-
International Review of Neurobiology 2018Accumulating evidence reveal important applications of endogenous pain modulation assessment in healthy controls and in patients in clinical settings, as dysregulations... (Review)
Review
Accumulating evidence reveal important applications of endogenous pain modulation assessment in healthy controls and in patients in clinical settings, as dysregulations in the balance of pain modulatory circuits may facilitate pain and promote chronification of pain. This article reviews data on pain modulation, focusing on the mechanisms and translational aspects of pain modulation from conditioned pain modulation (CPM) to placebo and nocebo effects in experimental and clinical pain. The specific roles of expectations, learning, neural and neurophysiological mechanisms of the central nervous system are briefly reviewed herein. The interaction between CPM and placebo systems in pain inhibitory pathways is highly relevant in the clinic and in randomized controlled trials yet remains to be clarified. Examples of clinical implications of CPM and its relationship to placebo and nocebo effects are provided. A greater understanding of the role of pain modulation in various pain states can help characterize the manifestation and development of chronic pain and assist in predicting the response to pain-relieving treatments. Placebo and nocebo effects, intrinsic to every treatment, can be used to develop personalized therapeutic approaches that improve clinical outcomes while limiting unwanted effects.
Topics: Humans; Nocebo Effect; Pain; Pain Management; Pain Measurement; Placebos
PubMed: 30146050
DOI: 10.1016/bs.irn.2018.07.024 -
JAMA Apr 2021Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea.
OBJECTIVE
To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes.
DESIGN, SETTING, AND PARTICIPANTS
Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-β0 thalassemia, or S-β+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included.
INTERVENTIONS
A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194).
MAIN OUTCOMES AND MEASURES
Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup.
RESULTS
Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%).
CONCLUSIONS AND RELEVANCE
Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01737814.
Topics: Adolescent; Adult; Analgesics, Opioid; Anemia, Sickle Cell; Child; Double-Blind Method; Female; Humans; Male; Pain; Placebos; Poloxamer; Vasodilator Agents; Young Adult
PubMed: 33877274
DOI: 10.1001/jama.2021.3414 -
PLoS Biology Feb 2017
-
Psychiatria Danubina Jun 2015Permissibility of placebo controls in psychiatric research is raising everlasting controversies. The main ethical issue remains: whether, when, under what conditions,... (Review)
Review
Permissibility of placebo controls in psychiatric research is raising everlasting controversies. The main ethical issue remains: whether, when, under what conditions, and to what extent is it justifiable to disregard subject's present (best) interest for the presumably "greater" ones. In relation to this main ethical concern, two distinct arguments arose: proponents of placebo controls trials (placebo ortxodoxy) and proponents of active controls trials (active-control orthodoxy). More recently, in new ethical guidelines, Declaration of Helsinki and International Ethical Guidelines for Biomedical Research Involving Human Subjects, a "middle way" approach was formulated, acceptable to both sides of the argument, saying placebo controls can be justified under certain conditions: when and only when, they firstly present undisputed methodological reasoning, and secondly, fulfill certain ethical considerations - mainly regarding the permissibility of accompanied risks. These ethical evaluations are inevitably contextual and evoke the need for the principle of proportionality. In scope of recent findings of substantial and progressively increasing placebo response in psychiatric research, contextual factors are identified and both theoretical and practical challenges are discussed.
Topics: Biomedical Research; Controlled Clinical Trials as Topic; Helsinki Declaration; Humans; Placebos; Practice Guidelines as Topic; Psychiatry
PubMed: 26057306
DOI: No ID Found -
Proceedings of the National Academy of... May 2018Placebo effect refers to beneficial changes induced by the use of inert treatment, such as placebo-induced relief of physical pain and attenuation of negative affect. To... (Randomized Controlled Trial)
Randomized Controlled Trial
Placebo effect refers to beneficial changes induced by the use of inert treatment, such as placebo-induced relief of physical pain and attenuation of negative affect. To date, we know little about whether placebo treatment could facilitate social functioning, a crucial aspect for well-being of a social species. In the present study, we develop and validate a paradigm to induce placebo effects on social trust and approach behavior (social placebo effect), and show robust evidence that placebo treatment promotes trust in others and increases preference for a closer interpersonal distance. We further examine placebo effects in real-life social interaction and show that placebo treatment makes single, but not pair-bonded, males keep closer to an attractive first-met female and perceive less social anxiety in the female. Finally, we show evidence that the effects of placebo treatment on social trust and approach behavior can be as strong as the effect of intranasal administration of oxytocin, a neuropeptide known for its function in facilitating social cognition and behavior. The finding of the social placebo effect extends our understanding of placebo effects on improvement of physical, mental, and social well-being and suggests clinical potentials in the treatment of social dysfunction.
Topics: Adult; Choice Behavior; Female; Humans; Interpersonal Relations; Male; Oxytocin; Placebo Effect; Placebos; Social Behavior; Trust; Young Adult
PubMed: 29760054
DOI: 10.1073/pnas.1800779115 -
Handbook of Clinical Neurology 2016Placebo therapy can produce meaningful, clinical relief for a variety of conditions. While placebos are not without their ethically fraught history, they continue to be... (Review)
Review
Placebo therapy can produce meaningful, clinical relief for a variety of conditions. While placebos are not without their ethically fraught history, they continue to be used, largely covertly, even today. Because the prognosis for psychogenic disorders is often poor and recovery may be highly dependent on the patient's belief in the diagnosis and treatment regimen, some physicians find placebo therapy for psychogenic disorders compelling, but also particularly contentious. Yet placebos also have a long tradition of being used for provocative diagnosis (wherein placebo is used to elicit and/or terminate the symptoms as a way of diagnosing symptoms as "psychogenic"). In this chapter we discuss cases describing placebo as therapy for psychogenic disorders and the challenges related to embedded Cartesian beliefs in Western medicine. The legitimate ethical reservations against placebo therapy, in general, have been related to assumptions about their "inertness" and a requirement for deception, both which are being refuted by emerging data. In this chapter, we also re-evaluate the concerns associated with placebo therapy for psychogenic disorders by asking, "Are we harming patients by withholding placebo treatment?"
Topics: Conversion Disorder; Humans; Nervous System Diseases; Placebos; Psychophysiologic Disorders
PubMed: 27719875
DOI: 10.1016/B978-0-12-801772-2.00049-7 -
The Journal of Physiology Oct 2016We analysed the placebo response at the single-neuron level in the thalamus of Parkinson patients to see the differences between first-time administration of placebo and...
KEY POINTS
We analysed the placebo response at the single-neuron level in the thalamus of Parkinson patients to see the differences between first-time administration of placebo and administration after pharmacological pre-conditioning. When the placebo was given for the first time, it induced neither clinical improvement, as assessed through muscle rigidity reduction at the wrist, nor neuronal changes in thalamic neurons. However, if placebo was given after two, three or four prior administrations of an anti-Parkinson drug, apomorphine, it produced both clinical and neuronal responses. Both the magnitude and the duration of these placebo responses depended on the number of prior exposures to apomorphine, according to the rule: the greater the number of previous apomorphine administrations, the larger the magnitude and the longer the duration of the clinical and neuronal placebo responses. These findings show that learning plays a crucial role in the placebo response and suggest that placebo non-responders can be turned into placebo responders, with important clinical implications.
ABSTRACT
Placebos have been found to affect the patient's brain in several conditions, such as pain and motor disorders. For example, in Parkinson's disease, a placebo treatment induces a release of dopamine in the striatum and changes the activity of neurons in both thalamic and subthalamic nuclei. The present study shows that placebo administration for the first time induces neither clinical nor neuronal improvement in Parkinson patients who undergo implantation of electrodes for deep brain stimulation. However, this lack of placebo responsiveness can be turned into substantial placebo responses following previous exposure to repeated administrations of the anti-Parkinson agent apomorphine. As the number of apomorphine administrations increased from one to four, both the clinical response and the neuronal activity in the ventral anterior and anterior ventrolateral thalamus increased. In fact, after four apomorphine exposures, placebo administration induced clinical responses that were as large as those to apomorphine, along with long-lasting neuronal changes. These clinical placebo responses following four apomorphine administrations were again elicited after a re-exposure to a placebo 24 h after surgery, but not after 48 h. These data indicate that learning plays a crucial role in placebo responsiveness and suggest that placebo non-responders can be turned into responders, with important implications in the clinical setting.
Topics: Aged; Apomorphine; Deep Brain Stimulation; Dopamine Agonists; Female; Humans; Male; Middle Aged; Neurons; Parkinson Disease; Placebo Effect; Placebos
PubMed: 26861164
DOI: 10.1113/JP271322 -
Annals of Behavioral Medicine : a... Jan 2020Choice has been found to facilitate placebo effects for single-session treatments where standard placebo treatment without choice failed to elicit a placebo effect.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Choice has been found to facilitate placebo effects for single-session treatments where standard placebo treatment without choice failed to elicit a placebo effect. However, it is unknown whether choice can enhance the placebo effect for treatments occurring over a period of days and where placebo effects are readily established without choice.
PURPOSE
We tested whether single or daily choice between two (placebo) treatments enhanced the placebo effect for sleep difficulty relative to no choice and no treatment over a 1 week period.
METHODS
One-hundred and seventeen volunteers self-identifying with sleep difficulty were recruited under the guise of a hypnotic trial and randomized to one of the four groups. Self-reported outcomes included insomnia severity, fatigue, total sleep time (TST), sleep onset latency (SOL), perceived sleep quality (PSQ), and treatment satisfaction. Objective TST and SOL were assessed in a subsample via actigraphy.
RESULTS
Overall, placebo treatment significantly improved insomnia severity, fatigue, and PSQ, confirming a placebo effect on these outcomes. However, both traditional and Bayesian analysis indicated no benefit of choice on the placebo effect on any sleep outcome. Mediation analysis of the overall placebo effect indicated that expectancy completely mediated the placebo effects for insomnia severity and PSQ and partially mediated the placebo effect for fatigue.
CONCLUSION
These findings suggest that choice does not enhance the placebo effect over longer treatment periods (up to 7 days) when placebo effects are readily established without choice. As such, any benefit of choice on placebo effects may be confined to quite specific circumstances.
CLINICAL TRIALS REGISTRATION
ACTRN12618001199202.
Topics: Actigraphy; Adolescent; Adult; Anticipation, Psychological; Choice Behavior; Fatigue; Female; Humans; Male; Outcome Assessment, Health Care; Placebo Effect; Placebos; Severity of Illness Index; Sleep Initiation and Maintenance Disorders; Young Adult
PubMed: 31504091
DOI: 10.1093/abm/kaz030 -
Nature Jul 2016
Topics: Apomorphine; Chronic Pain; Conditioning, Psychological; Dopamine; Endocannabinoids; Endorphins; Humans; Irritable Bowel Syndrome; Magnetic Resonance Imaging; Parkinson Disease; Placebo Effect; Placebos; Prostaglandins; Receptors, Opioid; Self Report
PubMed: 27410526
DOI: 10.1038/535S14a -
Nederlands Tijdschrift Voor Geneeskunde Jun 2018A recent meta-analysis showed that antidepressants are more effective than placebo. In placebo-controlled trials, the placebo effect is subtracted from the verum effect...
A recent meta-analysis showed that antidepressants are more effective than placebo. In placebo-controlled trials, the placebo effect is subtracted from the verum effect to find the specific effect of each antidepressant. In clinical practice, however, the situation is the other way around: non-specific ('placebo') effects are added to the specific effect of the antidepressant and together these effects determine the outcome. The non-specific aspects comprise strength of the therapeutic relation, conviction of both doctor and patient in the diagnosis and treatment, and hope that treatment will induce remission. In 2006, it was found that the psychiatrist who gave the treatment had a larger effect on the outcome than the effect of verum plus placebo. Some psychiatrists induced improvement, even with placebo, while others made patients worse, even with verum. This implies that while choosing the right antidepressant is important, choosing the right psychiatrist is even more important. When a doctor loses faith in antidepressants, so will his patients and non-specific aspects will have nocebo rather than placebo effects.
Topics: Antidepressive Agents; Attitude of Health Personnel; Depression; Humans; Placebos; Psychiatry; Treatment Outcome
PubMed: 30040321
DOI: No ID Found