Author (Year)	Study Type	Mechanism and Effect Placebo	Population	Outcomes and Limitations
Benedetti et al. (2005) [140]	Narrative review	Neurobiological mechanisms of placebo effect	General population	Outcomes:
				Identified several neurobiological mechanisms underlying placebo effects.
				Highlighted the role of opioid and non-opioid neurotransmitter systems in placebo analgesia.
				Described how placebo effects can modulate various physiological systems beyond pain, including motor performance and immune responses.
				Limitations:
				The complexity of placebo mechanisms makes it challenging to isolate specific factors.
				Many studies cited were conducted in experimental settings, which may not fully reflect clinical realities.
				The review doesn’t address potential differences in placebo mechanisms across different medical conditions or populations.
Eippert (2009) [88]	Experimental	Descending modulation mechanisms in placebo analgesia	Healthy volunteers	Outcomes:
				Placebo analgesia is associated with increased activity in the dorsolateral prefrontal cortex, rostral anterior cingulate cortex, and periaqueductal gray matter.
				This activation was reversed by the opioid antagonist naloxone, indicating the involvement of endogenous opioids.
				The study provided indirect evidence that opioidergic descending pain control circuits underlie placebo analgesia.
				Limitations:
				Relatively small sample size.
				The study was conducted on healthy volunteers, which may limit generalizability to clinical pain conditions.
				The use of experimental pain may not fully reflect chronic pain experiences.
				The study focused on short-term effects and did not address long-term placebo responses.
Schweinhardt et al. (2009) [89]	Experimental	Placebo analgesia and personality traits	Healthy volunteers	Outcomes:
				The study suggests that the anatomy of the mesolimbic reward system may predispose individuals to placebo analgesia.
				Found a correlation between placebo analgesic responses and gray matter density in the mesolimbic reward system: ventral striatum, insula, and medial prefrontal cortex.
				Identified a link between placebo analgesia and personality traits: ego-resiliency and straightforwardness.
				Limitations:
				Small sample size limits generalizability.
				The study was conducted on healthy volunteers, which may not reflect responses in clinical pain populations.
				The correlational nature of the findings limits causal inferences.
				The study focused on brain structure rather than function, which may not capture the full complexity of placebo responses.
Hróbjartsson, Gøtzsche (2010) [91]	Systematic review and meta-analysis	Placebo interventions for all clinical conditions	Patients with various clinical conditions	Outcomes:
				Found no evidence that placebo interventions have important clinical effects in general.
				Possible small benefits in studies with continuous subjective outcomes and for the treatment of pain.
				In general, no significant effects outcomes.
				Limitations:
				High heterogeneity among studies.
				Difficulty in distinguishing genuine placebo effects from bias.
				Lack of data on harms of placebo interventions.
Stein et al. (2012) [146]	Experimental	White matter integrity and placebo analgesia	Healthy volunteers	Outcomes:
				Found that white matter integrity of the descending pain modulatory system, particularly in the dorsolateral prefrontal cortex and rostral anterior cingulate cortex, predicted individual differences in placebo analgesia.
				Suggests a neuroanatomical basis for variability in placebo responses.
				Limitations:
				Small sample size.
				Study conducted on healthy volunteers, limiting generalizability to clinical populations.
				Focus on acute experimental pain may not reflect chronic pain conditions.
Amanzio (2013) [142]	Meta-analysis	Brain connectivity in placebo analgesia	Healthy volunteers	Outcomes:
				Identified consistent activation patterns associated with placebo analgesia, including in the rCCA, CPFDL, and PAG.
				Deactivation was observed in areas processing pain.
				The study supports the involvement of opioid and non-opioid mechanisms in placebo analgesia.
				Limitations:
				Focus on experimental pain in healthy volunteers may limit generalizability to clinical pain.
				Heterogeneity in study designs and analysis methods across included studies.
				The meta-analysis was based on a relatively small number of neuroimaging studies
Atlas, Wager (2014) [141]	Meta-analysis	Placebo analgesia and expectancy-based pain modulation	Healthy volunteers	Outcomes:
				Consistent placebo-induced reductions in pain-related brain regions (dorsal anterior cingulate, thalamus, insula, amygdala, striatum)
				Increased activation in prefrontal cortex, midbrain, and rCCA.
				Suggests placebo effects impact both pain processing and emotion/value systems.
				Limitations:
				Variability in experimental designs across studies.
				Focus on contrasts rather than correlations with behavior.
				Limited ability to determine causal mechanisms.
Büchel (2014) [145]	Perspective/Review	Placebo hypoalgesia and predictive coding	N/A (Not applicable)	Outcomes:
				Proposes a hierarchical Bayesian framework based on predictive coding to explain placebo hypoalgesia.
				Suggests that placebo hypoalgesia results from combining top-down prior expectations with bottom-up sensory signals.
				Emphasizes the importance of both the mean and precision of predictions and sensory signals.
				Reframes the ascending and descending pain systems as a recurrent system implementing predictive coding.
				Limitations:
				Conceptual framework, not an empirical study.
				Focuses only on acute pain in healthy individuals.
				Precise neurobiological implementation of the model remains speculative.
Colloca (2014) [78]	Narrative review	Placebo and nocebo responses in pain management	General population	Outcomes:
				The paper synthesizes mechanisms behind placebo and nocebo effects, particularly in pain management, highlighting the role of cognitive, emotional, and contextual factors in modulating pain perception.
				Neurobiological pathways (e.g., endogenous opioids, dopamine) are explored.
				Limitations:
				The study is a synthesis, lacking direct empirical data.
				It heavily relies on secondary sources, which may introduce bias in interpretation.
				The generalizability of findings across diverse clinical scenarios remains uncertain.
Peciña, Zubieta (2014) [139]	Narrative review	Molecular mechanisms of placebo responses in humans	Patients with various clinical conditions	Outcomes:
				The study investigates the role of the μ-opioid receptor system in mediating placebo analgesia.
				It identifies specific neurobiological pathways, showing that placebo effects are influenced by the brain’s pain and reward modulation systems.
				The interaction between dopamine and opioid pathways is highlighted in placebo responses.
				Limitations:
				This is a review paper, so it is based on secondary data and may be biased.
				Further research is needed to explore these mechanisms in diverse clinical populations.
Wager, Atlas (2015) [94]	Review	Neuroscience of placebo effects, focusing on context, learning, and health	General population	Outcomes:
				The review explores neural mechanisms of placebo effects, highlighting the role of the prefrontal cortex, endogenous opioid and dopamine pathways, and the influence of learning and context on treatment outcomes.
				Limitations:
				Lacks new empirical data and focuses broadly on neuroscience, limiting its applicability to specific clinical contexts like musculoskeletal care.
				Further research is needed to validate these mechanisms in diverse settings.
Cerritelli (2016) [132]	Systematic Review	Placebo/sham therapy in osteopathy	Healthy population and population with different clinical conditions.	Outcomes:
				Evaluation of the application of placebo and sham therapies in osteopathic clinical trials.
				The lack of standardized methods and variability in sham approaches across studies are highlighted.
				High heterogeneity in the design of placebo controls, making clear conclusions on the effectiveness of sham therapies difficult.
				Limitations:
				High risk of bias in studies, particularly in allocation, blinding and selective reporting.
				Variation in sham therapy methodologies and insufficient reported information make it difficult to assess placebo effects in osteopathy.
				A quantitative analysis could not be performed due to these methodological limitations.
				The article highlights the need to develop standardized guidelines for placebo controls in manual medicine trials.
Testa, Rossettini (2016) [83]	Narrative review	Placebo and nocebo effects in physiotherapy	General population undergoing physiotherapy	Outcomes:
				The review examines the neurobiology of placebo and nocebo effects in physiotherapy.
				It highlights the role of contextual factors, such as the physiotherapist’s and patient’s characteristics, the therapist–patient relationship, and the healthcare environment.
				Contextual factors are identified as key modulators of clinical outcomes.
				Focus is placed on enhancing placebo effects and minimizing nocebo effects in physiotherapy treatments.
				Limitations:
				The review is a narrative synthesis, relying on existing literature without new empirical data.
				It centers on general placebo and nocebo concepts but lacks specific experimental evidence.
				The clinical applicability of the discussed effects in physiotherapy remains unvalidated through direct experimentation.
Ashar (2017) [92]	Narrative review	Placebo mechanisms and affective appraisal	Not specified	Outcomes:
				This review provides an overview of the placebo effect and its underlying brain mechanisms, particularly how appraisals of treatments influence outcomes.
				It identifies how placebo treatments, including those for pain, engage a core network of brain regions associated with self-evaluation, emotion, and reward processing, within the default mode network.
				The review emphasizes that placebo effects work by modifying how people evaluate their symptoms and future well-being.
				Limitations:
				The review does not introduce new empirical data or clinical trials.
				The generality of the findings, based on cognitive and neural appraisals, limits its direct applicability to specific clinical conditions or populations.
Beedie et al. (2018) [93]	Editorial	The role of placebo effects in CAM use in sports medicine and physiotherapy	Athletes and practitioners (elite and non-elite)	Outcomes:
				This review discusses the role of placebo and nocebo effects in complementary and alternative medicine (CAM) in sports medicine, emphasizing the complexity and variability of placebo effects.
				It presents placebo mechanisms like dopamine and opioid systems.
				Highlights challenges in using placebo effects to legitimize CAM, including variability, negative placebo effects (nocebo), and ethical concerns around deception.
				Suggests “headroom” mechanisms: the capacity to respond to placebos could indicate reserve capacity for legitimate treatments.
				Limitations:
				The review is based on existing literature and lacks original empirical data.
				Limited to placebo mechanisms, not addressing the full spectrum of CAM effects or evidence.
				Caveats in using placebo mechanisms for CAM are not fully explored, especially with regards to practical application in sports physiotherapy.
				Some recommendations may not be directly applicable across all CAM practices.
Blasini et al. (2018) [82]	Narrative review	The role of patient-practitioner relationships in placebo and nocebo phenomena	Pain patients (general clinical setting)	Outcomes:
				Identifies the biopsychosocial factors influencing placebo and nocebo effects in the patient-practitioner relationship.
				Emphasizes the role of expectancies and contextual factors (verbal suggestions, conditioning, and social observation) in shaping therapeutic outcomes.
				Found that macro (cultural, societal) and micro (individual psychobiological traits) factors influence expectancies.
				Empathy, friendliness, and competence of the practitioner enhance positive expectancies and placebo effects.
				Patient-practitioner caring and warm interactions improve the therapeutic experience, particularly for pain patients.
				Limitations:
				The review is based on existing literature without new empirical data.
				Focuses on theoretical models, lacking direct experimental evidence in the clinical setting.
				Subjective interpretations and lack of systematic analysis may reduce generalizability of findings across different clinical populations.
				The review does not provide concrete guidelines for integrating these findings into clinical practice.
Cai, He (2019) [137]	Narrative review	Placebo effects and molecular biological components involved	General clinical setting	Outcomes:
				Summarizes the history and characteristics of placebo effects.
				Identifies key molecular components involved in placebo effects, including the dopamine, opioid, serotonin, and endocannabinoid systems.
				Introduces the concept of placebome, aiming to understand the genetic and molecular basis of placebo effects.
				Discusses placebome studies and the need for no-treatment control (NTC) to identify genetic targets.
				Limitations:
				The placebome concept is still in its early stages.
				Lacks experimental data and new empirical findings.
				No clinical trials were included to test the molecular findings in real clinical settings.
				Emphasizes theoretical bioinformatics analysis rather than practical evidence in the clinical context.
				Need for NTC-controlled placebo studies to validate results and further explore the genetic targets related to placebo effects.
Anderson, Stebbins (2020) [80]	Narrative review	Determinants of placebo effects and responses	General clinical and research settings	Outcomes:
				Explores intrinsic factors influencing placebo responses, including patient expectations, previous experiences, neural systems under treatment, personality traits, and situational factors.
				Identifies clinician determinants, such as empathy, perceived expertise, clinical relationship quality, and belief in treatment efficacy.
				Analyzes extrinsic factors, such as study design, advertising, branding, and cultural influences, highlighting their combined impact on placebo effects.
				Limitations:
				Provides a theoretical framework without new empirical evidence.
				Focuses on general determinants of placebo effects rather than specific contexts, such as musculoskeletal care.
				Does not evaluate how identified factors quantitatively influence placebo responses in clinical practice or research.
Crawford et al. (2021) [144]	Experimental study	Brainstem mechanisms involved in placebo analgesia and nocebo hyperalgesia	Healthy volunteers	Outcomes:
				Found altered activity in key pain modulatory brainstem nuclei during placebo and nocebo responses.
				Identified distinct recruitment of the PAG-RVM pathway during greater placebo analgesia and nocebo hyperalgesia.
				Demonstrated differential activation of the parabrachial nucleus and overlapping activation in the substantia nigra and locus coeruleus for both effects.
				Suggests that the PAG-RVM pathway influences pain modulation at the level of the dorsal horn.
				Limitations:
				Small sample size (N = 25) limits generalizability of findings. Study focuses on acute experimental pain, reducing relevance to chronic pain scenarios.
				Deceptive conditioning may introduce variability in participants’ responses.
				Findings are correlational, limiting causal inference about brainstem circuitry and pain modulation.
Shi et al. (2021) [79]	Experimental study	Placebo and nocebo responses in acute lower back pain (ALBP)	Healthy volunteers	Outcomes:
				Significant differences in VAS pain scores observed for placebo and nocebo interventions compared to baseline and between placebo and nocebo groups.
				Placebo network involves negative lagged-temporal correlation between the DLPFC, secondary somatosensory cortex, ACC, and IC.
				Positive correlations were found between IC, thalamus, ACC, and SMA.
				Nocebo network includes positive correlations among primary somatosensory cortex, caudate, DLPFC, and SMA.
				Placebo response engages the reward system, inhibits the pain network, and activates opioid-mediated analgesia and emotion pathways.
				Nocebo response deactivates emotional control and primarily engages pain-related pathways.
				Verified that placebo and nocebo networks share brain regions but also have distinct features.
				Limitations:
				Small sample size (N = 20) limits the generalizability of findings.
				Study was conducted in healthy individuals, which may not reflect responses in clinical populations with chronic pain.
				Correlational nature of findings limits causal interpretations.
				fMRI-based GCA may be influenced by methodological biases, such as signal variability and lag-time estimation.
Thomson et al. (2021) [95]	Editorial/review	Exploration of contextual factors (CFs) in osteopathy and musculoskeletal care	N/A	Outcomes:
				Highlights the critical role of contextual factors such as clinician habits, patient expectations, therapeutic relationships, and treatment environments in shaping clinical outcomes.
				Suggests CFs influence outcomes via placebo and nocebo effects.
				Discusses the lack of CF awareness in osteopathic education and its implications for enhancing patient outcomes.
				Proposes research directions for better integration and evaluation of CFs in osteopathy and healthcare.
				Limitations:
				The study is narrative and does not include new empirical data or quantitative analysis.
				Limited generalizability due to its focus on osteopathy, though findings may apply broadly.
				Recommendations are theoretical and require further research validation through robust empirical methods.
				Does not specify direct evidence linking CF manipulation to improved outcomes in osteopathy.
Zunhammer et al. (2021) [148]	Systematic meta-analysis	Neural systems and brain mechanisms underlying placebo analgesia, based on experimental fMRI studies	Healthy volunteers	Outcomes:
				Identifies placebo analgesia as a multifaceted phenomenon involving multiple brain areas, including ventral attention networks (mid-insula), somatomotor networks (posterior insula), thalamus, habenula, mid-cingulate cortex, and supplementary motor area.
				Behavioral placebo analgesia correlates with reduced pain-related activity and increased frontoparietal activity, highlighting mechanisms of nociception, affect, and decision-making in pain.
				Significant between-study heterogeneity suggests variability in cerebral mechanisms across studies.
				Limitations:
				High between-study heterogeneity limits the ability to generalize findings across placebo analgesia contexts.
				Focuses on healthy participants; results may not directly translate to clinical populations with chronic pain.
				While robust at the neural level, behavioral and psychological interpretations of findings are limited.
				Excluded eight eligible studies due to lack of participant-level data, potentially introducing selection bias.
Bieniek, Bąbel (2023) [86]	Experimental study	Placebo hypoalgesia induced through operant conditioning using verbal, social, and token-based rewards and punishers	Healthy volunteers	Outcomes:
				Placebo hypoalgesia was successfully induced in groups with social and token-based reinforcement, but not with verbal reinforcement alone.
				Expectations of pain mediated the hypoalgesic effect, suggesting cognitive involvement.
				The number of reinforcers received predicted the magnitude of hypoalgesia, highlighting the role of conditioning intensity.
				Findings suggest token-based and social consequences may optimize pain management interventions.
				Limitations:
				Focused on healthy participants, limiting generalizability to clinical populations with chronic pain.
				Did not evaluate the long-term stability of placebo hypoalgesia effects.
				The study lacked diversity in participant demographics, potentially influencing the broader applicability of findings.
				While results highlight conditioning effects, their translation to clinical practice requires further investigation.
Testa et al. (2023) [84]	Book chapter/review	Management of cognitive, relational, and environmental contextual factors to optimize placebo effects and minimize nocebo effects in clinical practice	General population	Outcomes:
				Contextual factors, including beliefs, expectations, and therapeutic relationships, significantly enhance the outcomes of evidence-based treatments.
				Effective management of negative mindsets through empathic relationships can improve patient experience.
				Clinician’s attitude and skills in addressing contextual effects add measurable value to the therapeutic process.
				Limitations:
				The review provides theoretical guidance but lacks empirical validation of specific strategies for managing contextual factors.
				Generalized conclusions may not apply across all patient populations or clinical settings.
				Limited discussion of practical implementation challenges in clinical practice.
Colloca et al. (2023) [85]	Book chapter/review	Cultural influences on placebo and nocebo responses, including beliefs, rituals, and healthcare relationships	General population	Outcomes:
				Cultural beliefs, norms, and values shape treatment expectations and responses to placebo and nocebo effects.
				Physical and aesthetic preferences, influenced by culture, affect the perceived efficacy of treatments.
				Spiritual and religious beliefs impact coping strategies and treatment responses.
				Rituals and healthcare provider-patient dynamics (e.g., verbal and nonverbal cues) are critical in shaping placebo/nocebo responses.
				Limitations:
				The review is theoretical and lacks empirical data directly validating the role of cultural factors in placebo/nocebo responses.
				Generalizations are based on broad cultural concepts, which may not capture specific individual or subgroup variations.
				Limited exploration of how cultural factors interact with biological or psychological mechanisms.
Crawford et al. (2023) [144]	Experimental study	Brain mechanisms of placebo analgesia	Healthy volunteers	Outcomes:
				No significant differences in gamma-aminobutyric acid (GABA) or other metabolites between placebo responders and non-responders in the right DLPFC.
				Identified an inverse relationship between glutamate levels and pain rating variability during conditioning.
				Demonstrated altered functional connectivity between the DLPFC and midbrain periaqueductal gray (PAG) during placebo analgesia.
				Highlighted the role of the DLPFC in shaping stimulus-response relationships during conditioning.
				Limitations:
				The study was conducted on healthy individuals, limiting its applicability to clinical populations.
				The small sample size (38 participants) reduces the generalizability of findings.
				The study focuses only on acute pain scenarios, limiting its relevance to chronic pain contexts.
				Correlational nature of findings does not establish causation between DLPFC activity and placebo response.
Hartmann et al. (2023) [81]	Experimental study	Empathy-related psychological and structural brain differences between placebo analgesia responders and non-responders	Healthy volunteers	Outcomes:
				Placebo analgesia responders exhibited higher helping behavior and lower psychopathic traits compared to non-responders.
				Responders showed greater pain-related empathic concern.
				Structural brain differences: non-responders had increased gray matter volume in areas like the left inferior temporal and parietal supramarginal cortical regions and increased cortical surface area in the bilateral middle temporal cortex.
				Limitations:
				Uncorrected results in some analyses may lead to overestimated conclusions.
				Focus on a relatively narrow trait-based classification (e.g., empathy, psychopathy) without comprehensive exploration of other individual differences.
				Study paradigm and setting could influence outcomes, suggesting that contextual factors were not fully controlled for.
Meeuwis et al. (2023) [87]	Systematic Review and Meta-analysis	The effect of observational learning on placebo hypoalgesia and nocebo hyperalgesia	Healthy volunteers	Outcomes:
				Invest Observational learning (OL) had a small-to-medium effect on pain ratings (SMD = 0.44).
				- OL had a large effect on pain expectancy (SMD = 1.11).
				Empathic concern of the observer was positively correlated with the magnitude of placebo/nocebo effects (r = 0.14).
				Type of observation (in-person vs. videotaped) influenced the effect size (p < 0.01).
				Limitations:
				Moderate heterogeneity across studies.
				No clear clinical application of findings in chronic pain populations.
				Lack of placebo type modulation in the results (p = 0.23), suggesting further research is needed to clarify its role.
				Limited exploration of other empathy-related factors beyond empathic concern.
Rossettini et al. (2023) [138]	State of the art review	Overview of placebo and nocebo effects in experimental and chronic pain	Healthy volunteers and chronic pain patients	Outcomes:
				Strong evidence that placebo and nocebo effects are influenced by the psychosocial context.
				Psychological mechanisms and neurobiological/genetic determinants of placebo and nocebo effects are detailed.
				Differences in the occurrence of these effects between experimental settings (healthy participants) and clinical settings (chronic pain patients).
				Emphasizes the heterogeneity of pain in chronic patients affecting the magnitude of these effects.
				Limitations:
				Heterogeneity of pain in chronic patients makes results difficult to generalize.
				No unified results on the magnitude and occurrence of placebo/nocebo effects in chronic pain patients.
				Lacks specific experimental data to validate the proposed mechanisms in clinical settings.
				Calls for future research to address these gaps and improve the understanding of contextual factors.
Caliskan et al. (2024) [97]	Clinical update Review	Focus on treatment expectations, placebo/nocebo effects, and contextual factors	Patients in clinical settings, with an emphasis on pain management	Outcomes:
				Treatment expectations significantly influence treatment outcomes, acting as powerful modulators of health outcomes.
				Contextual factors that modify expectations can improve therapy success.
				Placebo analgesia and nocebo hyperalgesia are key mechanisms in the management of pain, with the expectations contributing to the overall treatment success.
				Further research is needed to personalize treatment strategies based on individual patient expectations.
				Limitations:
				The article is a clinical update and relies on existing evidence, with limited experimental data.
				It discusses variability in placebo/nocebo responses but does not identify clear predictors for individual responses.
				Calls for future research to explore personalized approaches to modulating treatment expectations.
				Does not address all clinical conditions in depth beyond pain.
Pedersen et al. (2024) [96]	Systematic review and meta-analysis	Focus on placebo effects, specific treatment effects, and changes observed without treatment in interventions for chronic nonspecific low back pain (NSLBP)	Adults with chronic nonspecific low back pain (NSLBP)	Outcomes:
				Approximately half of the overall treatment effect in conservative interventions for chronic NSLBP is attributed to changes observed without treatment, with smaller contributions from specific treatment and placebo effects.
				For pain intensity, 33% is attributed to specific treatment effects, 18% to placebo effects, and 49% to no-treatment changes.
				For physical function and HRQoL, 53% and 48% of the effect, respectively, is due to no treatment changes.
				Limitations:
				Low certainty of evidence, suggesting that the true effects might differ significantly from the reported estimates.
				The study is focused on conservative and passive interventions, which limits the applicability to other treatment types.
				The findings are based on short-term treatment effects and may not reflect long-term outcomes.
Saueressig et al. (2024) [46]	Review and methodological analysis	Focus on the methods used to quantify contextual effects in clinical care, particularly in placebo-controlled studies	N/A	Outcomes:
				The study critiques existing methods for quantifying contextual effects and proposes that the most effective method is comparing a placebo group with a non-treated control group.
				Other methods (such as the placebo control arm alone or proportional contextual effect calculation) are deemed inappropriate.
				This paper aims to provide guidance on best practices for estimating contextual effects in clinical research.
				Limitations:
				The review lacks empirical data as it is a methodological analysis, meaning it does not directly address clinical outcomes or interventions.
				It focuses only on theoretical frameworks and does not provide practical examples or real-world clinical applications.
				The effectiveness of the proposed method has not been fully tested or validated in diverse clinical settings.