{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T06:34:23Z","timestamp":1783060463653,"version":"3.54.6"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T00:00:00Z","timestamp":1714694400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100004875","name":"DFG","doi-asserted-by":"publisher","award":["SFB 289 Project A02"],"award-info":[{"award-number":["SFB 289 Project A02"]}],"id":[{"id":"10.13039\/100004875","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004875","name":"DFG","doi-asserted-by":"publisher","award":["422744262\u2013TRR 289"],"award-info":[{"award-number":["422744262\u2013TRR 289"]}],"id":[{"id":"10.13039\/100004875","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010663","name":"ERC","doi-asserted-by":"publisher","award":["AdG-883892"],"award-info":[{"award-number":["AdG-883892"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>While treatment side effects may adversely impact patients, they could also potentially function as indicators for effective treatment. In this study, we investigated whether and how side effects can trigger positive treatment expectations and enhance treatment outcomes.<\/jats:p>\n                  <jats:p>In this pre-registered trial (DRKS00026648), 77 healthy participants were made to believe that they will receive fentanyl nasal sprays before receiving thermal pain in a controlled experimental setting. However, nasal sprays did not contain fentanyl, rather they either contained capsaicin to induce a side effect (mild burning sensation) or saline (inert). After the first session, participants were randomized to two groups and underwent functional MRI. One group continued to believe that the nasal sprays could contain fentanyl while the other group was explicitly informed that no fentanyl was included. This allowed for the independent manipulation of the side effects and the expectation of pain relief.<\/jats:p>\n                  <jats:p>Our results revealed that nasal sprays with a side effect lead to lower pain than inert nasal sprays without side effects. The influence of side effects on pain was dependent on individual beliefs about how side effects are related to treatment outcome, as well as on expectations about received treatment. Functional MRI data indicated an involvement of the descending pain modulatory system including the anterior cingulate cortex and the periaqueductal gray during pain after experiencing a nasal spray with side effects.<\/jats:p>\n                  <jats:p>In summary, our data show that mild side effects can serve as a signal for effective treatment thereby influencing treatment expectations and outcomes, which is mediated by the descending pain modulatory system. Using these mechanisms in clinical practice could provide an efficient way to optimize treatment outcome. In addition, our results indicate an important confound in clinical trials, where a treatment (with potential side effects) is compared to placebo.<\/jats:p>","DOI":"10.1093\/brain\/awae132","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T07:48:38Z","timestamp":1714549718000},"page":"2643-2651","source":"Crossref","is-referenced-by-count":10,"title":["How side effects can improve treatment efficacy: a randomized trial"],"prefix":"10.1093","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7866-6193","authenticated-orcid":false,"given":"Lieven A","family":"Schenk","sequence":"first","affiliation":[{"name":"Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf , 20246 Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahmine","family":"Fadai","sequence":"additional","affiliation":[{"name":"Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf , 20246 Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"B\u00fcchel","sequence":"additional","affiliation":[{"name":"Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf , 20246 Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,5,3]]},"reference":[{"key":"2024080113020361600_awae132-B1","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1146\/annurev-psych-010418-102907","article-title":"Psychobiological mechanisms of placebo and nocebo effects: Pathways to improve treatments and reduce side effects","volume":"70","author":"Petrie","year":"2019","journal-title":"Annu Rev Psychol"},{"key":"2024080113020361600_awae132-B2","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1097\/PSY.0b013e3182294a50","article-title":"The nocebo effect and its relevance for clinical practice","volume":"73","author":"Colloca","year":"2011","journal-title":"Psychosom Med"},{"key":"2024080113020361600_awae132-B3","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1097\/j.pain.0000000000000870","article-title":"Side effects can enhance treatment response through expectancy effects: An experimental analgesic randomized controlled trial","volume":"158","author":"Berna","year":"2017","journal-title":"Pain"},{"key":"2024080113020361600_awae132-B4","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1152\/physrev.00043.2012","article-title":"Placebo and the new physiology of the doctor-patient relationship","volume":"93","author":"Benedetti","year":"2013","journal-title":"Physiol Rev"},{"key":"2024080113020361600_awae132-B5","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1056\/NEJMp1504023","article-title":"Placebo effects in medicine","volume":"373","author":"Kaptchuk","year":"2015","journal-title":"N Engl J Med"},{"key":"2024080113020361600_awae132-B6","doi-asserted-by":"crossref","first-page":"e202907","DOI":"10.1001\/jamanetworkopen.2020.2907","article-title":"Effect of treatment expectation on placebo response and analgesic efficacy: A secondary aim in a randomized clinical trial","volume":"3","author":"Sanders","year":"2020","journal-title":"JAMA Netw Open"},{"key":"2024080113020361600_awae132-B7","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.1016\/j.pain.2012.09.007","article-title":"The hidden effects of blinded, placebo-controlled randomized trials: An experimental investigation","volume":"153","author":"Rief","year":"2012","journal-title":"Pain"},{"key":"2024080113020361600_awae132-B8","doi-asserted-by":"crossref","first-page":"e0202211","DOI":"10.1371\/journal.pone.0202211","article-title":"How often do general practitioners use placebos and non-specific interventions? Systematic review and meta-analysis of surveys","volume":"13","author":"Linde","year":"2018","journal-title":"PLoS One"},{"key":"2024080113020361600_awae132-B9","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.jclinepi.2017.03.001","article-title":"Active placebo control groups of pharmacological interventions were rarely used but merited serious consideration: A methodological overview","volume":"87","author":"Jensen","year":"2017","journal-title":"J Clin Epidemiol"},{"issue":"1\u20132","key":"2024080113020361600_awae132-B10","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.pain.2005.08.027","article-title":"Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network","volume":"120","author":"Bingel","year":"2006","journal-title":"Pain"},{"key":"2024080113020361600_awae132-B11","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.neuron.2009.07.014","article-title":"Activation of the opioidergic descending pain control system underlies placebo analgesia","volume":"63","author":"Eippert","year":"2009","journal-title":"Neuron"},{"issue":"1\u20132","key":"2024080113020361600_awae132-B12","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S0304-3959(97)00016-X","article-title":"Classical conditioning and the placebo effect","volume":"72","author":"Montgomery","year":"1997","journal-title":"Pain"},{"key":"2024080113020361600_awae132-B13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/08870449908407311","article-title":"The beliefs about medicines questionnaire: The development and evaluation of a new method for assessing the cognitive representation of medication","volume":"14","author":"Horne","year":"1999","journal-title":"Psychol Health"},{"key":"2024080113020361600_awae132-B14","doi-asserted-by":"crossref","first-page":"258","DOI":"10.20982\/tqmp.18.3.p258","article-title":"A step-by-step tutorial for performing a moderated mediation analysis using PROCESS","volume":"18","author":"Clement","year":"2022","journal-title":"Quant Methods Psychol"},{"key":"2024080113020361600_awae132-B15","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/978-3-662-44519-8_3","volume-title":"Placebo","author":"Atlas","year":"2014"},{"key":"2024080113020361600_awae132-B16","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.neuroimage.2011.11.095","article-title":"Neuroimaging of the periaqueductal gray: State of the field","volume":"60","author":"Linnman","year":"2012","journal-title":"Neuroimage"},{"key":"2024080113020361600_awae132-B17","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1006\/nimg.1997.0291","article-title":"Psychophysiological and modulatory interactions in neuroimaging","volume":"6","author":"Friston","year":"1997","journal-title":"Neuroimage"},{"key":"2024080113020361600_awae132-B18","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1038\/nrn3976","article-title":"The neuroscience of placebo effects: Connecting context, learning and health","volume":"16","author":"Wager","year":"2015","journal-title":"Nat Rev Neurosci"},{"key":"2024080113020361600_awae132-B19","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1152\/physiol.00024.2008","article-title":"Imaging CNS modulation of pain in humans","volume":"23","author":"Bingel","year":"2008","journal-title":"Physiology"},{"key":"2024080113020361600_awae132-B20","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1126\/science.1093065","article-title":"Placebo-Induced changes in fMRI in the anticipation and experience of pain","volume":"303","author":"Wager","year":"2004","journal-title":"Science"},{"key":"2024080113020361600_awae132-B21","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/npp.2012.227","article-title":"Personality trait predictors of placebo analgesia and neurobiological correlates","volume":"38","author":"Peci\u00f1a","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"2024080113020361600_awae132-B22","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/j.biopsych.2010.01.014","article-title":"Induction of depressed mood disrupts emotion regulation neurocircuitry and enhances pain unpleasantness","volume":"67","author":"Berna","year":"2010","journal-title":"Biol Psychiatry"},{"key":"2024080113020361600_awae132-B23","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1038\/s41467-021-21179-3","article-title":"Meta-analysis of neural systems underlying placebo analgesia from individual participant fMRI data","volume":"12","author":"Zunhammer","year":"2021","journal-title":"Nat Commun"},{"key":"2024080113020361600_awae132-B24","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1097\/SPC.0000000000000419","article-title":"Assessment of conditioned pain modulation in healthy participants and patients with chronic pain: Manifestations and implications for pain progression","volume":"13","author":"Petersen","year":"2019","journal-title":"Curr Opin Support Palliat Care"},{"key":"2024080113020361600_awae132-B25","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.pain.2007.06.029","article-title":"Determinants of endogenous analgesia magnitude in a diffuse noxious inhibitory control (DNIC) paradigm: Do conditioning stimulus painfulness, gender and personality variables matter?","volume":"136","author":"Granot","year":"2008","journal-title":"Pain"},{"key":"2024080113020361600_awae132-B26","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1056\/NEJMra1907805","article-title":"Placebo and nocebo effects","volume":"382","author":"Colloca","year":"2020","journal-title":"N Engl J Med"},{"key":"2024080113020361600_awae132-B27","doi-asserted-by":"crossref","first-page":"k3889","DOI":"10.1136\/bmj.k3889","article-title":"Open label placebo: Can honestly prescribed placebos evoke meaningful therapeutic benefits?","volume":"363","author":"Kaptchuk","year":"2018","journal-title":"BMJ"},{"key":"2024080113020361600_awae132-B28","doi-asserted-by":"crossref","first-page":"e040134","DOI":"10.1136\/bmjopen-2020-040134","article-title":"Changing mindsets about side effects","volume":"11","author":"Leibowitz","year":"2021","journal-title":"BMJ Open"},{"key":"2024080113020361600_awae132-B29","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1159\/000490354","article-title":"Implications of placebo and nocebo effects for clinical practice: Expert consensus","volume":"87","author":"Evers","year":"2018","journal-title":"Psychother Psychosom"},{"key":"2024080113020361600_awae132-B30","doi-asserted-by":"crossref","first-page":"e699","DOI":"10.1097\/PR9.0000000000000699","article-title":"How to prevent, minimize, or extinguish nocebo effects in pain: A narrative review on mechanisms, predictors, and interventions","volume":"4","author":"Mana\u00ef","year":"2019","journal-title":"Pain Rep"},{"key":"2024080113020361600_awae132-B31","doi-asserted-by":"crossref","first-page":"S48","DOI":"10.1097\/j.pain.0000000000001981","article-title":"Placebo 2.0: The impact of expectations on analgesic treatment outcome","volume":"161","author":"Bingel","year":"2020","journal-title":"Pain"},{"key":"2024080113020361600_awae132-B32","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1136\/bmj.316.7126.201","article-title":"Understanding controlled trials: Why are randomised controlled trials important?","volume":"316","author":"Sibbald","year":"1998","journal-title":"BMJ"},{"key":"2024080113020361600_awae132-B33","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S0304-3959(02)00060-X","article-title":"Blinding effectiveness and association of pretreatment expectations with pain improvement in a double-blind randomized controlled trial","volume":"99","author":"Turner","year":"2002","journal-title":"Pain"},{"key":"2024080113020361600_awae132-B34","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1001\/archpsyc.1997.01830200078011","article-title":"Double-blindness procedures, rater blindness, and ratings of outcome: Observations from a controlled trial","volume":"54","author":"Basoglu","year":"1997","journal-title":"Arch Gen Psychiatry"},{"key":"2024080113020361600_awae132-B35","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1002\/mpr.148","article-title":"A comparison of antidepressant trials using active and inert placebos","volume":"12","author":"Moncrieff","year":"2003","journal-title":"Int J Methods Psychiatr Res"},{"key":"2024080113020361600_awae132-B36","first-page":"CD003351","article-title":"Ketamine as an adjuvant to opioids for cancer pain","volume":"6","author":"Bell","year":"2017","journal-title":"Cochrane Database Syst Rev"},{"key":"2024080113020361600_awae132-B37","first-page":"CD012509","article-title":"Adverse events associated with medium- and long-term use of opioids for chronic non-cancer pain: An overview of Cochrane Reviews","volume":"2017","author":"Els","year":"2017","journal-title":"Cochrane Database Syst Rev"},{"key":"2024080113020361600_awae132-B38","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1177\/1740774510367916","article-title":"Participant expectancies in double-blind randomized placebo-controlled trials: Potential limitations to trial validity","volume":"7","author":"Colagiuri","year":"2010","journal-title":"Clin Trials"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awae132\/58336769\/awae132.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/147\/8\/2643\/58712407\/awae132.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/147\/8\/2643\/58712407\/awae132.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T17:43:04Z","timestamp":1722534184000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/147\/8\/2643\/7664309"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,3]]},"references-count":38,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,5,3]]},"published-print":{"date-parts":[[2024,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awae132","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.11.22.23298877","asserted-by":"object"}]},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,8]]},"published":{"date-parts":[[2024,5,3]]}}}