Placebos in chronic pain: evidence, theory, ethics, and use in clinical practice

BMJ ◽  
2020 ◽  
pp. m1668 ◽  
Author(s):  
Ted J Kaptchuk ◽  
Christopher C Hemond ◽  
Franklin G Miller
Keyword(s):  
Chronic Pain ◽  
Clinical Practice ◽  
Predictive Coding ◽  
Evidence Theory ◽  
Placebo Treatment ◽  
Placebo Effects ◽  
Unified Framework ◽  
Open Label ◽  
Double Blind ◽  
Bayesian Brain

ABSTRACTDespite their ubiquitous presence, placebos and placebo effects retain an ambiguous and unsettling presence in biomedicine. Specifically focused on chronic pain, this review examines the effect of placebo treatment under three distinct frameworks: double blind, deception, and open label honestly prescribed. These specific conditions do not necessarily differentially modify placebo outcomes. Psychological, clinical, and neurological theories of placebo effects are scrutinized. In chronic pain, conscious expectation does not reliably predict placebo effects. A supportive patient-physician relationship may enhance placebo effects. This review highlights “predictive coding” and “bayesian brain” as emerging models derived from computational neurobiology that offer a unified framework to explain the heterogeneous evidence on placebos. These models invert the dogma of the brain as a stimulus driven organ to one in which perception relies heavily on learnt, top down, cortical predictions to infer the source of incoming sensory data. In predictive coding/bayesian brain, both chronic pain (significantly modulated by central sensitization) and its alleviation with placebo treatment are explicated as centrally encoded, mostly non-conscious, bayesian biases. The review then evaluates seven ways in which placebos are used in clinical practice and research and their bioethical implications. In this way, it shows that placebo effects are evidence based, clinically relevant, and potentially ethical tools for relieving chronic pain.

Clinical and attentional effects of acute nicotine treatment in Tourette’s syndrome

2004 ◽  
Vol 19 (2) ◽  
pp. 102-112 ◽  
Author(s):  
Anne L. Howson ◽  
Sue Batth ◽  
Vadim Ilivitsky ◽  
Armand Boisjoli ◽  
Martine Jaworski ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Event Related Potentials ◽  
Placebo Treatment ◽  
Tourette's Syndrome ◽  
Tourette’S Syndrome ◽  
Continuous Performance Task ◽  
Open Label ◽  
Double Blind ◽  
Nicotine Treatment ◽  
Related Potentials

AbstractEvidence from pre-clinical infrahuman investigations, open-label clinical trials, and a single controlled trial found acute nicotine treatment potentiated up to 4 weeks neuroleptic-induced reductions of dyskinetic symptoms characterizing Tourette’s syndrome (TS). Given the attentional disturbances associated with this syndrome, and the improvements in attentional processes reported with nicotine, this randomized, double-blind, placebo-controlled trial examined the acute (4 h) and sustained (2 weeks) effects of a single dose of transdermal nicotine on clinical (i.e., tics), attentional (continuous performance task, event-related potentials, patient and parental reports) and behavioral symptoms in 23 children and adolescents with TS receiving neuroleptic treatment. In the 14 evaluable patients with complete primary efficacy data, nicotine (compared to placebo) failed to alter symptoms at 4 h but counteracted ERP-P300 signs of diminished attention seen 2 weeks following placebo treatment. Secondary efficacy measures, including patient self-reports and parental ratings, found nicotine to reduce complex tics and improve behaviors related to inattention. Additional work with intermittent dosing schedules is required to characterize optimal clinical and cognitive effects with nicotine treatment.

scholarly journals 35 Long-term Improvements in Site-Rated Outcomes with Deutetrabenazine Treatment in Patients with Tardive Dyskinesia

CNS Spectrums ◽  
2019 ◽  
Vol 24 (1) ◽  
pp. 193-194
Author(s):  
Karen E. Anderson ◽  
David Stamler ◽  
Mat D. Davis ◽  
Nicholas Gross ◽  
Robert A. Hauser ◽  
...  
Keyword(s):  
New York ◽  
Clinical Practice ◽  
Tardive Dyskinesia ◽  
Real World ◽  
Treatment Success ◽  
Open Label ◽  
Double Blind ◽  
Abnormal Movements ◽  
Global Impression Of Change

AbstractBackgroundTardive dyskinesia (TD) is an often-irreversible movement disorder that may intensify the stigma of patients with psychiatric disorders and worsen quality of life. In two randomized, double-blind, placebo (PBO)-controlled, 12-week trials, ARM-TD and AIM-TD (‘parent studies’), deutetrabenazine (DTB) demonstrated statistically significant improvements in centrally read Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with PBO and was generally well tolerated.Study ObjectiveTo evaluate the long-term efficacy of DTB in an open-label safety study following double-blind treatment using site-rated efficacy measures: AIMS, the Clinical Global Impression of Change (CGIC) and the Patient Global Impression of Change (PGIC), which may be used in real-world clinical practice settings.MethodPatients with TD who completed the parent studies were eligible to enter this open-label, long-term extension (OLE) after completing the 1-week washout period and final evaluation in the blinded portion of the trial. This extension comprised a 6-week titration period followed by a long-term maintenance phase. Patients began DTB at 12mg/day, titrating up to a maximum total dose of 48mg/day based on dyskinesia control and tolerability. Efficacy endpoints included in this analysis are the change in site-rated AIMS score (items 1–7) from parent study baseline, and the proportion of patients who were “Much Improved” or “Very Much Improved” (treatment success) on the CGIC and PGIC from OLE baseline.ResultsAt the end of the parent studies (Week 12), patients treated with DTB had experienced greater mean (standard error) improvements in site-rated AIMS score (–5.0[0.40]) than patients given PBO (–3.2[0.47]). With long-term DTB treatment, both groups experienced improvements in site-rated AIMS scores (prior DTB, –7.9[0.62]; prior placebo, –6.6[0.64]) compared with parent study baseline. Similarly, at the end of the parent studies, a greater proportion of patients treated with DTB had treatment success on the CGIC (DTB, 51%; PBO, 32%) and the PGIC (DTB, 46%; PBO: 33%); whereas at Week 54 of the OLE study, treatment success on CGIC and PGIC were similar in both the CGIC (prior DTB: 66%; prior PBO: 68%) and PGIC (prior DTB: 62%; prior PBO: 62%) groups. DTB was generally well tolerated.ConclusionsPatients treated with DTB showed improvements in abnormal movements, as measured by site-rated AIMS, CGIC, and PGIC scores, which may be used in real-world clinical practice settings. These results corroborate the previously reported efficacy of DTB as observed in the 12-week, double-blind ARM-TD and AIM-TD trials, in which central raters were used to evaluate AIMS scores.Presented at: American Psychiatric Association Annual Meeting; May 5–9, 2018, New York, New York, USAFunding Acknowledgements: Funding: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.

scholarly journals 3523 Innovative Approaches to Clinical Research on Placebo Effects: A Regulatory Science Perspective

2019 ◽  
Vol 3 (s1) ◽  
pp. 118-118
Author(s):  
Kimberly Uweh
Keyword(s):  
Low Back Pain ◽  
Back Pain ◽  
Placebo Effect ◽  
Controlled Trial ◽  
Placebo Response ◽  
Current Treatment ◽  
Low Back ◽  
Placebo Effects ◽  
Open Label ◽  
Double Blind

OBJECTIVES/SPECIFIC AIMS: To analyze contemporary study design methods and clinical trial approaches in placebo research. METHODS/STUDY POPULATION: An analysis was conducted on the following studies: I. “Managing” the Placebo Effect: The Single-Blind Placebo Lead-in Response in Two Pain Models by RN Haden, et al. The objective of the study was to consider elements of the placebo response in the context of two pain models using a “single-blind placebo lead-in” design (SBPLI) by engaging the “placebo response” prior to randomization to active drug and placebo-controlled conditions. The methods of the study included two pilot drug trials using knee osteoarthritis (KOA) and non-radicular low back pain (LBP) subjects, SBPLI protocols were conducted. In the first study, 36 subjects with non-radicular CLBP were enrolled in a double-blind, randomized, placebo-controlled trial of hydromorphone ER. In the second study, a total of 42 subjects with chronic KOA pain were enrolled in a double-blind, randomized, placebo-controlled study of milnacipran. Gender and/or diagnosis affected placebo responses as observed in changes in patient self-reported pain, depressive and pain anxiety symptoms were examined. Additionally, the placebo response on performance-based tests (stair climbing, range of motion (ROM), sit to stand repetitions, and 6-minute treadmill distance) was evaluated. II. Randomized Placebo-Controlled Placebo Trial to Determine the Placebo Effect Size by L. Gerdesmeyer, et al. The objective of the study was to analyze the pure placebo effect on clinical, chronic pain through a blinded RCT. The methods of the study included 182 patients suffering from chronic plantar heel pain for over 6 months, who failed to respond to conservative treatments, were screened and 106 of these patients were enrolled into this study. The patients were randomly assigned to receive either a blinded placebo shockwave treatment or an unblinded placebo shockwave treatment. The primary outcome measure was the differences in percentage change of visual analogue scale (VAS) scores 6 weeks after the intervention. The secondary outcome measure was the differences in Roles and Maudsley pain score (RMS) 6 weeks after intervention. III. Open-label placebo treatment in chronic low back pain: a randomized controlled trial by C. Carvalho, et al. The objective of the study was to investigate whether placebo effects in chronic low back pain could be harnessed ethically by adding open-label placebo (OLP) treatment to treatment as usual (TAU) for 3 weeks. The methods of the study included 97 randomized participants in a 3-week randomized control trial comparing current treatment plus OLP to current treatment alone (TAU). RESULTS/ANTICIPATED RESULTS: N/a DISCUSSION/SIGNIFICANCE OF IMPACT: The aforementioned studies provide placebo researchers with contemporary and reliable methodologies to examine placebo effects on participants. These methodologies provide scientists with clinical translational research methodology styles based on the foundation of regulatory science.

scholarly journals Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-analysis

2016 ◽  
Vol 19 (2;2) ◽  
pp. 11-24 ◽  
Author(s):  
Giustino Varrassi
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Mast Cells ◽  
Pain Intensity ◽  
Meta Analysis ◽  
Open Label ◽  
Double Blind ◽  
Pooled Data ◽  
Kaplan Meier ◽  
Variance Explained

Background: A growing body of evidence suggests that neuroinflammation, which is characterized by infiltration of immune cells, activation of mast cells and glial cells, and production of inflammatory mediators in the peripheral and central nervous systems, has an important role in the induction and maintenance of chronic pain. These findings support the notion that new therapeutic opportunities for chronic pain might be based on anti-inflammatory and pro-resolving mediators that act on immune cells, in particular mast cells and glia, to mitigate or abolish neuroinflammation. Among anti-inflammatory and pro-resolving lipid mediators, palmitoylethanolamide (PEA) has been reported to down-modulate mast cell activation and to control glial cell behaviors. Objective: The aim of this study was to perform a pooled meta-analysis to evaluate the efficacy and safety of micronized and ultra-micronized palmitoylethanolamide (PEA) on pain intensity in patients suffering from chronic and/or neuropathic pain. Study Design: Pooled data analysis consisting of double-blind, controlled, and open-label clinical trials. Methods: Double-blind, controlled, and open-label clinical trials were selected consulting the PubMed, Google Scholar, and Cochrane databases, and proceedings of neuroscience meetings. The terms chronic pain, neuropathic pain, and micronized and ultra-micronized PEA were used for the search. Selection criteria included availability of raw data and comparability between tools used to diagnose and assess pain intensity. Raw data obtained by authors were pooled in one database and analyzed by the Generalized Linear Mixed Model. The changes in pain over time, measured by comparable tools, were also assessed by linear regression post-hoc analysis and the Kaplan-Meier estimate. Twelve studies were included in the pooled meta-analysis, 3 of which were double-blind trials comparing active comparators vs placebo, 2 were open-label trials vs standard therapies, and 7 were open-label trials without comparators. Results: Results showed that PEA elicits a progressive reduction of pain intensity significantly higher than control. The magnitude of reduction equals 1.04 points every 2 weeks with a 35% response variance explained by the linear model. In contrast, in the control group pain, reduction intensity equals 0.20 points every 2 weeks with only 1% of the total variance explained by the regression. The Kaplan-Meier estimator showed a pain score ≤ 3 in 81% of PEA treated patients compared to only 40.9% in control patients by day 60 of treatment. PEA effects were independent of patient age or gender, and not related to the type of chronic pain. Limitations: Noteworthy, serious adverse events related to PEA were not registered and/or reported in any of the studies. Conclusion: These results confirm that PEA might represent an exciting, new therapeutic strategy to manage chronic and neuropathic pain associated with neuroinflammation. Key words: Chronic pain, neuropathic pain, neuroinflammation, astrocytes, glia, mast cells, microglia, micronized and ultra-micronized palmitoylethanolamide

scholarly journals Placebo effects in chronic pain conditions. Can placebo components enhance the efficacy of active treatments?

2016 ◽  
Vol 12 (23) ◽  
Author(s):  
Ina Skyt ◽  
Lene Vase
Keyword(s):  
Chronic Pain ◽  
Clinical Practice ◽  
Healthy Volunteers ◽  
Placebo Effect ◽  
Brain Activation ◽  
Review Literature ◽  
Endogenous Opioids ◽  
Placebo Effects ◽  
Placebo Analgesia ◽  
Chronic Pain Conditions

The conceptualization of the placebo phenomenon has changed. Previously placebo was seen as an inactive agent, but today placebo effects are viewed as related to patients’ perception of a treatment. During the last decades, the mechanisms underlying placebo analgesia effects have been specified and it has been shown that patients’ perception of a treatment is influenced by previous experiences, the patient-practitioner relationship as well as expectations and emotions. These factors are, in turn, associated with altered brain activation and release of endogenous opioids, thereby demonstrating that placebo analgesia has a psycho-neurobiological basis. The placebo effect has primarily been investigated in relation to healthy volunteers, but here we review literature on placebo mechanisms in relation to chronic pain states as this is important for an understanding of how placebo factors can be optimized in clinical practice. We outline some of the ethical discussions concerning the use of placebo in clinical practice and we illustrate how patients perception of a treatment contribute to the efficacy of active treatments, thereby showing how focus on patients perception of a treatment may help optimize the outcome of standard active pain treatments in ethically appropriate ways.

Abecarnil, a new beta-carboline, in the treatment of anxiety disorders

1998 ◽  
Vol 173 (S34) ◽  
pp. 55-63 ◽  
Author(s):  
B. Aufdembrinke
Keyword(s):  
Therapeutic Potential ◽  
Descriptive Analysis ◽  
Generalised Anxiety Disorder ◽  
Placebo Effects ◽  
Open Label ◽  
Double Blind ◽  
Frequent Adverse Event ◽  
Longterm Treatment ◽  
Hamilton Anxiety Scale ◽  
Active Controls

Background Abecarnil, a novel anxiolytic beta-carboline, was investigated in five four-week double-blind, European multicentre studies. Overall, 451 patients with generalised anxiety disorder were randomised to abecarnil, 461 to placebo and 464 to active controls.Method Data includes inferential statistics based on individual studies and descriptive analysis of 323 patients in open-label abecarnil longterm continuation up to 52 weeks.Results Abecarnil was safe, the most frequent adverse event being drowsiness. Onset of effect was at week I. At week 4 the Hamilton Anxiety Scale score had improved by 12–13 points on average. Due to notably large and variable placebo effects abecarnil was not consistently superior to placebo. No rebound or withdrawal symptoms were observed after fast-tapered discontinuation. Safety, extent of efficacy and incidence of rebound or withdrawal did not change during longterm treatment.Conclusions Abecarnil is safe and effective. Further research into its therapeutic potential seems warranted.

scholarly journals Can an Open-Label Placebo Be as Effective as a Deceptive Placebo? Methodological Considerations of a Study Protocol

Medicines ◽  
2020 ◽  
Vol 7 (1) ◽  
pp. 3
Author(s):  
Leo Druart ◽  
SaraEve Graham Longsworth ◽  
Carole Rolland ◽  
Maïa Dolgopoloff ◽  
Hugo Terrisse ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Crossover Trial ◽  
Ethical Issues ◽  
Cold Pressor ◽  
Placebo Treatment ◽  
Ethics Committee ◽  
Analog Scale ◽  
Open Label ◽  
Methodological Considerations ◽  
And Control

Background: Placebo has been studied for many years and is ever-present in healthcare. In clinical practice, its use is limited by ethical issues raised by the deception entailed by its administration. Objective: To investigate whether, when given detailed information about pain and underlying placebo mechanisms, subjects will have a response similar to that of those subjected to a procedure in which they receive a conventional placebo treatment. Methods: The study is designed as a non-inferiority randomized, parallel with a nested crossover trial. In addition, 126 subjects without any known pathology will be included. They will be randomized into two groups. Each subject will undergo three Cold Pressor Tests (CPT): calibration, condition of interest (deceptive placebo or educated placebo), and control. Our main judgment criterion will be the comparison in pain intensity experienced on the visual analog scale between the two CPTs with placebo conditions. Results: This study will allow us to rule on the non-inferiority of an “educated” placebo compared to a deceptive placebo in the context of an acute painful stimulation. It is another step towards the understanding of open-label placebo and its use in clinical practice. Conclusions: This study has been approved by the ethics committee in France (2017-A01643-50) and registered on ClinicalTrials.gov (NCT03934138).

scholarly journals Effect of recombinant human erythropoietin on platelet production in dialysis patients.

1993 ◽  
Vol 3 (10) ◽  
pp. 1672-1679
Author(s):  
C J Kaupke ◽  
G C Butler ◽  
N D Vaziri
Keyword(s):  
Platelet Count ◽  
Placebo Treatment ◽  
Recombinant Erythropoietin ◽  
Dialysis Patients ◽  
Normal Range ◽  
Open Label ◽  
Double Blind ◽  
Platelet Counts ◽  
Human Erythropoietin ◽  
Erythropoietic Response

Two hundred forty-four anemic hemodialysis patients were randomized into recombinant erythropoietin and placebo-treated groups during a 12-wk double-blind phase, followed by a 24-wk open-label period. Mean platelet count rose from the baseline value of 242 x 10(9)/L to 264 x 10(9)/L on day 5 of epoetin therapy (P < 0.001, paired t test). Mean platelet count peaked at 290 x 10(9)/L on day 40 and remained at a significantly elevated level below the peak thereafter. The peak platelet count did not exceed the normal range in a majority of cases. Platelet count was unaffected by placebo. Patients without an erythropoietic response during the first few weeks of therapy exhibited a rise in platelet count comparable to that in patients with a satisfactory erythropoiesis. Patients with low initial serum ferritin concentrations had baseline platelet counts comparable to those with normal or high ferritin values and showed a similar rise in platelet count during therapy. As a group, patients with baseline platelet counts above 400 x 10(9)/L showed no rise in platelet count, whereas those with normal or reduced platelet counts showed a marked thrombopoietic response to epoetin. Erythropoietin therapy did not significantly alter the incidence of blood access thrombosis when compared with placebo treatment.

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