The Biology of Placebo and Nocebo Effects on Experimental and Chronic Pain: State of the Art
Abstract
:1. Introduction
2. State of the Art
2.1. Experimental Approaches to Study Placebo and Nocebo Effects
2.2. Neurobiology
2.2.1. Pharmacological Evidence
2.2.2. Neuroimaging Studies
Temporal Aspects
Central Nervous System
- High Central Nervous System Levels
- Low Central Nervous System Levels
2.3. Genetics
2.4. Placebo and Nocebo Effects in Chronic Pain
3. Future Directions for Clinical Practice
4. Future Directions for Research and Clinical Trials
5. Conclusions and Limitations
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
RCT | Randomized Controlled Trial |
fMRI | functional Magnetic Resonance Imaging |
PET | Positron Emission Tomography |
EEG | electroencephalography |
VAS | Visual Analogue Scale |
NRS | Numerical Rating Scale |
CI | Confidence Interval |
rTMS | repetitive Transcranial Magnetic Stimulation |
ROI | Regions of Interest |
M | Male |
F | Female |
Appendix A
Paper ID | Sample Size (M, F, Not Analysed) * | Population Type | Pain Type/Pain Induction | Investigated Outcome | Outcome Measure | Level of Significance |
---|---|---|---|---|---|---|
Amanzio and Benedetti, 1999 [20] | 229 (132, 97) | Healthy subjects | Experimental ischemic pain | Behavioral (Pharmacological) | Pain tolerance (min) | p < 0.05 |
Amanzio et al., 2001 [21] | 364 (278 patients; 86 healthy controls) | Patients (thoracic surgery) and healthy controls | Postoperative pain; experimental ischemic arm pain | Behavioral (Pharmacological) | NRS (0–10) | p < 0.05 |
Benedetti et al., 1995 [40] | 93 (52, 41) | Patients (thoracotomy for lung surgery) | Post-surgery pain | Behavioral (Pharmacological) | NRS (0–10) | p < 0.02 |
Benedetti et al., 1996 [39] | 340 (154, 186) | Healthy subjects | Experimental ischemic pain | Behavioral (Pharmacological) | NRS (0–10) | p < 0.05 |
Benedetti et al., 1997 [38] | 180 (119, 61) | Patients (video-assisted thoracoscopy) | Post-surgery pain | Behavioral (Pharmacological) | NRS (0–10) | p < 0.05 |
Benedetti et al., 2006 [42] | 49 (23, 26) | Healthy subjects | Experimental ischemic pain | Behavioral (Pharmacological) | NRS (0–10) | p < 0.05 |
Benedetti et al., 2006 [86] | 44 (28 patients (11, 17), 16 controls) | Patients (Alzheimer’s disease) and healthy subjects | Burning pain after venipuncture | Electrophysiological (EEG) | NRS (0–10) | p < 0.05 |
Benedetti et al., 2010 [41] | 40 (20, 20) | Healthy subjects | Experimental ischemic pain | Behavioral (Pharmacological) | Tolerance time | p < 0.05 |
Benedetti et al., 2011 [36] | 82 (41, 41) | Healthy subjects | Experimental ischemic pain | Behavioral (Pharmacological) | Tolerance time | 95%CI |
Benedetti et al., 2014 [54] | 74 (30, 44) | Healthy subjects | Hypobaric hypoxia headache | Behavioral (Pharmacological) | NRS (0–10) | 95%CI |
Benedetti et al., 2022 [37] | 149 (82, 67) | Healthy subjects | Experimental ischemic pain | Behavioral (Pharmacological) | 0–10 rating scale | p < 0.05 |
Bingel et al. 2011 [85] | 22 (15, 7) | Healthy subjects | Heat pain | Neuroimaging (fMRI) | VAS (0–100) | p < 0.05 |
Bingel et al., 2022 [100] | 22 (15, 7) | Healthy subjects | Heat pain | Neuroimaging; functional connectivity (fMRI) | VAS (0–100) | p < 0.05 |
Bush et al., 2021 [95] | 37 (12, 25) | Healthy subjects | Heat pain | Neuroimaging; functional connectivity (fMRI) | VAS (0–100) | p < 0.05 |
Camerone et al., 2021 [16] | 166 (78, 88, 9) | Healthy subjects | Electrical stimuli | Behavioral | NRS (0–10) | p < 0.05 |
Camerone et al., 2021 [17] | 77 (24, 24, 29) | Healthy subjects | Cold pressor test (CPT) | Behavioral | Numerical Pain Intensity (0–100) | p < 0.05 |
Camerone et al., 2022 [18] | 51 (24, 27, 10) | Healthy subjects | Cold pressor test (CPT) | Behavioral | NRS (0–10) | p < 0.05 |
Carlino et al., 2015 [73] | 34 (20, 14) | Healthy subjects | Laser stimulation | Electrophysiology (EEG) | NRS (0–10) | p < 0.05 |
Carlino et al., 2016 [26] | 80 (34, 46) | Healthy subjects | Electrical stimuli | Behavioral | NRS (0–10) | p < 0.05 |
Colloca et al., 2006 [24] | 30 (5, 25) | Healthy subjects | Electrical stimuli | Behavioral | NRS (0–10) | p < 0.05 |
Colloca et al., 2008 [21] | 116 (0, 116) | Healthy subjects | Electrical stimuli | Behavioral | NRS (0–10) | p < 0.05 |
Colloca et al., 2010 [25] | 46 (16, 30) | Healthy subjects | Electrical stimuli | Behavioral | VAS (0–10 | p < 0.05 |
Colloca et al., 2016 [50] | 109 (55, 54, 1) | Healthy subjects | Electrical stimuli | Behavioral | VAS (0–10) | p < 0.05 |
Colloca et al., 2019 [105] | 160 (58, 102) | Healthy subjects | Electrical and heat stimuli | DNA genotyping; epistasis | VAS (0–10) | p < 0.001 |
Colloca et al., 2020 [121] | 763 (363 patients (85, 278); 400 healthy controls (162; 238) | Patients (chronic orofacial pain) and healthy subjects | Heat stimuli | Behavioral | VAS | p < 0.05 |
Disley et al., 2021 [30] | 104 (10, 65, 29) | Healthy subjects | Cold pressor test (CPT) | Behavioral | VAS (0–100) | p = 0.05 |
Eippert et al., 2009 [34] | 48 (48, -, 8) | Healthy subjects | Heat pain | Neuroimaging (fMRI) | VAS (0–100) | p ≤ 0.05 |
Eippert et al., 2009 [92] | 15 (15, 0) | Healthy subjects | Heat pain | Neuroimaging (fMRI) | VAS (0–100) | p < 0.05 |
Ellerbrock et al., 2015 [35] | 40 (20, 20, 1) | Healthy subjects | Heat pain | Neuroimaging; functional connectivity (fMRI) | VAS (0–100) | p < 0.05 |
Fuentes et al., 2014 [164] | 117 | Patients (chronic low back pain) | - | Behavioral | NRS (0–10) | p < 0.05 |
Hashmi et al., 2014 [91] | 42 | Patients (chronic knee osteoarthritis) | Heat pain | Neuroimaging (fMRI) | Gracely Sensory Scale (0–20) | p < 0.05 |
Jarcho et al., 2016 [46] | 15 (0, 15) | Healthy subjects | Heat pain | Neuroimaging (PET; fMRI) | VAS (0–100) | p < 0.005 |
Kaptchuk et al., 2008 [111] | 262 (63, 199) | Patients (irritable bowel syndrome) | - | Behavioral | Global improvement scale (range 1–7); adequate relief of symptoms; symptom severity | p < 0.01 |
Kelley et al., 2009 [165] | 189 | Patients (irritable bowel syndrome) | - | Behavioral | Combined outcome (IBS Symptom Severity Scale; IBS Quality of Like Scale; IBS Global Improvement Scale; IBS Adequate Relief) | p < 0.05 |
Kessner et al., 2013 [51] | 80 (80, 0) | Healthy subjects | Heat pain | Behavioral (Pharmacological) | Visual Analogue Scale (0–100) | p < 0.05 |
Klinger et al., 2017 [112] | 48 (12, 36) | Patients (chronic back pain) | Electrical stimuli | Behavioral | NRS (0–10) | 95% CI |
Kong et al., 2006 [57] | 24 (13, 11) | Healthy subjects | Heat pain | Neuroimaging (fMRI) | 0–20 Sensory Box Scale | p < 0.0001 for ROI p = 0.05 |
Kong et al., 2008 [71] | 20 (5, 8, 7) | Healthy subjects | Heat pain | Neuroimaging (fMRI) | Gracely Sensory and Affective Scales | p < 0.05 |
Koyama et al., 2005 [70] | 10 (8, 2) | Healthy subjects | Heat pain | Neuroimaging (fMRI) | VAS | p < 0.01 |
Krummenacher et al., 2010 [87] | 40 (40, 0) | Healthy subjects | Heat pain | rTMS | VAS (0–10) | p ≤ 0.05 |
Kube et al., 2020 [29] | 117 (48, 53, 16) | Healthy subjects | Heat pain | Behavioral | Pain tolerance | p < 0.05 |
Lieberman et al., 2004 [58] | 52 (29 active drug; 23 placebo condition) | Patients (irritable bowel syndrome) | - | Neuroimaging (PET) | Symptom diary (4 weeks) | p < 0.005 |
Malfiet et al., 2019 [79] | 83 | Patients (chronic neck pain) | - | Behavioral | VAS (0–100) | p = 0.05 |
Martins et al., 2022 [125] | 56 | Patients (chronic knee osteoarthritis) | - | Neuroimaging; functional connectivity (fMRI) | VAS (0–10) | p < 0.05 |
Morton et al., 2010 [74] | 67 (21, 35, 11) | Healthy subjects | Laser stimulation | Electrophysiological (EEG) | 0–10 scale | p = 0.05 |
Müller et al., 2016 [118] | 50 (27, 32, 1) | Patients (chronic pain) | Pressure-pain stimuli | Behavioral | VAS (0–100) | p < 0.05 |
Olson et al., 2021 [113] | 280 (65, 215) | Patients (chronic orofacial pain) | Heat pain | Behavioral | VAS (0–100) | p < 0.05 |
Peciña et al., 2015 [106] | 50 (21, 29) | Healthy subjects | 5% hypertonic saline | DNA genotyping; Neuroimaging (PET) | VAS (0–100) | p < 0.05 |
Petrovic et al., 2002 [60] | 9 | Healthy subjects | Heat stimuli | Neuroimaging (PET) | VAS (0–100) | p = 0.005 |
Petrovic et al., 2010 [59] | 24 (9, 15) | Healthy subjects | Heat stimuli | Neuroimaging (PET; fMRI) | VAS (0–100) | p < 0.05 |
Piedimonte et al., 2017 [23] | 34(16, 18, -) | Healthy subject | Electrical stimuli | Electrophysiological (EEG) | NRS (0–10) | p < 0.05 |
Ploghaus et al., 1999 [67] | 12 (7, 5) | Healthy subjects | Heat stimuli | Neuroimaging (fMRI) | VAS (0–10) | p < 0.05 |
Pollo et al., 2001 [81] | 38 | Patients (thoracotomized patients) | - | Behavioral | NRS (0–10) | p < 0.01 |
Porro et al., 2002 [69] | 30 (10, 16, 4) | Healthy subjects | Acid solution injection | Neuroimaging (fMRI) | 0–100 scale rating | p < 0.05 |
Price et al., 1999 [162] | 40 (16, 24) | Healthy subjects | Heat pain | Behavioral | VAS (0–10) | p < 0.05 |
Price et al., 2007 [61] | 9 | Patients (irritable bowel syndrome) | Barostat balloon distension—pressure stimuli | Neuroimaging (fMRI) | 100-unit rating scale | p < 0.05 |
Prossin et al., 2022 [55] | 37 (12, 25) | Healthy subjects | Hypertonic saline injection | Neuroimaging (PET, MRI) | VAS (0–100) | p < 0.05 |
Rief et al., 2012 [168] | 144 (50, 904) | Healthy participants | Heat pain | Behavioral | Pain threshold change in °C | p < 0.05 |
Ruscheweyh et al., 2014 [98] | 60 (30 patients, 30 controls) | Patients (cerebellum infarction) and healthy subjects | Heat; pressure; pinprick pain | Behavioral | NRS (0–10) | p < 0.05 |
Sawamoto et al., 2000 [83] | 10 (10, 0) | Healthy subjects | Laser thermal stimulation | Neuroimaging (fMRI) | 0–100 scale | p < 0.05 |
Schmid et al., 2015 [84] | 44 (22, 22) | Healthy subjects | Rectal distension | Neuroimaging (fMRI) | VAS (0–100) | p < 0.05 |
Schwartz et al., 2022 [161] | 44 (18, 26) | Patients (chronic low back pain) | - | Behavioral | NRS (0–10) | p < 0.05 |
Scott et al., 2007 [49] | 48 (30 Study1; 16 Study2; 18 Male controls) | Healthy subjects | 5% hypertonic saline injection | Neuroimaging (Study1—PET, fMRI Study2—fMRI) | VAS (0–100) | p < 0.05 |
Scott et al., 2008 [43] | 20 (9, 11); 18 (18, 0) | Healthy subjects | Sustained muscle pain challenge | Neuroimaging (PET, MRI) | VAS (0–100) | p < 0.0001 for ROI p = 0.05 |
Skyt et al., 2018 [47] | 19 (10, 9) | Patients (neuropathic pain) | Pinprick-evoked pain; wind-up-like pain | Behavioral | VAS (0–10; 0–100) | p < 0.05 |
Tétreault et al., 2016 [89] | 98 (17 Study1; 39 Study2; 42 Study3) | Patients (chronic knee osteoarthritis pain) | - | Neuroimaging (fMRI) | VAS (0–10); Western Ontario and McMaster Universities Osteoarthritis Index | p < 0.05 |
Tinnermann et al., 2017 [99] | 57 (27, 22, 8) | Healthy subjects | Heat stimuli | Neuroimaging (fMRI) | VAS (0–100) | p < 0.05 |
Tu et al., 2021 [88] | 81 (44, 37) | Healthy subjects | Heat stimuli | Neuroimaging (fMRI); tDCS | Gracely Sensory Scale (0–20) | p < 0.05 |
Vachon-Presseau et al., 2018 [90] | 129 (43 placebo group, 20 controls, 66 excluded) | Patients (chronic back pain) | Back pain intensity | Neuroimaging (MRI, fMRI) | VAS (0–10) | p < 0.05 |
Vachon-Presseau et al., 2022 [144] | 181 (94 randomized to 3 arms, 87 excluded) | Patients (chronic low back pain) | Back pain intensity | Neuroimaging (fMRI) | Likert Scale (twice a day) | p < 0.05 |
Van der Meulen et al., 2017 [72] | 30 (13, 17) | Healthy subjects | Heat stimuli | Neuroimaging (fMRI) | VAS (0–100) | p < 0.05 |
Vase et al., 2003 [82] | 13 | Patients (irritable bowel syndrome) | Evoked rectal distension; heat pain | Behavioral | VAS (0–10) | p < 0.05 |
Vase et al., 2005 [110] | 26 (0, 26) | Patients (irritable bowel syndrome) | Rectal distension | Behavioral (Pharmacological) | VAS (0–10) | p < 0.05 |
Vecchio et al., 2021 [77] | 63 (31, 32) | Healthy subjects | Electrical stimuli | Electrophysiological (EEG) | 7 point Likert scale | p = 0.05 |
Wager et al., 2004 [64] | 47 | Healthy subjects | Shock pain; heat pain | Neuroimaging (fMRI) | 10 point scale | p < 0.05 |
Wager et al., 2007 [65] | 15 (15, 0) | Healthy subjects | Heat stimuli | Neuroimaging (PET) | VAS (0–10) | p < 0.05 |
Wager et al., 2011 [63] | 47 | Healthy subjects | Shock pain; heat pain | Neuroimaging (fMRI) | 10 point scale | p < 0.001 |
Wanigasekera et al., 2018 [96] | 16 | Patients (Post-traumatic neuropathic pain) | - | Neuroimaging (MRI) | NRS (0–10) | p = 0.05 |
Weimer et al., 2019 [108] | 39 (25 monozygotic; 14 dizygotic twin pairs) | Healthy subjects | Heat pain | Behavioral | NRS (0–10) | p < 0.05 |
Wrobel et al., 2014 [48] | 50 (28, 32, 12) | Healthy subjects | Heat pain | Neuroimaging (fMRI); Pharmacological | VAS (0–100) | p < 0.05 |
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Rossettini, G.; Campaci, F.; Bialosky, J.; Huysmans, E.; Vase, L.; Carlino, E. The Biology of Placebo and Nocebo Effects on Experimental and Chronic Pain: State of the Art. J. Clin. Med. 2023, 12, 4113. https://doi.org/10.3390/jcm12124113
Rossettini G, Campaci F, Bialosky J, Huysmans E, Vase L, Carlino E. The Biology of Placebo and Nocebo Effects on Experimental and Chronic Pain: State of the Art. Journal of Clinical Medicine. 2023; 12(12):4113. https://doi.org/10.3390/jcm12124113
Chicago/Turabian StyleRossettini, Giacomo, Francesco Campaci, Joel Bialosky, Eva Huysmans, Lene Vase, and Elisa Carlino. 2023. "The Biology of Placebo and Nocebo Effects on Experimental and Chronic Pain: State of the Art" Journal of Clinical Medicine 12, no. 12: 4113. https://doi.org/10.3390/jcm12124113