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Journal of Pain Research 2021The literature lacks information about the characteristics of the placebo effect following sham spine procedures for chronic low back pain. We aim to evaluate the effect... (Review)
Review
BACKGROUND
The literature lacks information about the characteristics of the placebo effect following sham spine procedures for chronic low back pain. We aim to evaluate the effect using pain score data from the sham arms of published trials.
METHODS
Relevant trials were selected and reviewed. Baseline and post-procedure pain scores were collected. Each follow up pain score was considered an episode and compared to its baseline for significance. Patients and episodes were pooled and analyzed using three parameters: patient reported outcome measures (PROMs) (Oswestry Disability Index [ODI], Visual Analog Scale [VAS], Numerical Rating Scale [NRS] and Short Form-36 [SF]), anatomical targets (disc, facet, sacroiliac joint [SIJ], ramus communicans nerve [RCN], basivertebral nerve [BVN], and caudal) and follow up periods (early: 0-2, intermediate: >2-4 and late: >4-6) in months. The percentage of pooled patients in the episodes that had significant reduction in pain scores was termed placebo effect. The outcome was defining the magnitude of the placebo effect and determining if it was influenced by the three parameters.
RESULTS
Seventeen studies that reported 535 patients and 55 pain scoring episodes were considered eligible. Significant reduction in pain scores was reported in 21 episodes. The overall placebo effect among the patients during the studied period was 53.2%. The rate ranged according to PROMs from 42.4% to 72.1%, anatomical targets from 11.1% to 100% and follow up periods from 47.9% to 59%. The placebo effect differed significantly between the various domains in the three parameters.
CONCLUSION
Placebo effect was observed in nearly half of the patients during the first 6 months following a sham spine procedure. The effect was influenced by utilized PROMs, anatomical target and follow up period. The findings should be considered in the design of new sham spine procedure trials. Further research is required to delineate the effect of bias on the findings.
PubMed: 34616178
DOI: 10.2147/JPR.S317697 -
Pediatric Research Jan 2017A potential larger perceived placebo effect in children compared with adults could influence the detection of the treatment effect and the extrapolation of the treatment... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A potential larger perceived placebo effect in children compared with adults could influence the detection of the treatment effect and the extrapolation of the treatment benefit from adults to children. This study aims to explore this potential difference, using a meta-epidemiological approach.
METHODS
A systematic review of the literature was done to identify trials included in meta-analyses evaluating a drug intervention with separate data for adults and children. The standardized mean change and the proportion of responders (binary outcomes) were used to calculate the perceived placebo effect. A meta-regression analysis was conducted to test for the difference between adults and children of the perceived placebo effect.
RESULTS
For binary outcomes, the perceived placebo effect was significantly more favorable in children compared with adults (β = 0.13; P = 0.001). Parallel group trials (β = -1.83; P < 0.001), subjective outcomes (β = -0.76; P < 0.001), and the disease type significantly influenced the perceived placebo effect.
CONCLUSION
The perceived placebo effect is different between adults and children for binary outcomes. This difference seems to be influenced by the design, the disease, and outcomes. Calibration of new studies for children should consider cautiously the placebo effect in children.
Topics: Adult; Age Factors; Child; Humans; Perception; Placebo Effect; Randomized Controlled Trials as Topic; Regression Analysis
PubMed: 27648807
DOI: 10.1038/pr.2016.181 -
British Journal of Clinical Pharmacology Aug 2022The placebo effect and the specific effect are often thought to add up (additive model). Whether additivity holds can dramatically influence the external validity of a... (Review)
Review
AIM
The placebo effect and the specific effect are often thought to add up (additive model). Whether additivity holds can dramatically influence the external validity of a trial. This assumption of additivity was tested by Kleijnen et al in 1994 but the data produced since then have not been synthetized. In this review, we aimed to systematically review the literature to determine whether additivity held.
METHODS
We searched Medline and PsychInfo up to 10 January 2019. Studies using the balanced placebo design (BPD), testing two different strengths of placebos, were included. The presence of interaction was evaluated by comparing each group in the BPD with analysis of variance or covariance.
RESULTS
Thirty studies were included and the overall risk of bias was high: four found evidence of additivity and 16 studies found evidence of interaction (seven had evidence of positive additivity).
CONCLUSION
Evidence of additivity between placebo and specific features of treatments was rare in included studies. We suggest interventions for placebo-sensitive ailments should be tested in trials designed to take interactions seriously once an exploratory RCTs has proven their efficacy with sufficient internal validity.
Topics: Humans; Placebo Effect
PubMed: 35384004
DOI: 10.1111/bcp.15345 -
Rheumatology (Oxford, England) Apr 2022To determine the placebo response rate in PsA randomized clinical trials (RCTs), its contributing factors and impact on the effect size of active treatments. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To determine the placebo response rate in PsA randomized clinical trials (RCTs), its contributing factors and impact on the effect size of active treatments.
METHODS
We searched multiple databases, from inception to 20 December 2020, for placebo-controlled RCTs in PsA. We used a random-effects meta-analysis to pool the response rates for the ACR20 criteria in the placebo arm, determined the risk difference for treatment vs placebo, and used meta-regression to determine the factors associated with placebo response rates. The risk of bias was assessed in duplicate. The study protocol was registered with PROSPERO: CRD42021226000.
RESULTS
We included 42 RCTs (5050 patients receiving placebo) published between 2000 and 2020. The risk of bias was low in 28 trials, high in four, and with some concerns in 10. The pooled placebo response rate was 20.3% (95% CI: 18.6%, 22.1%; predicted intervals, 11.7-29.0%), with significant between-trial heterogeneity (I2 = 56.8%, P < 0.005). The pooled risk difference for treatment vs placebo was 27% (95% CI: 24%, 31%). In the multivariable meta-regression, there was a 15% (95% CI: 2.9%, 29.8%) increase in the odds of achieving the placebo response for each 5-year increment in publication year (P = 0.016). In addition, the active treatment risk difference decreased for every 5-year increment in publication year (β = -0.053, 95% CI: -0.099, -0.007; P = 0.024) but was not associated with the placebo response.
CONCLUSION
Despite increasing over time, the placebo response for ACR20 in PsA RCTs was not associated with the active treatment effect size.
Topics: Arthritis, Psoriatic; Humans; Placebo Effect
PubMed: 34664615
DOI: 10.1093/rheumatology/keab774 -
International Journal of Behavioral... Jun 2022Nocebo effect, the occurrence of adverse symptoms fallowing an inactive treatment, is much less understood than its opposite, placebo effect. This systematic... (Review)
Review
BACKGROUND
Nocebo effect, the occurrence of adverse symptoms fallowing an inactive treatment, is much less understood than its opposite, placebo effect. This systematic review of contemporary studies exploring the nocebo effect focuses on (1) the mechanisms underlying the nocebo effect, (2) the characteristics of participants exhibiting a more intensive nocebo response, and (3) the circumstances that might reduce or prevent the nocebo effect.
METHOD
We included experimental nocebo studies published in English that examined the occurrence of nocebo in various domains (i.e., types of sensations and symptoms) and different levels of nocebo response (e.g., performance, self-assessment) and in different populations of participants (healthy and clinical). Using Web of Science, PsycInfo and PubMed, we identified 25 papers (35 studies) that met our criteria with a total of N = 2614 participants, mostly healthy volunteers.
RESULTS
Nocebo was invoked by manipulating expectations, conditioning or both. A narrative content synthesis was conducted. Nocebo was successfully invoked in a range of domains (e.g., pain, nausea, itch, skin dryness) and levels (sensory, affective, psychological, and behavioral). Various characteristics of the conditioning procedure and participants' emotions, expectations, and dispositions are found to be related to the nocebo response, which sheds insight into the possible mechanisms of the nocebo effect. Strategies successful and unsuccessful in diminishing the nocebo response are identified. Limitations of this review include a small sample of studies.
CONCLUSION
These findings point to the universality of nocebo as well as to the importance of participant characteristics and experimental circumstances in invoking the nocebo effect. Further research should examine the nocebo effect in clinical populations.
Topics: Healthy Volunteers; Humans; Nocebo Effect; Pain; Placebo Effect; Pruritus
PubMed: 34405336
DOI: 10.1007/s12529-021-10016-y -
Pain Physician 2016There is conflicting evidence from previous qualitative reviews on the effect of vitamin D supplementation on pain. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
There is conflicting evidence from previous qualitative reviews on the effect of vitamin D supplementation on pain.
OBJECTIVE
To determine with quantitative methods if vitamin D supplementation lowers pain levels.
STUDY DESIGN
Quantitative meta-analysis of published randomized controlled trials (RCTs).
SETTING
This meta-analysis examined all studies involving the effect of vitamin D supplementation on pain score.
METHOD
Electronic sources (Medline, Embase, Cochrane Central Register of Controlled Trials, clinical trials website, and Google scholar) were systematically searched for RCTs of vitamin D supplementation and pain from inception of each database to October 2015.
RESULTS
Nineteen RCTs with 3,436 participants (1,780 on vitamin D supplementation and 1,656 on placebo) were included in the meta-analysis. For the primary outcome (mean change in pain score from baseline to final follow-up), 8 trials with 1,222 participants on vitamin D and 1,235 on placebo reported a significantly greater mean decrease in pain score for the vitamin D group compared to placebo (mean difference -0.57, 95% CI: -1.00 to -0.15, P = 0.007). The effect from vitamin D was greater in patients recruited with pre-existing pain (P-value for interaction = 0.03). Fourteen studies (1,548 on vitamin D, 1,430 on placebo) reported the mean pain score at final follow-up outcome, and no statistical difference was observed (mean difference -0.06, 95%CI: -0.44 to 0.33, P = 0.78). In 4 studies which reported pain improvement (209 on vitamin D, 146 on placebo), the effect size although not significant, shows participants in the vitamin D supplementation group were more likely to report pain improvement compared with the placebo group (relative risk 1.38, 95%CI: 0.93 to 2.05, P = 0.11).
LIMITATIONS
Only a few studies reported the mean score change from baseline to final follow-up, and we do not have enough data to determine any modifying effect of baseline vitamin D status and different doses of vitamin D supplementation on pain.
CONCLUSION
A significantly greater mean decrease in pain score (primary outcome) was observed with vitamin D supplementation compared with placebo in people with chronic pain. These results suggest that vitamin D supplementation could have a role in the management of chronic pain.
KEY WORDS
Meta-analysis, pain, randomized controlled trials, vitamin D supplementation.
Topics: Dietary Supplements; Humans; Pain; Randomized Controlled Trials as Topic; Vitamin D; Vitamins
PubMed: 27676659
DOI: No ID Found -
Journal of Clinical Epidemiology Apr 2015It has been suggested that some placebo interventions might be associated with larger clinical effects than others. In a systematic review, we investigated whether there... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
It has been suggested that some placebo interventions might be associated with larger clinical effects than others. In a systematic review, we investigated whether there is evidence from direct comparisons in randomized clinical trials including two or more placebo groups supporting this hypothesis.
STUDY DESIGN AND SETTING
Eligible trials were identified through electronic database searches and citation tracking up to February 2013. Placebo interventions in a trial were categorized into a more intense and a less intense intervention based on complexity, invasiveness, or route of administration and time needed for application.
RESULTS
Twelve studies with 1,059 patients receiving placebo met the eligibility criteria. Studies were highly heterogeneous regarding patients, interventions, outcomes, and risk of bias. Seven studies did not find any significant differences between the more intense and the less intense placebo intervention, four studies found differences for single outcomes, and one study consistently reported significantly larger effects of the more intense placebo. An explorative meta-analysis yielded a standardized mean difference -0.22 (95% confidence interval: -0.46, 0.02; P = 0.07; I(2) = 68%).
CONCLUSION
In the studies included in this review, more intense placebos were not consistently associated with larger effects than less intense placebos.
Topics: Humans; Placebo Effect; Placebos; Randomized Controlled Trials as Topic
PubMed: 25639981
DOI: 10.1016/j.jclinepi.2014.11.018 -
European Journal of Pain (London,... Oct 2021The current treatments of primary musculoskeletal low back pain (LBP) have a low to moderate efficacy, which might be improved by looking at the contribution of placebo... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND OBJECTIVE
The current treatments of primary musculoskeletal low back pain (LBP) have a low to moderate efficacy, which might be improved by looking at the contribution of placebo effects. However, the size of true placebo effects in LBP is unknown. Therefore, a systematic review and meta-analysis were executed of randomized controlled trials investigating placebo effects in LBP.
DATABASES AND DATA TREATMENT
The study protocol was registered in the international prospective register of systematic reviews Prospero (CRD42019148745). A literature search (in PubMed, Embase, The Cochrane Library, CINAHL and PsycINFO) up to 2021 February 16th yielded 2,423 studies. Two independent reviewers assessed eligibility and risk of bias.
RESULTS
Eighteen studies were eligible for the systematic review and 5 for the meta-analysis. Fourteen of the 18 studies were clinical treatment studies, and 4 were experimental studies specifically assessing placebo effects. The clinical treatment studies provided varying evidence for placebo effects in chronic LBP but insufficient evidence for acute and subacute LBP. Most experimental studies investigating chronic LBP revealed significant placebo effects. The meta-analysis of 5 treatment studies investigating chronic LBP depicted a significant moderate effect size of placebo for pain intensity (SMD = 0.57) and disability (SMD = 0.52).
CONCLUSIONS
This review shows a significant contribution of placebo effects to chronic LBP symptom relief in clinical and experimental conditions. The meta-analysis revealed that placebo effects can influence chronic LBP intensity and disability. However, additional studies are required for more supporting evidence and evidence for placebo effects in acute or subacute LBP.
SIGNIFICANCE
This systematic review and meta-analysis provides evidence of true placebo effects in low back pain (LBP). It shows a significant contribution of placebo effects to chronic LBP symptom relief. The results highlight the importance of patient- and context-related factors in fostering treatment effects in this patient group. New studies could provide insight into the potential value of actively making use of placebo effects in clinical practice.
Topics: Chronic Pain; Humans; Low Back Pain; Placebo Effect
PubMed: 34051018
DOI: 10.1002/ejp.1811 -
Sleep Medicine Jun 2023New drug treatments are under development in obstructive sleep apnea (OSA). The placebo effect is well recognized in various conditions, but its relevance in OSA is... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
New drug treatments are under development in obstructive sleep apnea (OSA). The placebo effect is well recognized in various conditions, but its relevance in OSA is debated. In the current study we determined the influence of a placebo effect in studies of drug therapy in OSA.
METHODS
A systematic review and meta-analysis (PROSPERO CRD42021229410) with searches in MEDLINE, Scopus, Web of Science and Cochrane CENTRAL from inception to 2021-01-19. Inclusion criteria were (i) RCTs of adults with OSA, (ii) drug intervention with placebo baseline and follow-up sleep study (iii) outcomes: apnea hypopnea index (AHI), mean oxygen saturation (mSaO), oxygen desaturation index (ODI) and/or Epworth Sleepiness Scale (ESS). Risk-of-bias was assessed with Cochrane RoB 2.
RESULTS
7436 articles were identified and 29 studies included (n = 413). Studies were generally small (median n = 14), with 78% men, baseline AHI range 9-74 events/h and treatment duration range 1-120 days. Meta-analyses were conducted for main outcomes. Mean change of the primary outcome, AHI, was -0.84 (95% CI -2.98 to 1.30); mSaO and ODI estimations were also non-significant. ESS showed a trend towards a reduction of -1 unit. Subgroup analysis did not show significant differences. Risk-of-bias assessment indicated mostly low risk but studies were small with wide confidence intervals.
CONCLUSIONS
In this meta-analysis we did not identify systematic placebo effects on the AHI, ODI or mSaO while ESS score showed a trend for a small reduction. These results have an impact on the design and interpretation of drug trials in OSA.
Topics: Humans; Oxygen; Placebo Effect; Sleep Apnea, Obstructive; Sleepiness
PubMed: 37023489
DOI: 10.1016/j.sleep.2023.03.019 -
The Cochrane Database of Systematic... Dec 2016Risperidone is the first new-generation antipsychotic drug made available in the market in its generic form. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Risperidone is the first new-generation antipsychotic drug made available in the market in its generic form.
OBJECTIVES
To determine the clinical effects, safety and cost-effectiveness of risperidone compared with placebo for treating schizophrenia.
SEARCH METHODS
On 19th October 2015, we searched the Cochrane Schizophrenia Group Trials Register, which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. We checked the references of all included studies and contacted industry and authors of included studies for relevant studies and data.
SELECTION CRITERIA
Randomised clinical trials (RCTs) comparing oral risperidone with placebo treatments for people with schizophrenia and/or schizophrenia-like psychoses.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened studies, assessed the risk of bias of included studies and extracted data. For dichotomous data, we calculated the risk ratio (RR), and the 95% confidence interval (CI) on an intention-to-treat basis. For continuous data, we calculated mean differences (MD) and the 95% CI. We created a 'Summary of findings table' using GRADE (Grading of Recommendations Assessment, Development and Evaluation).
MAIN RESULTS
The review includes 15 studies (N = 2428). Risk of selection bias is unclear in most of the studies, especially concerning allocation concealment. Other areas of risk such as missing data and selective reporting also caused some concern, although not affected on the direction of effect of our primary outcome, as demonstrated by sensitivity analysis. Many of the included trials have industry sponsorship of involvement. Nonetheless, generally people in the risperidone group are more likely to achieve a significant clinical improvement in mental state (6 RCTs, N = 864, RR 0.64, CI 0.52 to 0.78, very low-quality evidence). The effect withstood, even when three studies with >50% attrition rate were removed from the analysis (3 RCTs, N = 589, RR 0.77, CI 0.67 to 0.88). Participants receiving placebo were less likely to have a clinically significant improvement on Clinical Global Impression scale (CGI) than those receiving risperidone (4 RCTs, N = 594, RR 0.69, CI 0.57 to 0.83, very low-quality evidence). Overall, the risperidone group was 31% less likely to leave early compared to placebo group (12 RCTs, N = 2261, RR 0.69, 95% CI 0.62 to 0.78, low-quality evidence), but Incidence of significant extrapyramidal side effect was more likely to occur in the risperidone group (7 RCTs, N = 1511, RR 1.56, 95% CI 1.13 to 2.15, very low-quality evidence).When risperidone and placebo were augmented with clozapine, there is no significant differences between groups for clinical response as defined by a less than 20% reduction in PANSS/BPRS scores (2 RCTs, N = 98, RR 1.15, 95% CI 0.93 to 1.42, low-quality evidence) and attrition (leaving the study early for any reason) (3 RCTs, N = 167, RR 1.13, 95% CI 0.53 to 2.42, low quality evidence). One study measured clinically significant responses using the CGI, no effect was evident (1 RCT, N = 68, RR 1.12 95% CI 0.87 to 1.44, low quality evidence). No data were available for extrapyramidal adverse effects.
AUTHORS' CONCLUSIONS
Based on low quality evidence, risperidone appears to be benefitial in improving mental state compared with placebo, but it also causes more adverse events. Eight out of the 15 included trials were funded by pharmaceutical companies. The currently available evidence isvery low to low quality.
Topics: Administration, Oral; Antipsychotic Agents; Humans; Placebos; Publication Bias; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia
PubMed: 27977041
DOI: 10.1002/14651858.CD006918.pub3