlled trial including healthy subjects randomly assigned to one of three groups receiving different verbal suggestions about the effects of dry needling and the occurrence of post needling soreness (positive, negative, or neutral). Then, dry needling on a latent trigger point of the upper trapezius muscle was performed and the following outcomes were measured immediately after, 24, 48, and 72 h, and one week after the intervention: post-needling soreness intensity, pressure pain threshold (PPT), temporal summation (TS) and conditioned pain modulation (CPM). RESULTS Seventy-three consecutive participants were screened and 42 participants (12 men and 30 women, aged: 24 ± 8 years old) were eligible and finished the study protocol. The results showed that verbal suggestion did not influence the perception of post-needling soreness, since there were no differences between groups (p < 0.05) on the intensity of post-needling soreness or tenderness over a one-week follow-up. Moreover, verbal suggestion did not associate with changes in sensorimotor variables of TS and CPM. CONCLUSIONS The induction of different types of expectations through verbal suggestion does not influence the perception of acute pain perceived during the performance of a deep dry needling technique and post-needling pain or soreness after deep dry needling on a latent upper trapezius myofascial trigger point (MTrP).
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42
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Nerve growth factor inhibitors for low back pain: balancing the risks and benefits. Pain 2021; 161:1941-1942. [PMID: 32453138 DOI: 10.1097/j.pain.0000000000001927] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 05/15/2020] [Indexed: 11/26/2022]
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Schulze J, Neumann I, Magid M, Finzi E, Sinke C, Wollmer MA, Krüger THC. Botulinum toxin for the management of depression: An updated review of the evidence and meta-analysis. J Psychiatr Res 2021; 135:332-340. [PMID: 33578275 DOI: 10.1016/j.jpsychires.2021.01.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 01/07/2021] [Accepted: 01/15/2021] [Indexed: 12/18/2022]
Abstract
Botulinum toxin (BTX) treatment of glabellar frown lines is one of the most common procedures in aesthetic medicine. In addition to its cosmetic effect, the neurotoxin has been shown to have a positive influence on mood and affect. Several randomized clinical trials (RCTs) have examined the effect of botulinum toxin on the treatment of depression. Combining the results of the five RCTs in a random effects meta-analysis revealed that patients treated with BTX showed a more intense improvement of depressive symptoms in comparison to subjects that received placebo injections (d = 0.98). Despite methodological limitations, the results of this study emphasize the effectiveness of BTX in the treatment of depression and therefore pave the way for its use in the field of psychiatry.
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Affiliation(s)
- Jara Schulze
- Hannover Medical School, Division of Clinical Psychology and Sexual Medicine, Department of Psychiatry, Social Psychiatry and Psychotherapy, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
| | - Insa Neumann
- Asklepios Clinic North - Ochsenzoll, Asklepios Campus Hamburg, Medical Faculty, Semmelweis University, Langenhorner Chaussee 560, 22419, Hamburg, Germany
| | - Michelle Magid
- Department of Psychiatry, Dell Medical School, University of Texas at Austin, 1601 Trinity St., Bldg. B, Stop Z0600, Austin, TX, 78712, USA
| | - Eric Finzi
- Department of Psychiatry and Behavioral Sciences, George Washington School of Medicine, 2120 L Street, NW, Suite 600, Washington, DC, 20037, USA
| | - Christopher Sinke
- Hannover Medical School, Division of Clinical Psychology and Sexual Medicine, Department of Psychiatry, Social Psychiatry and Psychotherapy, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
| | - M Axel Wollmer
- Asklepios Clinic North - Ochsenzoll, Asklepios Campus Hamburg, Medical Faculty, Semmelweis University, Langenhorner Chaussee 560, 22419, Hamburg, Germany
| | - Tillmann H C Krüger
- Hannover Medical School, Division of Clinical Psychology and Sexual Medicine, Department of Psychiatry, Social Psychiatry and Psychotherapy, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany; Center for Systems Neuroscience, Bünteweg 2, 30559 Hannover, Germany.
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44
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Annoni M, Buergler S, Stewart-Ferrer S, Blease C. Placebo Studies and Patient Care: Where Are the Nurses? Front Psychiatry 2021; 12:591913. [PMID: 33790812 PMCID: PMC8006311 DOI: 10.3389/fpsyt.2021.591913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 02/15/2021] [Indexed: 12/30/2022] Open
Affiliation(s)
- Marco Annoni
- Centro Interdipartimentale per l'Etica e l'Integrità nella Ricerca, National Research Council of Italy, Roma, Italy.,Fondazione Umberto Veronesi, Milano, Italy
| | - Sarah Buergler
- Division of Clinical Psychology and Psychotherapy, Faculty of Psychology, University of Basel, Basel, Switzerland
| | - Sif Stewart-Ferrer
- Research Unit of General Practice, Department of Public Health, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Charlotte Blease
- Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
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Romão VC, Polido-Pereira J, Barros R, Luís R, Vidal B, Vieira-Sousa E, Vitorino E, Humby F, Kelly S, Pitzalis C, Saraiva F, Fonseca JE. Efficacy, Safety, and Sample Quality of Ultrasound-Guided Synovial Needle Biopsy in Clinical Practice and Research: A Prospective Observational Study. Arthritis Care Res (Hoboken) 2020; 72:1497-1505. [PMID: 31421034 DOI: 10.1002/acr.24050] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Accepted: 08/13/2019] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To study the efficacy, tolerability, safety, and sampling variation of ultrasound (US)-guided synovial biopsies performed in clinical practice and research. METHODS We included all patients who had a US-guided synovial needle biopsy from November 2013 to January 2018. Patients were evaluated for procedure safety and tolerability. Usefulness of synovial biopsy was considered based on contribution for achieving the proposed aims. We analyzed samples for presence and quality of synovial tissue, synovitis score/grade, and pathotype. Variation across patients, samples, section levels, and sampling order was assessed. RESULTS A total of 64 US-guided synovial biopsies were performed (n = 52 in clinical practice, n = 12 in research). Patient tolerability (70% no/mild discomfort) was remarkably high. There was no significant aggravation of symptoms or US synovitis in the biopsied joint. Procedures were overall safe, with few minor, 2 moderate, and no major adverse events. Usefulness of US-guided synovial biopsies was high, both in clinical practice (37% direct diagnostic impact, 100% positive/95% negative predictive values for infection) and in research (92% success). Synovial tissue was retrieved in 88% of biopsies, with a median of 75% gradable samples. There was significant variation in sample quality and synovitis features across patients and samples, but not between different section levels. Samples collected later in the procedure had a lower frequency of synovial tissue and were poorly concordant in pathotype with those collected earlier. CONCLUSION US-guided synovial needle biopsy is an effective, safe, and well-tolerated means to collect good quality synovial tissue for clinical and research purposes. Samples collected for different aims should be retrieved in parallel, rather than sequentially.
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Affiliation(s)
- Vasco C Romão
- Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, and Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon Academic Medical Centre, Lisbon, Portugal
| | - Joaquim Polido-Pereira
- Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, and Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon Academic Medical Centre, Lisbon, Portugal
| | - Rita Barros
- Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, and Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon Academic Medical Centre, Lisbon, Portugal
| | - Rita Luís
- Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, and Faculdade de Medicina, Universidade de Lisboa, Lisbon Academic Medical Centre, Lisbon, Portugal
| | - Bruno Vidal
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon Academic Medical Centre, Lisbon, Portugal
| | - Elsa Vieira-Sousa
- Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, and Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon Academic Medical Centre, Lisbon, Portugal
| | - Emília Vitorino
- Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon Academic Medical Centre, London, United Kingdom
| | - Frances Humby
- William Harvey Research Institute, Barts and the London School of Medicine , London, United Kingdom
| | - Stephen Kelly
- Mile End Hospital, Barts Health NHS Trust, London, UK
| | - Costantino Pitzalis
- William Harvey Research Institute, Barts and the London School of Medicine , London, United Kingdom
| | - Fernando Saraiva
- Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon Academic Medical Centre, London, United Kingdom
| | - João Eurico Fonseca
- Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, and Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon Academic Medical Centre, Lisbon, Portugal
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Howick J, Webster RK, Rees JL, Turner R, Macdonald H, Price A, Evers AWM, Bishop F, Collins GS, Bokelmann K, Hopewell S, Knottnerus A, Lamb S, Madigan C, Napadow V, Papanikitas AN, Hoffmann T. TIDieR-Placebo: A guide and checklist for reporting placebo and sham controls. PLoS Med 2020; 17:e1003294. [PMID: 32956344 PMCID: PMC7505446 DOI: 10.1371/journal.pmed.1003294] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Placebo or sham controls are the standard against which the benefits and harms of many active interventions are measured. Whilst the components and the method of their delivery have been shown to affect study outcomes, placebo and sham controls are rarely reported and often not matched to those of the active comparator. This can influence how beneficial or harmful the active intervention appears to be. Without adequate descriptions of placebo or sham controls, it is difficult to interpret results about the benefits and harms of active interventions within placebo-controlled trials. To overcome this problem, we developed a checklist and guide for reporting placebo or sham interventions. METHODS AND FINDINGS We developed an initial list of items for the checklist by surveying experts in placebo research (n = 14). Because of the diverse contexts in which placebo or sham treatments are used in clinical research, we consulted experts in trials of drugs, surgery, physiotherapy, acupuncture, and psychological interventions. We then used a multistage online Delphi process with 53 participants to determine which items were deemed to be essential. We next convened a group of experts and stakeholders (n = 16). Our main output was a modification of the existing Template for Intervention Description and Replication (TIDieR) checklist; this allows the key features of both active interventions and placebo or sham controls to be concisely summarised by researchers. The main differences between TIDieR-Placebo and the original TIDieR are the explicit requirement to describe the setting (i.e., features of the physical environment that go beyond geographic location), the need to report whether blinding was successful (when this was measured), and the need to present the description of placebo components alongside those of the active comparator. CONCLUSIONS We encourage TIDieR-Placebo to be used alongside TIDieR to assist the reporting of placebo or sham components and the trials in which they are used.
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Affiliation(s)
| | - Rebecca K. Webster
- University of Oxford, Oxford, United Kingdom
- King’s College London, London, United Kingdom
- University of Oxford, Oxford, United Kingdom
| | | | - Richard Turner
- Public Library of Science, San Francisco, California, United States of America and Cambridge, United Kingdom
| | | | - Amy Price
- University of Oxford, Oxford, United Kingdom
| | | | | | | | | | | | | | - Sarah Lamb
- University of Oxford, Oxford, United Kingdom
| | - Claire Madigan
- University of Oxford, Oxford, United Kingdom
- Sydney University, Sydney, Australia
| | - Vitaly Napadow
- Harvard Medical School, Cambridge, Massachusetts, United States of America
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47
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Kuperman P, Talmi D, Katz N, Treister R. Certainty in ascending sensory signals - The unexplored driver of analgesic placebo response. Med Hypotheses 2020; 143:110113. [PMID: 32721807 DOI: 10.1016/j.mehy.2020.110113] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 07/06/2020] [Accepted: 07/13/2020] [Indexed: 10/23/2022]
Abstract
Previous frameworks have failed to adequately explain the observed correlation between within-subject variability in pain reporting and analgesic placebo response. These relationships have been observed in both clinical and experimental setups. Within-subject variability of clinical pain scores is traditionally assessed based on daily pain diaries collected during the pre-intervention stage. Experimental variability can be assessed by the Focused Analgesia Selection Test (FAST), which calculates the relationship between noxious stimuli administrated at various intensities and pain reports. The variability, either clinical or experimental, has been shown to predict the placebo response. In explaining the placebo response, Bayesian Brain Hypothesis (BBH) posits that pain perception (posterior), is composed of certainty (precision) of expectations (priors due to belief or conditioning) and incoming sensory information (likelihood), with the bulk of research focused on the precision of priors. Virtually all placebo analgesia research has focused on the priors and their certainty, rather than on the certainty of the likelihood, mainly because it cannot be assessed directly. We propose that the within-subject variability, as encapsulated by the FAST, is a proxy for certainty in (or, precision of) ascending sensory signals, and our results suggest that it could not only be assessed, but also manipulated. If true, our hypothesis will facilitate new lines of research and could potentially promote precision analgesic medicine by use of variability of pain scores as a diagnostic method to identify pain patients who will benefit from specific treatments.
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Affiliation(s)
- P Kuperman
- The Clinical Pain Innovation Lab, University of Haifa, Haifa, Israel
| | - D Talmi
- Department of Psychology, University of Cambridge, UK
| | - Np Katz
- WCG Analgesic Solutions, Wayland, MA, USA; Department of Anaesthesiology and Perioperative Medicine, Tufts University School of Medicine, Boston, MA, USA
| | - R Treister
- The Clinical Pain Innovation Lab, University of Haifa, Haifa, Israel; Faculty of Social Welfare and Health Sciences, University of Haifa, Israel.
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48
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Zhao Z, Larkin TM, Cohen SP. Reflections on Innovative Interventional Pain-Relieving Procedures: Lessons Learned from Previous Mistakes. PAIN MEDICINE 2020; 21:655-658. [PMID: 32053202 DOI: 10.1093/pm/pnz380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Zirong Zhao
- Pain Management Program, Department of Neurology, Veterans Affairs Medical Center, Washington, DC
| | | | - Steven P Cohen
- Department of Anesthesiology & Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland.,Neurology and Physical Medicine & Rehabilitation, Johns Hopkins Medical Institutions, Baltimore, Maryland.,Department of Physical Medicine & Rehabilitation and Anesthesiology, Walter Reed National Military Medical Center, Bethesda, Maryland, USA
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49
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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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50
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Rodrigues FB, Ferreira JJ. Strategies to minimize placebo effects in research investigations. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2020; 153:49-70. [PMID: 32563293 DOI: 10.1016/bs.irn.2020.04.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Placebo-controlled trials are the research standard to evaluate new interventions for which there is no standard of care. While lessening performance and detection bias, such design provides a direct mode of comparison against the probed intervention. Still, using placebo arms may pose new challenges to the design, conduct and analysis of clinical trials. This is particularly relevant in circumstances of non-additivity between the therapeutic and the placebo effects, if the outcome of interest has floor or ceiling effects, or when the predicted effect size of the intervention is large and leads to small sample sizes. There are several possible strategies to mitigate the confounding effects of the placebo, each relevant to specific clinical trial designs. This chapter puts into context the new challenges created by the placebo effect, discusses possible ways around them, and explores the future of the field.
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Affiliation(s)
- Filipe B Rodrigues
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom; Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; Instituto de Medicina Molecular, Lisbon, Portugal
| | - Joaquim J Ferreira
- Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; Instituto de Medicina Molecular, Lisbon, Portugal; CNS-Campus Neurológico Sénior, Torres Vedras, Portugal.
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