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Psychosomatic Medicine Jan 2021Expectations are known to be key determinants of placebo and nocebo phenomena. In previous studies, verbal suggestions to induce such expectations have mainly focused on...
OBJECTIVE
Expectations are known to be key determinants of placebo and nocebo phenomena. In previous studies, verbal suggestions to induce such expectations have mainly focused on the direction and magnitude of the effect, whereas little is known about the influence of temporal information.
METHODS
Using an experimental placebo and nocebo design, we investigated whether information about the expected onset of a treatment effect modulates the start and time course of analgesic and hyperalgesic responses. Healthy volunteers (n = 166) in three placebo and three nocebo groups were informed that the application of an (inert) cream would reduce (placebo groups) or amplify pain (nocebo groups) after 5, 15, or 30 minutes. Two control groups were also included (natural history and no expectations). Participants' pain intensity rating of electrical stimuli administered before and 10, 20, and 35 minutes after cream application was obtained.
RESULTS
Mixed-method analysis of variance showed a significant interaction between group and time (F(12,262) = 18.172, p < .001, pη2 = 0.454), suggesting that pain variations differed across time points and between groups. Post hoc comparisons revealed that the placebo and nocebo groups began to show a significantly larger change in perceived pain intensity than the no-expectancy control group at the expected time point (p < .05) but not earlier (p > .05). Once triggered, the analgesic effect remained constant over the course of the experiment, whereas the hyperalgesic effect increased over time.
CONCLUSIONS
Our results indicate that temporal suggestions can shape expectancy-related treatment effects, which, if used systematically, could open up new ways to optimize treatment outcome.
Topics: Analgesia; Humans; Hyperalgesia; Nocebo Effect; Pain; Pain Management; Placebo Effect
PubMed: 33109926
DOI: 10.1097/PSY.0000000000000882 -
The Journal of Pain Dec 2019Placebo analgesia is a robust phenomenon readily observed in both experimental and clinical settings. While researchers have begun to unpack its psychobiological... (Randomized Controlled Trial)
Randomized Controlled Trial
Placebo analgesia is a robust phenomenon readily observed in both experimental and clinical settings. While researchers have begun to unpack its psychobiological mechanisms, important questions remain regarding how we can capitalize on the placebo effect to improve clinical pain outcomes. The current study tested whether providing individuals with instrumental control-that is, control over if and when they administer a treatment-is capable of enhancing placebo analgesia. Using an established electrocutaneous pain design, 87 healthy volunteers either received placebo conditioning with instrumental control over treatment administration, standard passive placebo conditioning without any control over treatment administration, or were allocated to natural history control group with no conditioning and were later tested at equivalent shock intensity with and without placebo applied. Both placebo groups demonstrated initial placebo analgesia. Importantly, however, those provided with instrumental control demonstrated significantly larger and longer lasting placebo analgesia as well as reduced anticipatory autonomic arousal than those receiving standard passive placebo conditioning. This suggests that providing instrumental control over treatment administration can facilitate placebo analgesia by enhancing its magnitude and durability. As such, providing instrumental control over treatment administration may be a cheap and ethical method of using the placebo effect to improve clinical pain outcomes. PERSPECTIVE: Placebo research typically involves passive designs where individuals have no control over treatment administration. We present novel data demonstrating that providing control over treatment administration substantially enhances both the magnitude and duration of placebo analgesia. As such, where possible, providing control may improve clinical pain outcomes via the placebo effect.
Topics: Adult; Analgesia, Patient-Controlled; Female; Humans; Male; Motivation; Placebo Effect; Transcutaneous Electric Nerve Stimulation; Young Adult
PubMed: 31150780
DOI: 10.1016/j.jpain.2019.05.013 -
International Review of Neurobiology 2018The analgesic placebo effect is well documented by numerous studies. Many important influencing factors, however, are yet to be discovered. In the arena of placebo... (Review)
Review
The analgesic placebo effect is well documented by numerous studies. Many important influencing factors, however, are yet to be discovered. In the arena of placebo effects and clinical implications, expectancies play a central role. Expectancies are shaped by processes of classical and social learning as well as verbal instructions and are strongly related to emotional factors. Expectancies trigger a cascade of endogenous opioids and non-opioids, which alter the experience of pain. For clinical application it is important to know, that placebo research yields ethical possibilities to use placebo effects without deception and without using placebos. Since placebo effects contribute to responses to active analgesics, it is feasible to enhance patients' benefits from pain treatments by increasing the additional placebo effect. There are several possibilities to use the placebo effects via shaping and adapting information about analgesic medication and via associating medication intake with a positive context. A positive patient-clinician communication atmosphere is very important to generate clinically meaningful placebo effects in pain medicine.
Topics: Analgesics; Humans; Pain; Placebo Effect; Placebos
PubMed: 30146044
DOI: 10.1016/bs.irn.2018.07.015 -
British Journal of Anaesthesia Aug 2019Over the past decade, the mechanisms underlying placebo effects have begun to be identified. At the same time, the placebo response appears to have increased in... (Review)
Review
Over the past decade, the mechanisms underlying placebo effects have begun to be identified. At the same time, the placebo response appears to have increased in pharmacological trials and marked placebo effects are found in neurostimulation and surgical trials, thereby posing the question whether non-pharmacological interventions should be placebo-controlled to a greater extent. In this narrative review we discuss how the knowledge of placebo mechanisms may help to improve placebo control in pharmacological and non-pharmacological trials. We review the psychological, neurobiological, and genetic mechanisms underlying placebo analgesia and outline the current problems and potential solutions to the challenges with placebo control in trials on pharmacological, neurostimulation, and surgical interventions. We particularly focus on how patients' perception of the therapeutic intervention, and their expectations towards treatment efficacy may help develop more precise placebo controls and blinding procedures and account for the contribution of placebo factors to the efficacy of active treatments. Finally, we discuss how systematic investigations into placebo mechanisms across various pain conditions and types of treatment are needed in order to 'personalise' the placebo control to the specific pathophysiology and interventions, which may ultimately lead to identification of more effective treatment for pain patients. In conclusion this review shows that it is important to understand how patients' perception and expectations influence the efficacy of active and placebo treatments in order to improve the test of new treatments. Importantly, this applies not only to assessment of drug efficacy but also to non-pharmacological trials on surgeries and stimulation procedures.
Topics: Analgesia; Humans; Pain; Placebo Effect; Placebos; Treatment Outcome
PubMed: 30915982
DOI: 10.1016/j.bja.2019.01.040 -
Journal of Crohn's & Colitis May 2016Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIMS
Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis [UC] clinical trials, and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them.
METHODS
MEDLINE, EMBASE, and the Cochrane Library were searched from inception through April 2014 for placebo-controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant, or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool.
RESULTS
In all, 51 trials [48 induction and 10 maintenance phases] were identified. Placebo response and remission rates were pooled according to random-effects models, and mixed-effects meta-regression models were used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7-13%) and 33% [95% CI 29-37%], respectively. Corresponding values for maintenance trials were 19% [95% CI 11-30%] and 22% [95% CI 17-28%]. Trials enrolling patients with more active disease confirmed by endoscopy [endoscopy subscore ≥ 2] were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits.
CONCLUSIONS
Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials.
Topics: Anti-Inflammatory Agents; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Induction Chemotherapy; Maintenance Chemotherapy; Models, Statistical; Placebo Effect; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome
PubMed: 26746169
DOI: 10.1093/ecco-jcc/jjw004 -
Medicine Aug 2016Placebo, defined as "false treatment," is a common gold-standard method to assess the validity of a therapy both in pharmacological trials and manual medicine research... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Placebo, defined as "false treatment," is a common gold-standard method to assess the validity of a therapy both in pharmacological trials and manual medicine research where placebo is also referred to as "sham therapy." In the medical literature, guidelines have been proposed on how to conduct robust placebo-controlled trials, but mainly in a drug-based scenario. In contrast, there are not precise guidelines on how to conduct a placebo-controlled in manual medicine trials (particularly osteopathy). The aim of the present systematic review was to report how and what type of sham methods, dosage, operator characteristics, and patient types were used in osteopathic clinical trials and, eventually, assess sham clinical effectiveness.
METHODS
A systematic Cochrane-based review was conducted by analyzing the osteopathic trials that used both manual and nonmanual placebo control. Searches were conducted on 8 databases from journal inception to December 2015 using a pragmatic literature search approach. Two independent reviewers conducted the study selection and data extraction for each study. The risk of bias was evaluated according to the Cochrane methods.
RESULTS
A total of 64 studies were eligible for analysis collecting a total of 5024 participants. More than half (43 studies) used a manual placebo; 9 studies used a nonmanual placebo; and 12 studies used both manual and nonmanual placebo. Data showed lack of reporting sham therapy information across studies. Risk of bias analysis demonstrated a high risk of bias for allocation, blinding of personnel and participants, selective, and other bias. To explore the clinical effects of sham therapies used, a quantitative analysis was planned. However, due to the high heterogeneity of sham approaches used no further analyses were performed.
CONCLUSION
High heterogeneity regarding placebo used between studies, lack of reporting information on placebo methods and within-study variability between sham and real treatment procedures suggest prudence in reading and interpreting study findings in manual osteopathic randomized controlled trials (RCTs). Efforts must be made to promote guidelines to design the most reliable placebo for manual RCTs as a means of increasing the internal validity and improve external validity of findings.
Topics: Controlled Clinical Trials as Topic; Humans; Osteopathic Medicine; Placebo Effect
PubMed: 27583913
DOI: 10.1097/MD.0000000000004728 -
Neurogastroenterology and Motility Feb 2023Placebo responses to an apparently inactive intervention are of interest from a scientific perspective as they suggest possible mechanism(s) at work beyond the... (Review)
Review
Placebo responses to an apparently inactive intervention are of interest from a scientific perspective as they suggest possible mechanism(s) at work beyond the intervention itself. They are also of interest from a clinical trials perspective since high rates of placebo response limit the potential to demonstrate worthwhile efficacy of a new intervention. This mini-review was motivated by the work of Bosman and colleagues(Neurogastroenterol Motil, 2022, and e14474) that is published in this issue of the journal in which they report on a systematic review and meta-analysis of placebo response in functional dyspepsia clinical trials. The review sets the scene for their work by putting it in the context of other disorders of brain-gut interaction and extra-gastrointestinal disorders. The review canvasses potential mechanisms of placebo response.
Topics: Humans; Dyspepsia; Gastrointestinal Diseases; Placebo Effect
PubMed: 36592054
DOI: 10.1111/nmo.14527 -
Neurological Sciences : Official... Feb 2022Nocebo effect is prevalent among neurological diseases, resulting in low adherence and treatment outcome. We sought to examine the nocebo effect in randomized controlled... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Nocebo effect is prevalent among neurological diseases, resulting in low adherence and treatment outcome. We sought to examine the nocebo effect in randomized controlled trials (RCTs) in multiple system atrophy (MSA).
METHODS
We searched RCTs in MSA from Medline since September, 2021. RCTs for drug treatment conducted in adult MSA patients with more than 5 cases in each treatment arm were included. We assessed the number of dropout due to placebo intolerance. We also did a symptomatic/disease-modifying subgroup analysis based on two different treatment purposes. The STATA software was used for statistical analysis. Overall heterogeneity was assessed using the Cochran Q and I.
RESULTS
Data were extracted from 11 RCTs fulfilling our search criteria. Of 540 placebo-treated patients, 64.2% reported at least one adverse event (AE) and 7.5% reported dropout because of AEs. The chance of dropping out because of an AE and experiencing at least one AE did not differ between placebo and active drug treatment arms. Besides, the pooled nocebo dropout rate in the symptomatic subgroup was similar to that of the disease-modifying subgroup.
CONCLUSION
In MSA RCTs, nocebo dropout rate was not at a low level among neurological disorders. Nocebo effect was an important reason of dropout because of AE in placebo and active drug treatment arms. Different treatment purposes may not influence nocebo effect.
Topics: Humans; MEDLINE; Multiple System Atrophy; Nocebo Effect; Treatment Outcome
PubMed: 34973075
DOI: 10.1007/s10072-021-05758-2 -
Movement Disorders : Official Journal... May 2016Two recent randomized, placebo-controlled trials of putative disease-modifying agents (davunetide, tideglusib) in progressive supranuclear palsy (PSP) failed to show... (Review)
Review
BACKGROUND
Two recent randomized, placebo-controlled trials of putative disease-modifying agents (davunetide, tideglusib) in progressive supranuclear palsy (PSP) failed to show efficacy, but generated data relevant for future trials.
METHODS
We provide sample size calculations based on data collected in 187 PSP patients assigned to placebo in these trials. A placebo effect was calculated.
RESULTS
The total PSP-Rating Scale required the least number of patients per group (N = 51) to detect a 50% change in the 1-year progression and 39 when including patients with ≤ 5 years disease duration. The Schwab and England Activities of Daily Living required 70 patients per group and was highly correlated with the PSP-Rating Scale. A placebo effect was not detected in these scales.
CONCLUSIONS
We propose the 1-year PSP-Rating Scale score change as the single primary readout in clinical neuroprotective or disease-modifying trials. The Schwab and England Activities of Daily Living could be used as a secondary outcome. © 2016 International Parkinson and Movement Disorder Society.
Topics: Activities of Daily Living; Humans; Oligopeptides; Outcome Assessment, Health Care; Placebo Effect; Randomized Controlled Trials as Topic; Research Design; Sample Size; Severity of Illness Index; Supranuclear Palsy, Progressive; Thiadiazoles
PubMed: 26948290
DOI: 10.1002/mds.26580 -
Current Neuropharmacology 2019Placebo response appears to be increasing in antidepressant, antipsychotic and various internal medicine trials. A similar trend has been reported for OCD during... (Review)
Review
BACKGROUND
Placebo response appears to be increasing in antidepressant, antipsychotic and various internal medicine trials. A similar trend has been reported for OCD during 1989-1999. Placebo response is generally considered as the extent to which placebo treatment is associated with core symptom improvement. In this analysis, we used Joinpoint regression to assess the time trend of both placebo response and placebo responder rates according to the year of publication with no time restriction in OCD drug trials.
METHODS
We included drug and/or psychotherapy trials vs. placebo from PubMed, Embase, CINAHL, and PsycINFO retrieved through the search (placebo OR sham) AND (obsessive* OR OCD). We included studies through investigator consensus. We then performed on data of included studies log-linear joinpoint segmented regression models using a p<0.05 cutoff.
RESULTS
We included 113 studies from 112 published papers. Placebo mean annual response rates in OCD studies significantly increased from 1991 to 2017 with an annual percent change (APC) of 0.66%, while placebo mean annual responder rates also significantly increased from 2010 to 2017, with an APC of 5.45%. Drug mean annual response rates in OCD studies significantly increased from 1987 to 2012 with an APC of 0.72%, while the corresponding responder rates did not show statistically significant APC changes between 1984 and 2017.
CONCLUSION
We observed a tendency for placebo to increase both measures of response in OCD clinical drug trials through the years that tend to approximate the responses shown by drugs. Changes in the type of study (moving from classical head to head comparisons to add-on studies in treatmentresistant populations) and countries involved in experimentation may partially account for some portion of these results. It appears that placebo effects are becoming more elusive and out of control.
Topics: Antidepressive Agents; Antipsychotic Agents; Humans; Obsessive-Compulsive Disorder; Placebo Effect; Selective Serotonin Reuptake Inhibitors
PubMed: 30370851
DOI: 10.2174/1570159X16666181026163922