Specifying the non-specific factors underlying opioid analgesia: expectancy, attention, and affect
Open accessAbstract
Rationale Psychological processes such as expectancy, attention, and affect directly influence clinical outcomes. These factors are grouped together as "nonspecific" factors, or placebo effects, in the medical literature, and their individual contributions are rarely considered. The pain-reducing effects of analgesic treatments may reflect changes in these psychological factors, rather than pure drug effects on pain. Furthermore, drug effects may not be isolated by drug vs. placebo comparisons if drugs interact with relevant psychological processes.Objectives We sought to determine whether the analgesic effects of opioid and placebo treatment are mediated by changes in attention, expectancy, or affect.Methods We crossed intravenous administration of a potent opioid analgesic, remifentanil, with information about drug delivery (treatment expectancy or placebo) using a balanced placebo design. We measured drug and treatment expectancy effects on pain, attention, and responses to emotional images. We also examined interactions with cue-based expectations about noxious stimulation or stimulus expectancy.Results Pain was additively influenced by treatment expectancy, stimulus expectancy, and drug concentration. Attention performance showed a small but significant interaction between drug and treatment expectancy. Finally, remifentanil enhanced responses to both positive and negative emotional images.Conclusions The pain-relieving effects of opioid drugs are unlikely to be mediated by changes in threat or affective processing. Standard open-label opioid administration influences multiple clinically relevant cognitive and emotional processes. Psychological factors can combine with drug effects to influence multiple outcomes in distinct ways. The influence of specific psychological factors should be considered when developing and testing pharmacological treatments.
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Longitudinal observational research supports a strong bidirectional link between mood disorders and persistent pain.
“longitudinal, observational research supports a strong bidirectional link between mood disorders and persistent pain”
From Evaluating psychosocial contributions to chronic pain outcomes (2018) · cites this paper as [13]
Depression, anxiety, and distress are among the strongest and most robust psychosocial predictors of transition from acute to chronic pain.
“psychosocial variables such as depression, anxiety, and distress are among the most potent and robust predictors of the transition from acute to chronic pain 13–18.”
From Evaluating psychosocial contributions to chronic pain outcomes (2018) · cites this paper as [13]
Developing an enduring pain condition substantially increases vulnerability for a later diagnosis of an affective disorder.
“the development of an enduring pain condition confers a substantially increased vulnerability for the subsequent diagnosis of an affective disorder”
From Evaluating psychosocial contributions to chronic pain outcomes (2018) · cites this paper as [13]
Depression and anxiety are linked to chronic pain and increased pain sensitivity.
“An abundance of evidence links depression and anxiety to chronic pain and increased pain sensitivity 11, 13, 32, 41.”
From Evaluating psychosocial contributions to chronic pain outcomes (2018) · cites this paper as [13]
Catastrophizing is associated with higher pain levels, poorer physical functioning and disability, and increased pain interference.
“catastrophizing is associated with higher pain levels, poorer physical functioning and disability, and increased pain interference 13, 32, 278, 279.”
From Evaluating psychosocial contributions to chronic pain outcomes (2018) · cites this paper as [13]
Catastrophizing is a risk factor for developing chronic pain, pain-related disability, increased healthcare costs, and increased pain sensitivity in low back pain and joint pain.
“Further, catastrophizing is a risk factor for the development of chronic pain, pain-related disability, increased healthcare costs, and increased pain sensitivity for low back pain and joint pain 13.”
From Evaluating psychosocial contributions to chronic pain outcomes (2018) · cites this paper as [13]
The findings are consistent with the nonspecific effects of placebo treatment observed in multiple pain conditions and different types of negative affect.
“The findings are consistent with the nonspecific effects of placebo treatment observed in multiple pain conditions and different types of negative affect (43, 44).”
From Placebo treatment facilitates social trust and approach behavior (2018) · cites this paper as [43]
The placebo effect is nonspecifically driven by expectation or belief.
“This lends further support to the notion that placebo effect is nonspecifically driven by expectation or belief (43, 45).”
From Placebo treatment facilitates social trust and approach behavior (2018) · cites this paper as [43]
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Hird, E., Charalambous, C., El‐Deredy, W., Jones, A. K. P., & Talmi, D. (2025) · Scientific Reports · doi:10.1038/s41598-025-14299-z
Exposure to false cardiac feedback alters pain perception and anticipatory cardiac frequencyPreprint
Parrotta, E., Bach, P., Pezzulo, G., Zaccaro, A., Perrucci, M. G., Costantini, M., & Ferri, F. (2026) · eLife · doi:10.7554/elife.90013.2
- Authors
- Atlas, L. Y., Wielgosz, J., Whittington, R. A., & Wager, T. D.
- Affiliations
- New York University (US)
- University of Wisconsin–Madison (US)
- Columbia University (US)
- University of Colorado Boulder (US)
- Corresponding author
- Atlas, Lauren Y.
- Venue
- Psychopharmacology
- Published
- 2013-10-06
- Volume
- 231
- Issue
- 5
- Pages
- 813-823
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- PMC
- PMC3945427
- OpenAlex
- W2153467347
- Cited by
- 44
- References
- 51
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 10 · 2022: 2 · 2021: 3 · 2020: 1 · 2019: 4 · 2018: 6 · 2017: 2 · 2016: 2 · 2015: 4 · 2014: 3
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH076136)
- National Institute on Drug Abuse (R01DA027794, R01DA035484)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- opioid analgesia, placebo effect, treatment expectancy, stimulus expectancy, attention, affect, remifentanil, pain perception, threat processing
- MeSH terms
- Remifentanil, Adult, Affect, Analgesics, Opioid, Attention, Female, Humans, Male, Pain, Piperidines, Placebo Effect, Randomized Controlled Trials as Topic, Young Adult, Anticipation, Psychological
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