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Bierman SF, Weil A, Dahmer S. Placebo and the law of identification. Front Psychiatry 2024; 15:1474558. [PMID: 39713767 PMCID: PMC11659211 DOI: 10.3389/fpsyt.2024.1474558] [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: 08/21/2024] [Accepted: 11/07/2024] [Indexed: 12/24/2024] Open
Abstract
Thousands of essays and studies have been published on placebo and nocebo. Yet, despite this plethora of information, we are not much closer to a comprehensive understanding of the fundamental mechanism producing placebo and nocebo effects than we were in 1946, when participants in the Cornell Conferences on Therapy speculated on the roles of authority, belief and expectancy. In this paper, we examine the weaknesses in current placebo and nocebo definitions and theories. We also propose a more concise and comprehensive definition and theory of placebo and nocebo by introducing the Law of Identification and the Generic Placebo Instruction (GPI). The latter being the placebo/nocebo information expressed or implied in virtually every clinical encounter and trial; the former (i.e., the Law of Identification), being what drives the GPI to actualization. Further, we demonstrate the explanatory power of this new theory and suggest clinical studies that test predictions arising from it - studies whose results, if positive, would translate universally into clinical practice.
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Affiliation(s)
- Steve F. Bierman
- College of Medicine, University of Arizona, Tucson,
AZ, United States
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2
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Copping R, Balamon P, Lau M, Catt J, Schlaphoff G. MethOxyfluraNe in InTerventiOnal Radiology (MONITOR): A randomised controlled trial. J Med Imaging Radiat Oncol 2024; 68:705-713. [PMID: 38923825 DOI: 10.1111/1754-9485.13726] [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: 03/18/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024]
Abstract
INTRODUCTION Procedural sedation and pain management in interventional radiology (IR) are of critical importance to successful outcomes but remain under-researched. Methoxyflurane has been previously used in some minor procedures with several advantages including rapid onset and offset and a good safety profile. The purpose of this study was to evaluate methoxyflurane for procedures in IR. METHODS A randomised, double-blind, placebo-controlled trial was performed between October 2021 and November 2022. Patients presenting for portacath insertion, portacath removal or solid organ biopsy were randomised to either methoxyflurane or placebo. Three hundred and fourteen patients were enrolled in total. Patients were supplied with one Penthrox inhaler containing either 3 mL methoxyflurane or placebo. The primary endpoints of the study were change in pain and anxiety scores compared with baseline, measured on a standardised visual analogue scale (VAS) pre-procedure, at 5-min intervals during the procedure and post-procedure. Baselines scores were controlled for in the statistical analysis. Safety analysis was also performed. RESULTS One hundred and sixty-nine patients received methoxyflurane and 145 received placebo. Baseline characteristics were similar between the two groups. The methoxyflurane group had lower pain and anxiety scores throughout the procedure (P < 0.001) with 2.5 times less pain (VAS 1.08/10) and 1.6 times less anxiety (VAS 0.97/10) on average. Lower post-procedure pain (mean 0.72 vs 1.44; P < 0.001) and anxiety (mean 0.55 vs 1.13; P = 0.008) were also observed with methoxyflurane. There were no drug or major procedure-related adverse events. CONCLUSION The results of this study suggest that methoxyflurane provides safe and effective analgesia and anxiolysis for some procedures in IR.
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Affiliation(s)
- Ross Copping
- Interventional Radiology Department, Liverpool Hospital, Sydney, New South Wales, Australia
- Discipline of Medicine, South West Sydney Clinical Campuses, UNSW Medicine and Health, Sydney, New South Wales, Australia
| | - Paul Balamon
- Interventional Radiology Department, Liverpool Hospital, Sydney, New South Wales, Australia
| | - Marcus Lau
- Interventional Radiology Department, Liverpool Hospital, Sydney, New South Wales, Australia
| | - Jules Catt
- Interventional Radiology Department, Liverpool Hospital, Sydney, New South Wales, Australia
| | - Glen Schlaphoff
- Interventional Radiology Department, Liverpool Hospital, Sydney, New South Wales, Australia
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3
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Ivanec D, Stanke KM, Tomić I, Matijaš S. Dominance-submissiveness cues modulate pain threshold for mechanical pressure. Q J Exp Psychol (Hove) 2023; 76:2371-2378. [PMID: 36420810 DOI: 10.1177/17470218221143759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/16/2023]
Abstract
Acute pain sensation is an inherently negative but adaptive experience; however, research on pain sensitivity shows that simple contextual cues can effectively attenuate the pain. In this study, we sought to investigate how dominance cues, manipulated as vertical spatial (i.e., height) distance between participants and experimenter, affect participants' pain sensitivity. Positioning participants in a spatially higher position relative to the experimenter was aimed to induce a feeling of dominance in participants. Conversely, a feeling of submissiveness was induced by placing the experimenter in a spatially higher position. In addition, we examined the role of dominance cues with respect to participants' and experimenters' gender. Two separate studies were conducted-Study 1 with a male experimenter measuring pain threshold in female and male participants (N = 137), and Study 2 with a female experimenter conducting pain measurement in a new sample of female and male participants (N = 122). The results of both studies demonstrated that participants in a dominant position reported a higher pain threshold relative to participants in a submissive position. Male participants had a higher pain threshold in both studies; however, Study 1 revealed a significant interaction of dominance manipulation and participant's gender, with the effect of dominance cues being larger in men.
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Affiliation(s)
- Dragutin Ivanec
- Department of Psychology, Faculty of Humanities and Social Sciences, University of Zagreb, Zagreb, Croatia
| | - Koraljka Modić Stanke
- Department of Psychology, Social Work Study Centre, Faculty of Law, University of Zagreb, Zagreb, Croatia
| | - Ivan Tomić
- Department of Psychology, Faculty of Humanities and Social Sciences, University of Zagreb, Zagreb, Croatia
| | - Sanja Matijaš
- Department of Psychology, Faculty of Humanities and Social Sciences, University of Zagreb, Zagreb, Croatia
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Tu Y, Zhang L, Kong J. Placebo and nocebo effects: from observation to harnessing and clinical application. Transl Psychiatry 2022; 12:524. [PMID: 36564374 PMCID: PMC9789123 DOI: 10.1038/s41398-022-02293-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/25/2022] Open
Abstract
Placebo and nocebo effects are salubrious benefits and negative outcomes attributable to non-specific symbolic components. Leveraging advanced experimental and analytical approaches, recent studies have elucidated complicated neural mechanisms that may serve as a solid basis for harnessing the powerful self-healing and self-harming capacities and applying these findings to improve medical practice and minimize the unintended exacerbation of symptoms in medical practice. We review advances in employing psychosocial, pharmacological, and neuromodulation approaches to modulate/harness placebo and nocebo effects. While these approaches show promising potential, translating these research findings into clinical settings still requires careful methodological, technical, and ethical considerations.
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Affiliation(s)
- Yiheng Tu
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China. .,Department of Psychology, University of Chinese Academy of Sciences, Beijing, China.
| | - Libo Zhang
- grid.9227.e0000000119573309CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China ,grid.410726.60000 0004 1797 8419Department of Psychology, University of Chinese Academy of Sciences, Beijing, China
| | - Jian Kong
- grid.32224.350000 0004 0386 9924Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA USA
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5
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De Pascalis V, Vecchio A. The influence of EEG oscillations, heart rate variability changes, and personality on self-pain and empathy for pain under placebo analgesia. Sci Rep 2022; 12:6041. [PMID: 35410362 PMCID: PMC9001726 DOI: 10.1038/s41598-022-10071-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 04/01/2022] [Indexed: 12/30/2022] Open
Abstract
We induced placebo analgesia (PA), a phenomenon explicitly attenuating the self-pain feeling, to assess whether this resulted in reduced empathy pain when witnessing a confederate undergoing such pain experience. We recorded EEG and electrocardiogram during a painful Control and PA treatment in healthy adults who rated their experienced pain and empathy for pain. We derived HRV changes and, using wavelet analysis of non-phase-locked event-related EEG oscillations, EEG spectral power differences for self-pain and other-pain conditions. First-hand PA reduced self-pain and self-unpleasantness, whereas we observed only a slight decrease in other unpleasantness. We derived linear combinations of HRV and EEG band power changes significantly associated with self-pain and empathy for pain changes using PCAs. Lower Behavioral Inhibition System scores predicted self-pain reduction through the mediating effect of a relative HR-slowing and a decreased midline ϑ-band (4-8 Hz) power factor moderated by lower Fight-Flight-Freeze System trait scores. In the other-pain condition, we detected a direct positive influence of Total Empathic Ability on the other-pain decline with a mediating role of the midline β2-band (22-30 Hz) power reduction. These findings suggest that PA modulation of first-hand versus other pain relies on functionally different physiological processes involving different personality traits.
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Affiliation(s)
- Vilfredo De Pascalis
- Department of Psychology, Sapienza Foundation, Sapienza University of Rome, Via dei Marsi, 78, 00185, Rome, Italy.
| | - Arianna Vecchio
- Department of Psychology, Sapienza Foundation, Sapienza University of Rome, Via dei Marsi, 78, 00185, Rome, Italy
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6
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Manipulating placebo analgesia and nocebo hyperalgesia by changing brain excitability. Proc Natl Acad Sci U S A 2021; 118:2101273118. [PMID: 33941677 DOI: 10.1073/pnas.2101273118] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Harnessing placebo and nocebo effects has significant implications for research and medical practice. Placebo analgesia and nocebo hyperalgesia, the most well-studied placebo and nocebo effects, are thought to initiate from the dorsal lateral prefrontal cortex (DLPFC) and then trigger the brain's descending pain modulatory system and other pain regulation pathways. Combining repeated transcranial direct current stimulation (tDCS), an expectancy manipulation model, and functional MRI, we investigated the modulatory effects of anodal and cathodal tDCS at the right DLPFC on placebo analgesia and nocebo hyperalgesia using a randomized, double-blind and sham-controlled design. We found that compared with sham tDCS, active tDCS could 1) boost placebo and blunt nocebo effects and 2) modulate brain activity and connectivity associated with placebo analgesia and nocebo hyperalgesia. These results provide a basis for mechanistic manipulation of placebo and nocebo effects and may lead to improved clinical outcomes in medical practice.
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Alter BJ, Aung MS, Strigo IA, Fields HL. Onset hyperalgesia and offset analgesia: Transient increases or decreases of noxious thermal stimulus intensity robustly modulate subsequent perceived pain intensity. PLoS One 2020; 15:e0231124. [PMID: 33290407 PMCID: PMC7723268 DOI: 10.1371/journal.pone.0231124] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 11/06/2020] [Indexed: 12/17/2022] Open
Abstract
Reported pain intensity depends not only on stimulus intensity but also on previously experienced pain. A painfully hot temperature applied to the skin evokes a lower subjective pain intensity if immediately preceded by a higher temperature, a phenomenon called offset analgesia. Previous work indicated that prior pain experience can also increase subsequent perceived pain intensity. Therefore, we examined whether a given noxious stimulus is experienced as more intense when it is preceded by an increase from a lower temperature. Using healthy volunteer subjects, we observed a disproportionate increase in pain intensity at a given stimulus intensity when this intensity is preceded by a rise from a lower intensity. This disproportionate increase is similar in magnitude to that of offset analgesia. We call this effect onset hyperalgesia. Control stimuli, in which a noxious temperature is held constant, demonstrate that onset hyperalgesia is distinct from receptor or central sensitization. The absolute magnitudes of offset analgesia and onset hyperalgesia correlate with each other but not with the noxious stimulus temperature. Finally, the magnitude of both offset analgesia and onset hyperalgesia depends on preceding temperature changes. Overall, this study demonstrates that the perceptual effect of a noxious thermal stimulus is influenced in a bidirectional manner depending upon both the intensity and direction of change of the immediately preceding thermal stimulus.
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Affiliation(s)
- Benedict J. Alter
- Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- * E-mail:
| | - Mya Sandi Aung
- Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America
| | - Irina A. Strigo
- San Francisco VA Health Care System & Department of Psychiatry, University of California San Francisco, San Francisco, California, United States of America
| | - Howard L. Fields
- Department of Neurology, University of California San Francisco, San Francisco, California, United States of America
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Egner LE, Sütterlin S, Calogiuri G. Proposing a Framework for the Restorative Effects of Nature through Conditioning: Conditioned Restoration Theory. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:E6792. [PMID: 32957693 PMCID: PMC7558998 DOI: 10.3390/ijerph17186792] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/09/2020] [Accepted: 09/15/2020] [Indexed: 12/02/2022]
Abstract
Natural environments have been shown to trigger psychological and physiological restoration in humans. A new framework regarding natural environments restorative properties is proposed. Conditioned restoration theory builds on a classical conditioning paradigm, postulating the occurrence of four stages: (i) unconditioned restoration, unconditioned positive affective responses reliably occur in a given environment (such as in a natural setting); (ii) restorative conditioning, the positive affective responses become conditioned to the environment; (iii) conditioned restoration, subsequent exposure to the environment, in the absence of the unconditioned stimulus, retrieves the same positive affective responses; and (iv) stimulus generalization, subsequent exposure to associated environmental cues retrieves the same positive affective responses. The process, hypothetically not unique to natural environments, involve the well-documented phenomenon of conditioning, retrieval, and association and relies on evaluative conditioning, classical conditioning, core affect, and conscious expectancy. Empirical findings showing that restoration can occur in non-natural environments and through various sensory stimuli, as well as findings demonstrating that previous negative experience with nature can subsequently lower restorative effects, are also presented in support of the theory. In integration with other existing theories, the theory should prove to be a valuable framework for future research.
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Affiliation(s)
- Lars Even Egner
- Citizens, Environment and Safety, Institute of Psychology, Norwegian University of Science and Technology, 7048 Trondheim, Norway
| | - Stefan Sütterlin
- Faculty of Health and Welfare Sciences, Østfold University College, 1757 Halden, Norway;
- Division of Clinical Neuroscience, Oslo University Hospital, 0450 Oslo, Norway
| | - Giovanna Calogiuri
- Faculty of Health and Social Sciences, University of South-Eastern Norway, 3045 Drammen, Norway;
- Department of Public Health and Sport Sciences, Inland Norway University of Applied Sciences, 2411 Elverum, Norway
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Abstract
Placebo effects influence symptom perceptions and treatment outcomes. Placebo effects can be explored in laboratory settings controlling for natural history and expectations. Such a mechanistic approach to neurological disorders has been implemented in the domain of chronic clinical pain and other neurological disorders. This article therefore focuses on definitions and historical notes related to placebo effects and mechanisms of placebo effects in chronic pain. Knowledge on mechanisms of placebo effects could inform current clinical practice for the treatment of neurological disorders by focusing on patients (and providers) expectations for outcome optimization.
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Affiliation(s)
- Luana Colloca
- Department of Pain Translational Symptoms Science, School of Nursing, University of Maryland, Baltimore, MD, United States; Center to Advance Chronic Pain Research, University of Maryland, Baltimore, MD, United States; Departments of Anesthesiology and Psychiatry, School of Medicine, University of Maryland, Baltimore, MD, United States.
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10
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Ackerman JM, Goesling J, Krishna A. Pain scales as placebos: Can pain scales change reported pain across measurements? JOURNAL OF EXPERIMENTAL SOCIAL PSYCHOLOGY 2020. [DOI: 10.1016/j.jesp.2020.103961] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Porter KM, Dayan AD, Dickerson S, Middleton PM. The role of inhaled methoxyflurane in acute pain management. Open Access Emerg Med 2018; 10:149-164. [PMID: 30410414 PMCID: PMC6200081 DOI: 10.2147/oaem.s181222] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Methoxyflurane is an inhaled analgesic administered via a disposable inhaler which has been used in Australia for over 40 years for the management of pain associated with trauma and for medical procedures in children and adults. Now available in 16 countries worldwide, it is licensed in Europe for moderate to severe pain associated with trauma in conscious adults, although additional applications are being made to widen the range of approved indications. Considering these ongoing developments, we reviewed the available evidence on clinical usage and safety of inhaled analgesic methoxyflurane in trauma pain and in medical procedures in both adults and children. Published data on methoxyflurane in trauma and procedural pain show it to be effective, well tolerated, and highly rated by patients, providing rapid onset of analgesia. Methoxyflurane has a well-established safety profile; adverse events are usually brief and self-limiting, and no clinically significant effects on vital signs or consciousness levels have been reported. Nephrotoxicity previously associated with methoxyflurane at high anesthetic doses is not reported with low analgesic doses. Although two large retrospective comparative studies in the prehospital setting showed inhaled analgesic methoxyflurane to be less effective than intravenous morphine and intranasal fentanyl, this should be balanced against the administration, supervision times, and safety profile of these agents. Given the limitations of currently available analgesic agents in the prehospital and emergency department settings, the ease of use and portability of methoxyflurane combined with its rapid onset of effective pain relief and favorable safety profile make it a useful nonopioid option for pain management. Except for the STOP! study, which formed the basis for approval in trauma pain in Europe, and a few smaller randomized controlled trials (RCTs), much of the available data are observational or retrospective, and further RCTs are currently underway to provide more robust data.
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Affiliation(s)
- Keith M Porter
- Trauma Department, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK
| | | | - Sara Dickerson
- Medical Affairs, Mundipharma International Limited, Cambridge, UK,
| | - Paul M Middleton
- Emergency Medicine Research Unit, Liverpool Hospital, Sydney, NSW, Australia
- Distributed Research in Emergency and Acute Medicine (DREAM) Collaboration, Sydney, NSW, Australia
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12
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13
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Bräscher AK, Kleinböhl D, Hölzl R, Becker S. Differential Classical Conditioning of the Nocebo Effect: Increasing Heat-Pain Perception without Verbal Suggestions. Front Psychol 2017; 8:2163. [PMID: 29321752 PMCID: PMC5733554 DOI: 10.3389/fpsyg.2017.02163] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 11/28/2017] [Indexed: 01/08/2023] Open
Abstract
Background: Nocebo effects, including nocebo hyperalgesia, are a common phenomenon in clinical routine with manifold negative consequences. Both explicit expectations and learning by conditioning are known to induce nocebo effects, but the specific role of conditioning remains unclear, because conditioning is rarely implemented independent of verbal suggestions. Further, although pain is a multidimensional phenomenon, nocebo effects are usually assessed in subjective ratings only, neglecting, e.g., behavioral aspects. The aim of this study was to test whether nocebo hyperalgesia can be learned by conditioning without explicit expectations, to assess nocebo effects in different response channels, and to exploratively assess, whether contingency awareness is a necessary condition for conditioned nocebo hyperalgesia. Methods: Twenty-one healthy volunteers were classically conditioned using painful and non-painful heat stimuli that followed two different cues. The conditioned nocebo effect was assessed by subjective ratings of perceived stimulation intensity on a visual analog scale and a behavioral discrimination task, assessing sensitization and habituation in response to the same stimulation following the two cues. Results: Results show a conditioned nocebo effect indicated by the subjective intensity ratings. Conditioned effects were also seen in the behavioral responses, but paradoxically, behavioral responses indicated decreased perception after conditioning, but only for subjects successfully conditioned as indicated by the subjective ratings. Explorative analyses suggested that awareness of the contingencies and the different cues was not necessary for successful conditioning. Conclusion: Nocebo effects can be learned without inducing additional explicit expectations. The dissociation between the two response channels, possibly representing the conditioned and a compensatory response, highlights the importance of considering different outcomes in nocebo responses to fully understand underlying mechanisms. The present results challenge the role of explicit expectations in conditioned nocebo effects and are relevant with implications in clinical contexts, e.g., when transient adverse effects become conditioned.
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Affiliation(s)
- Anne-Kathrin Bräscher
- Otto-Selz-Institute of Applied Psychology, Mannheim Centre for Work and Health, University of Mannheim, Mannheim, Germany.,Department for Clinical Psychology, Psychotherapy, and Experimental Psychopathology, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Dieter Kleinböhl
- Otto-Selz-Institute of Applied Psychology, Mannheim Centre for Work and Health, University of Mannheim, Mannheim, Germany.,Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Rupert Hölzl
- Otto-Selz-Institute of Applied Psychology, Mannheim Centre for Work and Health, University of Mannheim, Mannheim, Germany.,Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Susanne Becker
- Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.,Alan Edwards Centre for Research on Pain, Faculty of Dentistry, McGill University, Montreal, QC, Canada
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15
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Liu T. Route of placebo administration: Robust placebo effects in laboratory and clinical settings. Neurosci Biobehav Rev 2017; 83:451-457. [PMID: 28941577 DOI: 10.1016/j.neubiorev.2017.09.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 09/14/2017] [Accepted: 09/15/2017] [Indexed: 10/18/2022]
Abstract
Recent advances in laboratory and clinical research have greatly enhanced our understanding of placebo effects. However, little progress has been made in translational research that can well integrate these findings. This article examines pivotal role of placebo administration in subsequent placebo responses, providing a unified framework that accounts for robust placebo effects in both laboratory and clinical settings.
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Affiliation(s)
- Tao Liu
- Medical Research Center, Second Teaching Hospital, University of Jilin Norman Bethune School of Medicine, Changchun, China.
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16
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Wickström K, Edelstam G. Minimal clinically important difference for pain on the VAS scale and the relation to quality of life in women with endometriosis. SEXUAL & REPRODUCTIVE HEALTHCARE 2017; 13:35-40. [PMID: 28844356 DOI: 10.1016/j.srhc.2017.05.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 04/19/2017] [Accepted: 05/23/2017] [Indexed: 11/20/2022]
Abstract
OBJECTIVES The minimal important difference can be helpful in interpreting data from clinical trials. The objective of the study was to calculate the minimal important difference for improvement on the VAS scale for women with endometriosis. STUDY DESIGN A prospective study was conducted to evaluate the effect of pertubation with lignocaine on dysmenorrhea and quality of life in women with endometriosis. Data collected in the trial were used for additional analyses in the present descriptive study. Eligible women (n=37) had endometriosis with pain>VAS 50mm (visual analogue scale). MAIN OUTCOME MEASURES In a questionnaire, women evaluated their maximum pain on the VAS- scale during every menstrual period before and after treatment. They also estimated the changes in overall pain level by answering the response categories "much better", "somewhat better", "about the same", "somewhat worse" or "much worse". The women were grouped according to their own estimation of change in pain intensity after four months. The minimal important differences for change on the VAS scale correlate to the mean change for women who felt "somewhat better" (n=18) excluding those who were pain free (n=2). RESULTS The minimal important difference for improvement on the VAS scale was found to be -39mm and/or -49%. CONCLUSION If the patients have a pain level of at least 50mm on VAS scale at inclusion, the cut off for success in clinical trials is suggested to be defined as an either >40mm or a >50% decrease on VAS scale. Trial registry ClinicalTrials.gov Identifier: NCT01329796.
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Affiliation(s)
- Karin Wickström
- Karolinska Institutet, SE-171 77 Stockholm, Department of Obstetrics and Gynecology, Danderyd Hospital, SE-182 88 Stockholm, Sweden.
| | - Greta Edelstam
- Karolinska Institutet, SE-171 77 Stockholm, Department of Obstetrics and Gynecology, Danderyd Hospital, SE-182 88 Stockholm, Sweden.
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Tétreault P, Mansour A, Vachon-Presseau E, Schnitzer TJ, Apkarian AV, Baliki MN. Brain Connectivity Predicts Placebo Response across Chronic Pain Clinical Trials. PLoS Biol 2016; 14:e1002570. [PMID: 27788130 PMCID: PMC5082893 DOI: 10.1371/journal.pbio.1002570] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 09/23/2016] [Indexed: 12/17/2022] Open
Abstract
Placebo response in the clinical trial setting is poorly understood and alleged to be driven by statistical confounds, and its biological underpinnings are questioned. Here we identified and validated that clinical placebo response is predictable from resting-state functional magnetic-resonance-imaging (fMRI) brain connectivity. This also led to discovering a brain region predicting active drug response and demonstrating the adverse effect of active drug interfering with placebo analgesia. Chronic knee osteoarthritis (OA) pain patients (n = 56) underwent pretreatment brain scans in two clinical trials. Study 1 (n = 17) was a 2-wk single-blinded placebo pill trial. Study 2 (n = 39) was a 3-mo double-blinded randomized trial comparing placebo pill to duloxetine. Study 3, which was conducted in additional knee OA pain patients (n = 42), was observational. fMRI-derived brain connectivity maps in study 1 were contrasted between placebo responders and nonresponders and compared to healthy controls (n = 20). Study 2 validated the primary biomarker and identified a brain region predicting drug response. In both studies, approximately half of the participants exhibited analgesia with placebo treatment. In study 1, right midfrontal gyrus connectivity best identified placebo responders. In study 2, the same measure identified placebo responders (95% correct) and predicted the magnitude of placebo's effectiveness. By subtracting away linearly modeled placebo analgesia from duloxetine response, we uncovered in 6/19 participants a tendency of duloxetine enhancing predicted placebo response, while in another 6/19, we uncovered a tendency for duloxetine to diminish it. Moreover, the approach led to discovering that right parahippocampus gyrus connectivity predicts drug analgesia after correcting for modeled placebo-related analgesia. Our evidence is consistent with clinical placebo response having biological underpinnings and shows that the method can also reveal that active treatment in some patients diminishes modeled placebo-related analgesia. Trial Registration ClinicalTrials.gov NCT02903238 ClinicalTrials.gov NCT01558700.
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Affiliation(s)
- Pascal Tétreault
- Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - Ali Mansour
- Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - Etienne Vachon-Presseau
- Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - Thomas J. Schnitzer
- Department of Physical Medicine and Rehabilitation, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, United States of America
- Department of Internal Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - A. Vania Apkarian
- Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, United States of America
- Department of Physical Medicine and Rehabilitation, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, United States of America
- Department of Anesthesia, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, United States of America
- * E-mail: (AVA); (MNB)
| | - Marwan N. Baliki
- Department of Physical Medicine and Rehabilitation, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, United States of America
- Rehabilitation Institution of Chicago, Chicago, Illinois, United States of America
- * E-mail: (AVA); (MNB)
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Sütterlin S, Egner LE, Lugo RG, Wojniusz S. Beyond expectation: a case for nonpersonal contextual factors in a more comprehensive approach to the placebo effect and the contribution of environmental psychology. Psychol Res Behav Manag 2015; 8:259-62. [PMID: 26586970 PMCID: PMC4634835 DOI: 10.2147/prbm.s91774] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Creating an optimized health care environment to maximize the probability and magnitude of placebo effects draws on a number of well-researched mechanisms such as the patient’s positive expectation toward treatment outcome. Patient-centered communication styles influence expectations and can thus be considered as a form of supplemental treatment. Unconsciously processed contextual triggering and facilitating placebo effects are omnipresent in clinical settings as well as in all other social and physical environments. Contextual cues in both the social and physical domain exert influences on the recipient’s emotional state and recreational experiences. While the majority of research focuses on improving the patients’ expectations, classical conditioning effects of nonsocial contextual factors have been largely neglected in discussions on practical implementation of placebo-enhancing environments. Built on the empirically well-supported argument that conditioning processes act as a powerful tool to mobilize self-healing resources just as verbally induced expectations do, we argue for a stronger consideration of the effects of permanent, nonsocial and nonverbal environmental contexts. Environmental psychology is a new field of research within the psychological domain and offers a toolbox of opportunities for medical psychological research and health care practitioners to improve the treatment outcomes and benefits of health care environments.
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Affiliation(s)
- Stefan Sütterlin
- Section of Psychology, Lillehammer University College, Lillehammer, Norway ; Department of Psychosomatic Medicine, Division of Surgery and Clinical Neuroscience, Oslo University Hospital - Rikshospitalet, Oslo, Norway
| | - Lars E Egner
- Section of Psychology, Lillehammer University College, Lillehammer, Norway
| | - Ricardo G Lugo
- Section of Psychology, Lillehammer University College, Lillehammer, Norway
| | - Slawomir Wojniusz
- Department of Psychosomatic Medicine, Division of Surgery and Clinical Neuroscience, Oslo University Hospital - Rikshospitalet, Oslo, Norway ; Department of Physiotherapy, Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, Oslo, Norway
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Reduction of empathy for pain by placebo analgesia suggests functional equivalence of empathy and first-hand emotion experience. J Neurosci 2015; 35:8938-47. [PMID: 26063925 DOI: 10.1523/jneurosci.3936-14.2015] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Previous research in social neuroscience has consistently shown that empathy for pain recruits brain areas that are also activated during the first-hand experience of pain. This has been interpreted as evidence that empathy relies upon neural processes similar to those underpinning the first-hand experience of emotions. However, whether such overlapping neural activations imply that equivalent neural functions are engaged by empathy and direct emotion experiences remains to be demonstrated. We induced placebo analgesia, a phenomenon specifically modulating the first-hand experience of pain, to test whether this also reduces empathy for pain. Subjective and neural measures of pain and empathy for pain were collected using self-report and event-related potentials (ERPs) while participants underwent painful electrical stimulation or witnessed that another person was undergoing such stimulation. Self-report showed decreased empathy during placebo analgesia, and this was mirrored by reduced amplitudes of the pain-related P2, an ERP component indexing neural computations related to the affective-motivational component of pain. Moreover, these effects were specific for pain, as self-report and ERP measures of control conditions unrelated to pain were not affected by placebo analgesia. Together, the present results suggest that empathy seems to rely on neural processes that are (partially) functionally equivalent to those engaged by first-hand emotion experiences. Moreover, they imply that analgesics may have the unwanted side effect of reducing empathic resonance and concern for others.
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Abstract
UNLABELLED There is little information regarding changes in placebo responsiveness with age, although first predictors of placebo responders such as psychological and physiological processes have been identified. Reviews and meta-analyses indicate that placebo response rates in randomized controlled trials (RCTs) are higher in children and adolescents compared with adults. As these studies cannot control for age-dependent differences in the natural course of the disease, biases might contribute to different placebo rates in RCTs. To avoid these biases, this study investigated age-related differences in placebo responsiveness between children and adults in a well-established experimental model of placebo analgesia combining classic conditioning and expectation. Our data confirm placebo analgesic responses in children, which did not differ in magnitude from those of adults. The influence of previous experience on subsequent treatment outcome was stronger in children than in adults, indicating an increased relevance of learning processes for treatment outcomes in children. Further studies are needed to understand the influence of treatment-related learning processes in children and adolescents, which might critically determine treatment responsiveness during adulthood. PERSPECTIVE This study is the first to experimentally explore placebo analgesia and influences of previous experience on placebo responses in children compared with adults. We found comparable placebo responses in both groups and an increased relevance of learning processes for treatment outcomes in children.
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Horing B, Weimer K, Muth ER, Enck P. Prediction of Symptom Change in Placebo Versus No-Treatment Group in Experimentally Induced Motion Sickness. Appl Psychophysiol Biofeedback 2015; 40:163-72. [DOI: 10.1007/s10484-015-9284-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Vase L, Amanzio M, Price DD. Nocebo vs. placebo: the challenges of trial design in analgesia research. Clin Pharmacol Ther 2015; 97:143-50. [PMID: 25670519 DOI: 10.1002/cpt.31] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 10/28/2014] [Accepted: 11/04/2014] [Indexed: 02/06/2023]
Abstract
The placebo effect in randomized clinical trials appears to have increased thereby contributing to problems of demonstrating statistically reliable effects of treatments that directly target biological mechanisms. The shortcomings of randomized clinical trials are currently discussed along with potential improvements of trial designs. In this review we explain how utilizing knowledge from the placebo and nocebo mechanisms literature could improve the information that can be obtained from randomized clinical trials. We present three major challenges in randomized clinical trials: (i) increasing placebo effects, (ii) variability of the placebo effect, and (iii) risk of un-blinding. We then explain how recent placebo and nocebo studies of effects of verbal suggestion, expectancy, and emotions may improve understanding and discussion of increasing placebo effects, account/control for large parts of the variability of placebo effects, and suggest ways to improve blinding in future trials.
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Affiliation(s)
- L Vase
- Department of Psychology and Behavioural Sciences, School of Business and Social Sciences, Aarhus University, Aarhus, Denmark
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Abstract
The Theory of neural Cognition (TnC) states that the brain does not process information, it only represents information (i.e., it is ‘only’ a memory). The TnC explains how a memory can become an actor pursuing various goals, and proposes explanations concerning the implementation of a large variety of cognitive abilities, such as attention, memory, language, planning, intelligence, emotions, motivation, pleasure, consciousness and personality. The explanatory power of this new framework extends further though, to tackle special psychological states such as hypnosis, the placebo effect and sleep, and brain diseases such as autism, Alzheimer's disease and schizophrenia. The most interesting findings concern robotics: because the TnC considers the cortical column to be the key cognitive unit (instead of the neuron), it reduces the requirements for a brain implementation to only 160,000 units (instead of 86 billion). A robot exhibiting human-like cognitive abilities is therefore within our reach.
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Martini M, Lee MCH, Valentini E, Iannetti GD. Intracortical modulation, and not spinal inhibition, mediates placebo analgesia. Eur J Neurosci 2014; 41:498-504. [PMID: 25523008 DOI: 10.1111/ejn.12807] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 11/17/2014] [Accepted: 11/19/2014] [Indexed: 12/01/2022]
Abstract
Suppression of spinal responses to noxious stimulation has been detected using spinal fMRI during placebo analgesia, which is therefore increasingly considered a phenomenon caused by descending inhibition of spinal activity. However, spinal fMRI is technically challenging and prone to false-positive results. Here we recorded laser-evoked potentials (LEPs) during placebo analgesia in humans. LEPs allow neural activity to be measured directly and with high enough temporal resolution to capture the sequence of cortical areas activated by nociceptive stimuli. If placebo analgesia is mediated by inhibition at spinal level, this would result in a general suppression of LEPs rather than in a selective reduction of their late components. LEPs and subjective pain ratings were obtained in two groups of healthy volunteers - one was conditioned for placebo analgesia while the other served as unconditioned control. Laser stimuli at three suprathreshold energies were delivered to the right hand dorsum. Placebo analgesia was associated with a significant reduction of the amplitude of the late P2 component. In contrast, the early N1 component, reflecting the arrival of the nociceptive input to the primary somatosensory cortex (SI), was only affected by stimulus energy. This selective suppression of late LEPs indicates that placebo analgesia is mediated by direct intracortical modulation rather than inhibition of the nociceptive input at spinal level. The observed cortical modulation occurs after the responses elicited by the nociceptive stimulus in the SI, suggesting that higher order sensory processes are modulated during placebo analgesia.
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Affiliation(s)
- M Martini
- Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK; Department of Psychology, Sapienza University of Rome, Rome, Italy; Fondazione Santa Lucia, Scientific Institute for Research, Hospitalization and Health Care, Rome, Italy
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25
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Horing B, Weimer K, Muth ER, Enck P. Prediction of placebo responses: a systematic review of the literature. Front Psychol 2014; 5:1079. [PMID: 25324797 PMCID: PMC4181242 DOI: 10.3389/fpsyg.2014.01079] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 09/08/2014] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Predicting who responds to placebo treatment-and under which circumstances-has been a question of interest and investigation for generations. However, the literature is disparate and inconclusive. This review aims to identify publications that provide high quality data on the topic of placebo response (PR) prediction. METHODS To identify studies concerned with PR prediction, independent searches were performed in an expert database (for all symptom modalities) and in PubMed (for pain only). Articles were selected when (a) they assessed putative predictors prior to placebo treatment and (b) an adequate control group was included when the associations of predictors and PRs were analyzed. RESULTS Twenty studies were identified, most with pain as dependent variable. Most predictors of PRs were psychological constructs related to actions, expected outcomes and the emotional valence attached to these events (goal-seeking, self-efficacy/-esteem, locus of control, optimism). Other predictors involved behavioral control (desire for control, eating restraint), personality variables (fun seeking, sensation seeking, neuroticism), or biological markers (sex, a single nucleotide polymorphism related to dopamine metabolism). Finally, suggestibility and beliefs in expectation biases, body consciousness, and baseline symptom severity were found to be predictive. CONCLUSIONS While results are heterogeneous, some congruence of predictors can be identified. PRs mainly appear to be moderated by expectations of how the symptom might change after treatment, or expectations of how symptom repetition can be coped with. It is suggested to include the listed constructs in future research. Furthermore, a closer look at variables moderating symptom change in control groups seems warranted.
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Affiliation(s)
- Bjoern Horing
- Department of Internal Medicine - Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen Tübingen, Germany ; Department of Psychology, Clemson University Clemson, SC, USA
| | - Katja Weimer
- Department of Internal Medicine - Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen Tübingen, Germany
| | - Eric R Muth
- Department of Psychology, Clemson University Clemson, SC, USA
| | - Paul Enck
- Department of Internal Medicine - Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen Tübingen, Germany
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26
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Watson DH, Drummond PD. Cervical Referral of Head Pain in Migraineurs: Effects on the Nociceptive Blink Reflex. Headache 2014; 54:1035-45. [DOI: 10.1111/head.12336] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2014] [Indexed: 12/16/2022]
Affiliation(s)
- Dean H. Watson
- School of Psychology; Murdoch University; Perth WA Australia
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27
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Kong J, Benedetti F. Placebo and nocebo effects: an introduction to psychological and biological mechanisms. Handb Exp Pharmacol 2014; 225:3-15. [PMID: 25304523 DOI: 10.1007/978-3-662-44519-8_1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Placebo and nocebo effects are essential components of medical practice and efficacy research, and can be regarded as a special case of context learning. A fundamental function of the central nervous system is to configure the way in which previous learned context becomes linked to corresponding responses. These responses could be either automatic procedures with little flexibility or highly adaptive procedures modified by associated contexts and consequences. Placebo and nocebo effects may represent a typical example of the combination of the two: conditioning effect, which is an inflexible, instinctual, and automatic response, and cognitive expectancy effect, which is a flexible adaptive response modified by prevailing conscious context. Given the fact that contextual learning originates in the brain, neuroimaging tools have been widely used to study placebo and nocebo effects. In addition, pretest resting state fMRI may be a valuable biomarker to predict placebo responses.
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Affiliation(s)
- Jian Kong
- Psychiatry Department, Massachusetts General Hospital, Harvard Medical School, Building 120, 2nd street, Suite 101C, Charlestown, MA, 02129, USA,
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28
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Adey-Wakeling Z, Crotty M, Shanahan EM. Suprascapular Nerve Block for Shoulder Pain in the First Year After Stroke. Stroke 2013; 44:3136-41. [DOI: 10.1161/strokeaha.113.002471] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background and Purpose—
Shoulder pain is a common complication after stroke that can impede participation in rehabilitation and has been associated with poorer outcomes. Evidence-based treatments for hemiplegic shoulder pain are limited. Suprascapular nerve block (SSNB) is a safe and effective treatment of shoulder pain associated with arthritic shoulder conditions, but its usefulness in a stroke population is unclear.
Methods—
We undertook a randomized controlled trial assessing the effectiveness of SSNB in a population of 64 stroke patients (onset < 1 year) with hemiplegic shoulder pain. The primary outcome was pain measured on a visual analogue scale (VAS). Secondary outcomes were disability (Modified Rankin Scale, Croft Disability Index) and quality of life (EuroQol Health Questionnaire). All participants were assessed before randomization, and at 1, 4, and 12 weeks postintervention. Both groups continued with routine therapy.
Results—
Although both intervention and control groups demonstrated reduction in pain score, participants who received SSNB consistently demonstrated superior, statistically significant pain reduction compared with placebo. Mean VAS reduction in the SSNB group was >18 mm greater than participants receiving placebo injection. The number needed to treat with SSNB to reduce 1 stroke survivor’s pain by 50% at 4 weeks is 4. No significant differences in function or quality of life were observed. No adverse events were reported.
Conclusions—
Suprascapular nerve block is a safe and effective treatment for patients with hemiplegic shoulder pain.
Clinical Trial Registration—
URL:
http://www.anzctr.org.au
. Unique identifier: ACTRN12609000621213.
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Affiliation(s)
- Zoe Adey-Wakeling
- From the Department of Rehabilitation and Aged Care (Z.A.-W., M.C.) and Department of Rheumatology (E.M.S.), Flinders University, Daw Park, South Australia
| | - Maria Crotty
- From the Department of Rehabilitation and Aged Care (Z.A.-W., M.C.) and Department of Rheumatology (E.M.S.), Flinders University, Daw Park, South Australia
| | - E. Michael Shanahan
- From the Department of Rehabilitation and Aged Care (Z.A.-W., M.C.) and Department of Rheumatology (E.M.S.), Flinders University, Daw Park, South Australia
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Murray D, Stoessl AJ. Mechanisms and therapeutic implications of the placebo effect in neurological and psychiatric conditions. Pharmacol Ther 2013; 140:306-18. [PMID: 23880289 DOI: 10.1016/j.pharmthera.2013.07.009] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Accepted: 07/09/2013] [Indexed: 12/19/2022]
Abstract
The power of a placebo to effect clinically meaningful neurobiological change comparable to pharmacological therapies has been demonstrated, although the mechanisms are not fully understood. Predicting placebo responsiveness has only recently received more attention, but psychological disposition, contextual and biological factors are now known to dramatically affect a person's susceptibility to the placebo effect. The placebo effect depends upon expectancies that can be modified in a number of ways, including conditioning through explicit or implicit learned associations. Based on the dopaminergic response to anticipation of benefit in Parkinson's disease, it was suggested that the placebo effect can be seen as analogous to the expectation of reward. Dopaminergic pathways have since been implicated in the placebo response in pain and depression. Additionally, endogenous opioid release is known to mediate many forms of placebo analgesia. We provide an overview of the mechanisms and the therapeutic implications of the placebo effect in neurological and psychiatric conditions. We include evidence for detrimental effects arising from seemingly inert interventions, termed the 'nocebo effect.' Neuroimaging has critically advanced the study of the placebo effect and provides some of the strongest evidence for the mechanisms of this phenomenon prevalent across an array of human health-related circumstances. This review specifically focuses on mechanisms of the placebo effect in the three conditions that have most significantly demonstrated this effect and for which a plausible physiological basis can be identified: pain, PD and depression. Other neurological and psychiatric diseases reviewed include multiple sclerosis, Huntington's disease, Alzheimer's disease, schizophrenia and epilepsy.
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Affiliation(s)
- Danielle Murray
- Pacific Parkinson's Research Centre and Department of Medicine, Division of Neurology, University of British Columbia & Vancouver Coastal Health, Canada
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30
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Pike AJ. Body-mindfulness in physiotherapy for the management of long-term chronic pain. PHYSICAL THERAPY REVIEWS 2013. [DOI: 10.1179/174328808x251957] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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Huber A, Lui F, Porro CA. Hypnotic susceptibility modulates brain activity related to experimental placebo analgesia. Pain 2013; 154:1509-1518. [PMID: 23664683 DOI: 10.1016/j.pain.2013.03.031] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Revised: 02/08/2013] [Accepted: 03/22/2013] [Indexed: 12/19/2022]
Abstract
Identifying personality traits and neural signatures that predict placebo responsiveness is important, both on theoretical and practical grounds. In the present functional magnetic resonance imaging (fMRI) study, we performed multiple-regression interaction analysis to investigate whether hypnotic susceptibility (HS), a cognitive trait referring to the responsiveness to suggestions, explains interindividual differences in the neural mechanisms related to conditioned placebo analgesia in healthy volunteers. HS was not related to the overall strength of placebo analgesia. However, we found several HS-related differences in the patterns of fMRI activity and seed-based functional connectivity that accompanied placebo analgesia. Specifically, in subjects with higher HS, the placebo response was related to increased anticipatory activity in a right dorsolateral prefrontal cortex focus, and to reduced functional connectivity of that focus with brain regions related to emotional and evaluative pain processing (anterior mid-cingulate cortex/medial prefrontal cortex); an opposite pattern of fMRI activity and functional connectivity was found in subjects with lower HS. During pain perception, activity in the regions reflecting attention/arousal (bilateral anterior thalamus/left caudate) and self-related processing (left precuneus and bilateral posterior temporal foci) was negatively related to the strength of the analgesic placebo response in subjects with higher HS, but not in subjects with lower HS. These findings highlight HS influences on brain circuits related to the placebo analgesic effects. More generally, they demonstrate that different neural mechanisms can be involved in placebo responsiveness, depending on individual cognitive traits.
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Affiliation(s)
- Alexa Huber
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena I-41125, Italy
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Bialosky JE, Bishop MD, George SZ, Robinson ME. Placebo response to manual therapy: something out of nothing? J Man Manip Ther 2012; 19:11-9. [PMID: 22294849 DOI: 10.1179/2042618610y.0000000001] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
The mechanisms through which manual therapy inhibits musculoskeletal pain are likely multifaceted and related to the interaction between the intervention, the patient, the practitioner, and the environment. Placebo is traditionally considered an inert intervention; however, the pain research literature suggests that placebo is an active hypoalgesic agent. Placebo response likely plays a role in all interventions for pain and we suggest that the same is true for the treatment effects associated with manual therapy. The magnitude of a placebo response may be influenced by negative mood, expectation, and conditioning. We suggest that manual therapists conceptualize placebo not only as a comparative intervention, but also as a potential active mechanism to partially account for treatment effects associated with manual therapy. We are not suggesting manual therapists include known sham or ineffective interventions in their clinical practice, but take steps to maximize placebo responses to reduce pain.
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Affiliation(s)
- Joel E Bialosky
- Department of Physical Therapy, University of Florida, Gainesville, FL, USA
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Stein N, Sprenger C, Scholz J, Wiech K, Bingel U. White matter integrity of the descending pain modulatory system is associated with interindividual differences in placebo analgesia. Pain 2012; 153:2210-2217. [PMID: 22959599 DOI: 10.1016/j.pain.2012.07.010] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2012] [Revised: 06/28/2012] [Accepted: 07/05/2012] [Indexed: 10/27/2022]
Abstract
The ability for endogenous pain control varies considerably among individuals. The mechanisms underlying this interindividual difference are incompletely understood. We used placebo analgesia as a classic model of endogenous pain modulation in combination with diffusion tensor magnetic resonance imaging to test the hypothesis of a structural predisposition for the individual capacity of endogenous pain control. Specifically we determined white matter integrity within and between regions of the descending pain modulatory system. Twenty-four healthy participants completed a placebo paradigm and underwent diffusion tensor magnetic resonance imaging. The individual placebo analgesic effect was correlated with white matter integrity indexed by fractional anisotropy. The individual placebo analgesic effect was positively correlated with FA in the right dorsolateral prefrontal cortex, left rostral anterior cingulate cortex, and the periaqueductal grey. Probabilistic tractography seeded in these regions showed that stronger placebo analgesic responses were associated with increased mean fractional anisotropy values within white matter tracts connecting the periaqueductal grey with pain control regions such as the rostral anterior cingulate cortex and the dorsolateral prefrontal cortex. Our findings provide the first evidence that the white matter integrity within and between regions of the descending pain modulatory network is critically linked with the individual ability for endogenous pain control.
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Affiliation(s)
- Niklas Stein
- Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Germany Department of Neurology, University Medical Center Hamburg-Eppendorf, Germany Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, Oxford, UK Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK Research Group Health Psychology, Department of Psychology, University of Leuven, Belgium
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Schneider H, Maheu E, Cucherat M. Symptom-modifying effect of chondroitin sulfate in knee osteoarthritis: a meta-analysis of randomized placebo-controlled trials performed with structum(®). Open Rheumatol J 2012; 6:183-9. [PMID: 22870166 PMCID: PMC3412198 DOI: 10.2174/1874312901206010183] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Revised: 06/24/2012] [Accepted: 06/27/2012] [Indexed: 11/22/2022] Open
Abstract
OBJECTIVE To perform a meta-analysis of randomized double-blind placebo-controlled clinical trials to assess the efficacy of a specific chondroitin sulfate preparation (Structum®, Laboratoires Pierre Fabre, Castres; France) as a symptom-modifying drug in osteoarthritis (OA) of the knee. METHODS A Medline search was conducted up to October 2010 and two articles reporting two trials were identified; one additional trial was identified through contacting the producer of Structum®. There was no evidence of heterogeneity across the trials and results were pooled using a fixed effects model. RESULTS Pooled results demonstrated a modest, but significant effect of Structum® (1 g daily) over placebo on the reduction of pain during activity following a treatment period of 3-6 months of 6 mm (95% confidence interval (CI) -9.50, -1.72, p=0.005) on the visual analog scale (VAS) and a reduction in the algo-functional Index (AFI) by a weighted mean difference of -0.73 (95% CI -1.28 to -0.18, p=0.01). In addition, the pooled analysis demonstrated a statistically significant increase in OMERACT-OARSI responders in the Structum®-treated patients by 20% (RR of 1.20 (95% CI 1.06 to 1.36, p=0.003)), compared to placebo. CONCLUSION These results demonstrate that this chondroitin sulfate preparation (Structum®) is effective on symptoms in patients with OA of the knee compared to placebo, and may therefore have a role in the management of patients with knee osteoarthritis of Kellgren-Lawrence grades II and III.
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Affiliation(s)
- Heinz Schneider
- HealthEcon AG, Steinentorstrasse 19, CH-4051 Basel, Switzerland
| | - Emmanuel Maheu
- AP-HP Saint-Antoine Hospital, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France
| | - Michel Cucherat
- Service de Pharmacologie Clinique, Faculté RTH Laënnec, Rue Guillaume Paradin - BP 8071, 69376 Lyon, France
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Lyby PS, Forsberg JT, Åsli O, Flaten MA. Induced fear reduces the effectiveness of a placebo intervention on pain. Pain 2012; 153:1114-1121. [PMID: 22464696 DOI: 10.1016/j.pain.2012.02.042] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Revised: 01/31/2012] [Accepted: 02/29/2012] [Indexed: 12/30/2022]
Abstract
Fear was induced by the anticipation of electric shock in order to investigate whether fear reduced the effectiveness of a placebo intervention on reported pain and the acoustic startle reflex. Thirty-three subjects participated in a 3 Condition (Natural History [NH], Placebo [P], Placebo+Fear [PF])×3 Test (Pretest, Posttest 1, Posttest 2) within-subject design, tested on 3 separate days. Measures of fear were fear of pain (FOP), measured by the Fear of Pain Questionnaire (FPQ-III); fear-potentiated startle; and a self-report measure that assessed the effectiveness of the fear induction procedure. In the pain intensity data, there was a trend towards a placebo effect. This trend was abolished by induced fear, and was most pronounced in subjects who were highest in measures of fear. The placebo manipulation also caused a reduction in startle reflex amplitude. This effect was abolished by induced fear, and was strongest amongst high FOP subjects. In conclusion, induced fear abolished placebo analgesia, and this effect was strongest in subjects who had high scores on measures of fear.
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Affiliation(s)
- Peter Solvoll Lyby
- Department of Psychology, Faculty of Health Sciences, University of Tromsø, Tromsø 9037, Norway
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37
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Nakamura Y, Donaldson GW, Kuhn R, Bradshaw DH, Jacobson RC, Chapman RC. Investigating dose-dependent effects of placebo analgesia: A psychophysiological approach. Pain 2012; 153:227-237. [DOI: 10.1016/j.pain.2011.10.024] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2011] [Revised: 08/08/2011] [Accepted: 10/17/2011] [Indexed: 11/25/2022]
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Flaten MA, Aslaksen PM, Lyby PS, Bjørkedal E. The relation of emotions to placebo responses. Philos Trans R Soc Lond B Biol Sci 2011; 366:1818-27. [PMID: 21576139 DOI: 10.1098/rstb.2010.0407] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The hypothesis put forth is that expectations of treatment effects reduce negative emotions and thereby reduce symptoms, e.g. pain. Negative emotions increase pain, and it is hypothesized that placebos reduce pain by reducing negative emotions, i.e. feelings of nervousness, fear and anxiety. Placebo analgesia has been shown to be mediated via opioid activity, and relaxation increases opioid activity. The placebo acquires its relaxing effect due to verbal information that pain will be reduced, or due to associations between the placebo and the reduction in pain after effective treatment. Thus, the placebo signals that unpleasantness will be less after administration of the placebo. This involves negative reinforcement which is due to activation of a dopaminergic system that has been found to be activated during placebo analgesia and is involved in positive emotions. The nocebo effect of increased pain is, consistent with this model, because of increased fear and anxiety. The new aspect of the presented model is the hypothesis that expectations reduce negative emotions, and that negative reinforcement that involves the dopaminergic reinforcement system should be a contributor to placebo responses.
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Affiliation(s)
- Magne Arve Flaten
- Department of Psychology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, Norway.
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Lyby PS, Aslaksen PM, Flaten MA. Variability in placebo analgesia and the role of fear of pain--an ERP study. Pain 2011; 152:2405-2412. [PMID: 21875771 DOI: 10.1016/j.pain.2011.07.010] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2011] [Revised: 06/13/2011] [Accepted: 07/18/2011] [Indexed: 01/01/2023]
Abstract
Fear of pain (FOP) and its effect on placebo analgesia was investigated. It was hypothesized that FOP should interfere with placebo-mediated pain inhibition and result in weaker placebo responding in pain intensity, pain unpleasantness, stress, and event-related potentials to contact heat pain. Thirty-three subjects participated in a balanced 2 condition (natural history, placebo)×3 test (pretest, posttest 1, posttest 2) within-subject design, tested on 2 separate days. FOP was measured by the Fear of Pain Questionnaire and subjective stress by the Short Adjective Check List. Placebo effects were found on reported pain unpleasantness and N2 and P2 amplitudes. FOP was related to reduced placebo responding in pain unpleasantness, but this was only evident for the subjects who received the placebo condition on day 1. Subjects who received the placebo condition on day 1 experienced more pretest stress than those who received the placebo condition on day 2 (ie, reversed condition order), and this explained the interaction effect on placebo responding. FOP was related to reduced placebo responding on P2 amplitude, whereas placebo responding on N2 amplitude was unaffected by FOP. Higher placebo responses on N2 and P2 amplitudes were both related to higher placebo analgesic magnitude in pain unpleasantness. In conclusion, increased FOP was found to reduce subjective and electrophysiological placebo analgesic responses.
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Affiliation(s)
- Peter Solvoll Lyby
- Department of Psychology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, Norway
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Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function. J Neurosci 2011; 31:7540-50. [PMID: 21593339 DOI: 10.1523/jneurosci.5280-10.2011] [Citation(s) in RCA: 440] [Impact Index Per Article: 31.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Chronic pain is associated with reduced brain gray matter and impaired cognitive ability. In this longitudinal study, we assessed whether neuroanatomical and functional abnormalities were reversible and dependent on treatment outcomes. We acquired MRI scans from chronic low back pain (CLBP) patients before (n = 18) and 6 months after (spine surgery or facet joint injections; n = 14) treatment. In addition, we scanned 16 healthy controls, 10 of which returned 6 months after the first visit. We performed cortical thickness analysis on structural MRI scans, and subjects performed a cognitive task during the functional MRI. We compared patients and controls, as well as patients before versus after treatment. After treatment, patients had increased cortical thickness in the left dorsolateral prefrontal cortex (DLPFC), which was thinner before treatment compared with controls. Increased DLPFC thickness correlated with the reduction of both pain and physical disability. Additionally, increased thickness in primary motor cortex was associated specifically with reduced physical disability, and right anterior insula was associated specifically with reduced pain. Left DLPFC activity during an attention-demanding cognitive task was abnormal before treatment, but normalized following treatment. These data indicate that functional and structural brain abnormalities-specifically in the left DLPFC-are reversible, suggesting that treating chronic pain can restore normal brain function in humans.
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Barrett B, Brown R, Rakel D, Rabago D, Marchand L, Scheder J, Mundt M, Thomas G, Barlow S. Placebo effects and the common cold: a randomized controlled trial. Ann Fam Med 2011; 9:312-22. [PMID: 21747102 PMCID: PMC3133578 DOI: 10.1370/afm.1250] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
PURPOSE We wanted to determine whether the severity and duration of illness caused by the common cold are influenced by randomized assignment to open-label pills, compared with conventional double-blind allocation to active and placebo pills, compared with no pills at all. METHODS We undertook a randomized controlled trial among a population with new-onset common cold. Study participants were allocated to 4 parallel groups: (1) those receiving no pills, (2) those blinded to placebo, (3) those blinded to echinacea, and (4) those given open-label echinacea. Primary outcomes were illness duration and area-under-the-curve global severity. Secondary outcomes included neutrophil count and interleukin 8 levels from nasal wash at intake and 2 days later. RESULTS Of 719 randomized study participants, 2 were lost and 4 exited early. Participants were 64% female, 88% white, and aged 12 to 80 years. Mean illness duration for each group was 7.03 days for those in the no-pill group, 6.87 days for those blinded to placebo, 6.34 days for those blinded to echinacea, and 6.76 days for those in the open-label echinacea group. Mean global severity scores for the 4 groups were no pills, 286; blinded to placebo, 264; blinded to echinacea, 236; and open-label echinacea, 258. Between-group differences were not statistically significant. Comparing the no-pill with blinded to placebo groups, differences (95% confidence interval [CI]) were -0.16 days (95% CI, -0.90 to 0.58 days) for illness duration and -22 severity points (95% CI, -70 to 26 points) for global severity. Comparing the group blinded to echinacea with the open-label echinacea group, differences were 0.42 days (95% CI, -0.28 to 1.12 days) and 22 severity points (95% CI, -19 to 63 points). Median change in interleukin 8 concentration and neutrophil cell count, respectively by group, were 30 pg/mL and 1 cell for the no-pill group, 39 pg/mL and 1 cell for the group binded to placebo, 58 pg/mL and 2 cells for the group blinded to echinacea, and 70 pg/mL and 1 cell for the group with open-label echinacea, also not statistically significant. Among the 120 participants who at intake rated echinacea's effectiveness as greater than 50 on a 100-point scale for which 100 is extremely effective, illness duration was 2.58 days shorter (95% CI, -4.47 to -0.68 days) in those blinded to placebo rather than no pill, and mean global severity score was 26% lower but not significantly different (-97.0, 95% CI, -249.8 to 55.8 points). In this subgroup, neither duration nor severity differed significantly between the group blinded to echinacea and the open-label echinacea group. CONCLUSIONS Participants randomized to the no-pill group tended to have longer and more severe illnesses than those who received pills. For the subgroup who believed in echinacea and received pills, illnesses were substantively shorter and less severe, regardless of whether the pills contained echinacea. These findings support the general idea that beliefs and feelings about treatments may be important and perhaps should be taken into consideration when making medical decisions.
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Affiliation(s)
- Bruce Barrett
- University of Wisconsin, Madison, Madison, Wisconsin, USA.
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Colloca L, Miller FG. How placebo responses are formed: a learning perspective. Philos Trans R Soc Lond B Biol Sci 2011; 366:1859-69. [PMID: 21576143 PMCID: PMC3130403 DOI: 10.1098/rstb.2010.0398] [Citation(s) in RCA: 218] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Despite growing scientific interest in the placebo effect and increasing understanding of neurobiological mechanisms, theoretical conceptualization of the placebo effect remains poorly developed. Substantial mechanistic research on this phenomenon has proceeded with little guidance by any systematic theoretical paradigm. This review seeks to present a theoretical perspective on the formation of placebo responses. We focus on information processing, and argue that different kinds of learning along with individuals' genetic make-up evolved as the proximate cause for triggering behavioural and neural mechanisms that enable the formation of individual expectations and placebo responses. Conceptualizing the placebo effect in terms of learning offers the opportunity for facilitating scientific investigation with a significant impact on medical care.
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Affiliation(s)
- Luana Colloca
- National Center for Complementary and Alternative Medicine (NCCAM), National Institutes of Health, Bethesda, MD, USA.
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Hansson E, Svensson H, Brorson H. Liposuction May Reduce Pain in Dercum's Disease (Adiposis Dolorosa). PAIN MEDICINE 2011; 12:942-52. [DOI: 10.1111/j.1526-4637.2011.01101.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Liu T, Yu CP. Placebo analgesia, acupuncture and sham surgery. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2011; 2011:943147. [PMID: 21785643 PMCID: PMC3139509 DOI: 10.1093/ecam/neq030] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2009] [Accepted: 03/08/2010] [Indexed: 01/25/2023]
Abstract
Invasive procedures, such as surgery and acupuncture, are likely better than the others in terms of eliciting placebo analgesia. Understanding how invasive procedures can elicit enhanced placebo responses may provide new insights into mechanisms underlying placebo analgesia. In this essay, it is argued that sensory, cognitive and emotional factors are major determinants of the magnitude of placebo analgesia. Sham surgery and acupuncture are good examples of placebo interventions, which generate robust placebo responses through simultaneously manipulating such three factors.
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Affiliation(s)
- Tao Liu
- Department of Traditional Chinese Medicine, 2nd Teaching Hospital, Norman Bethune Medical School, University of Jilin, 218 Ziqiang Street, Changchun 130041, Jilin Province, China
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Martel J, Dugas C, Dubois JD, Descarreaux M. A randomised controlled trial of preventive spinal manipulation with and without a home exercise program for patients with chronic neck pain. BMC Musculoskelet Disord 2011; 12:41. [PMID: 21303529 PMCID: PMC3045999 DOI: 10.1186/1471-2474-12-41] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2010] [Accepted: 02/08/2011] [Indexed: 01/29/2023] Open
Abstract
Background Evidence indicates that supervised home exercises, combined or not with manual therapy, can be beneficial for patients with non-specific chronic neck pain (NCNP). The objective of the study is to investigate the efficacy of preventive spinal manipulative therapy (SMT) compared to a no treatment group in NCNP patients. Another objective is to assess the efficacy of SMT with and without a home exercise program. Methods Ninety-eight patients underwent a short symptomatic phase of treatment before being randomly allocated to either an attention-group (n = 29), a SMT group (n = 36) or a SMT + exercise group (n = 33). The preventive phase of treatment, which lasted for 10 months, consisted of meeting with a chiropractor every two months to evaluate and discuss symptoms (attention-control group), 1 monthly SMT session (SMT group) or 1 monthly SMT session combined with a home exercise program (SMT + exercise group). The primary and secondary outcome measures were represented by scores on a 10-cm visual analog scale (VAS), active cervical ranges of motion (cROM), the neck disability index (NDI) and the Bournemouth questionnaire (BQ). Exploratory outcome measures were scored on the Fear-avoidance Behaviour Questionnaire (FABQ) and the SF-12 Questionnaire. Results Our results show that, in the preventive phase of the trial, all 3 groups showed primary and secondary outcomes scores similar to those obtain following the non-randomised, symptomatic phase. No group difference was observed for the primary, secondary and exploratory variables. Significant improvements in FABQ scores were noted in all groups during the preventive phase of the trial. However, no significant change in health related quality of life (HRQL) was associated with the preventive phase. Conclusions This study hypothesised that participants in the combined intervention group would have less pain and disability and better function than participants from the 2 other groups during the preventive phase of the trial. This hypothesis was not supported by the study results. Lack of a treatment specific effect is discussed in relation to the placebo and patient provider interactions in manual therapies. Further research is needed to delineate the specific and non-specific effects of treatment modalities to prevent unnecessary disability and to minimise morbidity related to NCNP. Additional investigation is also required to identify the best strategies for secondary and tertiary prevention of NCNP. Trial registration ClinicalTrials.gov: NCT00566930
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Affiliation(s)
- Johanne Martel
- Département de Chiropratique, Université du Québec à Trois-Rivières, Trois-Rivières G9A 5H7, Canada
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Gavaruzzi T, Carnaghi A, Lotto L, Rumiati R, Meggiato T, Polato F, Lazzari F. Recalling pain experienced during a colonoscopy: Pain expectation and variability. Br J Health Psychol 2010; 15:253-64. [DOI: 10.1348/135910709x458305] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Stroman PW, Coe BC, Munoz DP. Influence of attention focus on neural activity in the human spinal cord during thermal sensory stimulation. Magn Reson Imaging 2010; 29:9-18. [PMID: 20850240 DOI: 10.1016/j.mri.2010.07.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2010] [Revised: 06/28/2010] [Accepted: 07/13/2010] [Indexed: 02/04/2023]
Abstract
Perceptions of sensation and pain in healthy people are believed to be the net result of sensory input and descending modulation from brainstem and cortical regions depending on emotional and cognitive factors. Here, the influence of attention on neural activity in the spinal cord during thermal sensory stimulation of the hand was investigated with functional magnetic resonance imaging by systematically varying the participants' attention focus across and within repeated studies. Attention states included (1) attention to the stimulus by rating the sensation and (2) attention away from the stimulus by performing various mental tasks of watching a movie and identifying characters, detecting the direction of coherently moving dots within a randomly moving visual field and answering mentally-challenging questions. Functional MRI results spanning the cervical spinal cord and brainstem consistently demonstrated that the attention state had a significant influence on the activity detected in the cervical spinal cord, as well as in brainstem regions involved with the descending analgesia system. These findings have important implications for the detection and study of pain, and improved characterization of the effects of injury or disease.
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Affiliation(s)
- Patrick W Stroman
- Department of Diagnostic Radiology, Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada K7L 2V7.
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Yanchick J, Magelli M, Bodie J, Sjogren J, Rovati S. Time to significant pain reduction following DETP application vs placebo for acute soft tissue injuries. Curr Med Res Opin 2010; 26:1993-2002. [PMID: 20575621 DOI: 10.1185/03007995.2010.493099] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVE Nonsteroidal anti-inflammatory drugs (NSAIDs) provide fast and effective acute pain relief, but systemic administration has increased risk for some adverse reactions. The diclofenac epolamine 1.3% topical patch (DETP) is a topical NSAID with demonstrated safety and efficacy in treatment of acute pain from minor soft tissue injuries. Significant pain reduction has been observed in clinical trials within several hours following DETP application, suggesting rapid pain relief; however, this has not been extensively studied for topical NSAIDs in general. This retrospective post-hoc analysis examined time to onset of significant pain reduction after DETP application compared to a placebo patch for patients with mild-to-moderate acute ankle sprain, evaluating the primary efficacy endpoint from two nearly identical studies. RESEARCH DESIGN AND METHODS Data from two double-blind, randomized, parallel-group, placebo-controlled studies (N = 274) of safety and efficacy of the DETP applied once daily for 7 days for acute ankle sprain were evaluated post-hoc using statistical modeling to estimate time to onset of significant pain reduction following DETP application. MAIN OUTCOME MEASURES Pain on active movement on a 100 mm Visual Analog Scale (VAS) recorded in patient diaries; physician- and patient-assessed tolerability; and adverse events. RESULTS DETP treatment resulted in significant pain reduction within approximately 3 hours compared to placebo. Within-treatment post-hoc analysis based on a statistical model suggested significant pain reduction occurred as early as 1.27 hours for the DETP group. The study may have been limited by the retrospective nature of the analyses. In both studies, the DETP was well tolerated with few adverse events, limited primarily to application site skin reactions. CONCLUSION The DETP is an effective treatment for acute minor soft tissue injury, providing pain relief as rapidly as 1.27 hours post-treatment. Statistical modeling may be useful in estimating time to onset of pain relief for comparison of topical and oral NSAIDs.
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Affiliation(s)
- J Yanchick
- King Pharmaceuticals, Bridgewater, NJ, USA
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Borsook D, Upadhyay J, Chudler EH, Becerra L. A key role of the basal ganglia in pain and analgesia--insights gained through human functional imaging. Mol Pain 2010; 6:27. [PMID: 20465845 PMCID: PMC2883978 DOI: 10.1186/1744-8069-6-27] [Citation(s) in RCA: 234] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2010] [Accepted: 05/13/2010] [Indexed: 01/18/2023] Open
Abstract
The basal ganglia (BG) are composed of several nuclei involved in neural processing related to the execution of motor, cognitive and emotional activities. Preclinical and clinical data have implicated a role for these structures in pain processing. Recently neuroimaging has added important information on BG activation in conditions of acute pain, chronic pain and as a result of drug effects. Our current understanding of alterations in cortical and sub-cortical regions in pain suggests that the BG are uniquely involved in thalamo-cortico-BG loops to integrate many aspects of pain. These include the integration of motor, emotional, autonomic and cognitive responses to pain.
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Affiliation(s)
- David Borsook
- PAIN Group, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
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