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Clinical Interventions in Aging 2018Placebo analgesia refers to a perceived reduction in pain intensity following the administration of a simulated or otherwise medically ineffective treatment. Previous...
PURPOSE
Placebo analgesia refers to a perceived reduction in pain intensity following the administration of a simulated or otherwise medically ineffective treatment. Previous studies have shown that many factors can influence the magnitude of placebo analgesia. However, few investigations have examined the effect of age on placebo analgesia, and none have done it in the context of electrotherapeutic interventions. The objective of this study is to compare the placebo response induced by sham transcutaneous electrical nerve stimulation (TENS) between young and older individuals, using an experimental heat-pain paradigm.
PATIENTS AND METHODS
Twenty-two young (21-39 years) and 22 older (58-76 years) healthy adults participated in this comparative study. Experimental heat pain was evoked with a thermode (2-min stimulation at a constant individually adjusted temperature) applied on the lumbar region. Participants were asked to evaluate the intensity of their pain using a computerized visual analog scale. Experimental pain was induced before and after an unconditioned placebo intervention (placebo TENS) applied for 25 min.
RESULTS
In young individuals, no significant pain reductions were noted, whereas in older individuals, a statistically significant pain reduction was observed after the placebo stimulation (<0.01). Between-group analyses revealed that placebo analgesia was greater in older individuals (40% pain reduction) compared with young individuals (15% pain reduction) (<0.05). However, sham TENS increased heat-pain thresholds in the young group (<0.01), but not in the older group (=0.43).
CONCLUSION
Our results indicate that placebo analgesia is influenced by age, with older individuals showing larger placebo analgesia than young adults. Although these results should be confirmed in clinical pain populations, the current observations bear potentially important consequences for the design of future placebo-controlled trials and for healthcare professionals working with elderly patients.
Topics: Adult; Age Factors; Aged; Analgesia; Female; Humans; Male; Middle Aged; Pain; Pain Management; Pain Measurement; Placebos; Research Design; Transcutaneous Electric Nerve Stimulation
PubMed: 29535508
DOI: 10.2147/CIA.S152906 -
The British Journal of Surgery Aug 2020Placebo-controlled trials play an important role in the evaluation of healthcare interventions. However, they can be challenging to design and deliver for invasive...
BACKGROUND
Placebo-controlled trials play an important role in the evaluation of healthcare interventions. However, they can be challenging to design and deliver for invasive interventions, including surgery. In-depth understanding of the component parts of the treatment intervention is needed to ascertain what should, and should not, be delivered as part of the placebo. Assessment of risk to patients and strategies to ensure that the placebo effectively mimics the treatment are also required. To date, no guidance exists for the design of invasive placebo interventions. This study aimed to develop a framework to optimize the design and delivery of invasive placebo interventions in RCTs.
METHODS
A preliminary framework was developed using published literature to: expand the scope of an existing typology, which facilitates the deconstruction of invasive interventions; and identify placebo optimization strategies. The framework was refined after consultation with key stakeholders in surgical trials, consensus methodology and medical ethics.
RESULTS
The resulting DITTO framework consists of five stages: deconstruct treatment intervention into constituent components and co-interventions; identify critical surgical element(s); take out the critical element(s); think risk, feasibility and role of placebo in the trial when considering remaining components; and optimize placebo to ensure effective blinding of patients and trial personnel.
CONCLUSION
DITTO considers invasive placebo composition systematically, accounting for risk, feasibility and placebo optimization. Use of the framework can support the design of high-quality RCTs, which are needed to underpin delivery of healthcare interventions.
Topics: Humans; Placebos; Randomized Controlled Trials as Topic; Risk Assessment
PubMed: 32187680
DOI: 10.1002/bjs.11509 -
World Journal of Gastroenterology Feb 2010We evaluated the efficacy and tolerability of mebeverine, a musculotropic antispasmodic agent, in irritable bowel syndrome (IBS) and compared its usual dosages by... (Meta-Analysis)
Meta-Analysis Review
We evaluated the efficacy and tolerability of mebeverine, a musculotropic antispasmodic agent, in irritable bowel syndrome (IBS) and compared its usual dosages by meta-analysis. Medical databases and all relevant literature were searched from 1965 to June 2009 for any placebo-controlled clinical trials of mebeverine, using search terms such as mebeverine, clinical trials, and IBS. Eight randomized trials met our criteria, including six trials that compared mebeverine with placebo and two that compared mebeverine tablets with capsules. These eight trials included 555 patients randomized to receive either mebeverine or placebo with 352 (63%) women and 203 (37%) men in all subtypes of IBS. The pooled relative risk (RR) for clinical improvement of mebeverine was 1.13 (95% CI: 0.59-2.16, P = 0.7056) and 1.33 (95% CI: 0.92-1.93, P = 0.129) for relief of abdominal pain. The efficacy of mebeverine 200 mg compared to mebeverine 135 mg indicated RRs of 1.12 (95% CI: 0.96-1.3, P = 0.168) for clinical or global improvement and 1.08 (95% CI: 0.87-1.34, P = 0.463) for relief of abdominal pain. Thus, mebeverine is mostly well tolerated with no significant adverse effects; however, its efficacy in global improvement of IBS is not statistically significant.
Topics: Anticonvulsants; Databases, Factual; Female; Humans; Irritable Bowel Syndrome; Male; Parasympatholytics; Phenethylamines; Placebos; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 20128021
DOI: 10.3748/wjg.v16.i5.547 -
Proceedings of the National Academy of... Oct 2013Placebo analgesia is often conceptualized as a reward mechanism. However, by targeting only negative experiences, such as pain, placebo research may tell only half the... (Clinical Trial)
Clinical Trial
Placebo analgesia is often conceptualized as a reward mechanism. However, by targeting only negative experiences, such as pain, placebo research may tell only half the story. We compared placebo improvement of painful touch (analgesia) with placebo improvement of pleasant touch (hyperhedonia) using functional MRI and a crossover design. Somatosensory processing was decreased during placebo analgesia and increased during placebo hyperhedonia. Both placebo responses were associated with similar patterns of activation increase in circuitry involved in emotion appraisal, including the pregenual anterior cingulate, medial orbitofrontal cortex, amygdala, accumbens, and midbrain structures. Importantly, placebo-induced coupling between the ventromedial prefrontal cortex and periaqueductal gray correlated with somatosensory decreases to painful touch and somatosensory increases to pleasant touch. These findings suggest that placebo analgesia and hyperhedonia are mediated by activation of shared emotion appraisal neurocircuitry, which down- or up-regulates early sensory processing, depending on whether the expectation is reduced pain or increased pleasure.
Topics: Adult; Analysis of Variance; Brain; Cross-Over Studies; Emotions; Female; Humans; Magnetic Resonance Imaging; Male; Oxytocin; Pain; Perception; Physical Stimulation; Placebo Effect; Placebos; Pleasure
PubMed: 24127578
DOI: 10.1073/pnas.1305050110 -
Journal of Behavioral Medicine Jun 2011In a laboratory study we examined the hypothesis that placebo expectations enhance the initial identification of placebo-relevant sensations over placebo-irrelevant...
In a laboratory study we examined the hypothesis that placebo expectations enhance the initial identification of placebo-relevant sensations over placebo-irrelevant sensations. Participants (N = 102) were randomly assigned to one of three expectation groups. In the first group, participants ingested a placebo capsule and were told it was caffeine (deceptive expectation). In a second group, participants ingested a placebo capsule and were told it may be caffeine or it may be a placebo (double-blind expectation). Participants in the third group were given no expectation. All participants then tallied the placebo-relevant and placebo-irrelevant sensations they experienced during a 7-min period. Participants in the deceptive expectation group identified more placebo-relevant sensations than placebo-irrelevant sensations. No-expectation participants identified more placebo-irrelevant sensations than placebo-relevant sensations. Participants given the double-blind expectation identified an equal amount of placebo-relevant and irrelevant sensations. The amount of both placebo-relevant and placebo-irrelevant sensations detected mediated the relationship between the expectation manipulation and subsequent symptom reports. These data support the position that expectations cause placebo responding, in part, by altering how one identifies bodily sensations.
Topics: Adult; Attention; Deception; Female; Humans; Male; Perception; Placebo Effect; Placebos; Self Report
PubMed: 21046445
DOI: 10.1007/s10865-010-9301-9 -
Annals of Surgery Feb 2002To set ethical guidelines on the use of surgical placebo controls in the design of surgical trials.
OBJECTIVE
To set ethical guidelines on the use of surgical placebo controls in the design of surgical trials.
BACKGROUND DATA
Ethical concerns recently arose from surgical trials where subjects in the control arm underwent surgical procedures that had the appearance of a therapeutic intervention, but during which the essential therapeutic maneuver was omitted. Although there are ethical guidelines on the use of a placebo in drug trials, little attention has been paid to the use of a surgical placebo control in surgical trials.
METHODS
The Council on Ethical and Judicial Affairs developed ethical guidelines based on a wide literature search and consultation with experts.
RESULTS
Surgical placebo controls should be limited to studies of new surgical procedures aimed at treating diseases that are not amenable to other surgical therapies, and are reasonably anticipated to be susceptible to substantial placebo effects. If the standard nonsurgical treatment is efficacious and acceptable to the patient, then it must be offered as part of the study design.
CONCLUSIONS
Surgical placebo controls should be used only when no other trial design will yield the requisite data and should always be accompanied by a rigorous informed consent process and a careful consideration of the related risks and benefits. The recommended ethical guidelines were adopted as AMA ethics policy and are now incorporated in the AMA's Code of Medical Ethics.
Topics: Clinical Trials as Topic; Ethics, Medical; Humans; Placebos; Surgical Procedures, Operative
PubMed: 11807373
DOI: 10.1097/00000658-200202000-00021 -
Cortex; a Journal Devoted To the Study... Aug 2022Acute and chronic states of physical pain are inherently linked to our bodily perception. Bodily illusion paradigms have demonstrated that an experimentally induced... (Clinical Trial)
Clinical Trial
Acute and chronic states of physical pain are inherently linked to our bodily perception. Bodily illusion paradigms have demonstrated that an experimentally induced sense of body disownership can modulate both acute and chronic pain. Insight into the relationship between enduring clinical alterations in body perception and pain is much more limited. The current study examined both pain perception and placebo analgesia in Body Integrity Dysphoria (BID), a clinical model of long-term alterations of bodily disownership: in its most commonly studied variant, people feel like a part of their body does not belong to them, leading to a desire for amputation of a physically healthy limb. Heat stimulations were applied before and after a placebo intervention (sham analgesic cream) to the desired and the undesired leg of 19 patients with BID with a unilateral leg amputation desire. Pain perception was assessed using pain thresholds, and ratings for pain intensity and pain unpleasantness. Results show that pain perception and placebo efficacy were lower for the undesired than for the desired leg, demonstrating a potential link between a clinical disorder of body ownership, pain perception, and placebo analgesia.
Topics: Humans; Analgesia; Illusions; Pain; Pain Management; Pain Perception; Body Integrity Identity Disorder; Placebos; Placebo Effect
PubMed: 35588553
DOI: 10.1016/j.cortex.2022.03.023 -
Philosophical Transactions of the Royal... Jun 2011Placebo analgesic effects appear to be related to patients' perception of the therapeutic intervention. In this paper, we review quantitative findings of how the... (Review)
Review
Placebo analgesic effects appear to be related to patients' perception of the therapeutic intervention. In this paper, we review quantitative findings of how the relationship with the physician and the verbal suggestions given for relief may influence patients' perception of a treatment and how patients' expectations and emotional feelings may affect treatment outcome. We also present qualitative data from interviews with patients who have experienced pain relief following a placebo or an active treatment. A special focus is given to the temporal development of placebo analgesia at psychological and neurophysiological levels. Finally, we discuss the extent to which the quantitative and qualitative findings supplement or contrast with each other, and we touch upon possible implications of patients' direct experience as central for placebo analgesia.
Topics: Analgesia; Analgesics; Humans; Pain Management; Placebo Effect; Placebos
PubMed: 21576149
DOI: 10.1098/rstb.2010.0402 -
BMJ Open Mar 2016To find evidence, either corroborating or refuting, for many persisting beliefs regarding the feasibility of carrying out surgical randomised controlled trials with a... (Review)
Review
OBJECTIVES
To find evidence, either corroborating or refuting, for many persisting beliefs regarding the feasibility of carrying out surgical randomised controlled trials with a placebo arm, with emphasis on the challenges related to recruitment, funding, anaesthesia or blinding.
DESIGN
Systematic review.
DATA SOURCES AND STUDY SELECTION
The analysis involved studies published between 1959 and 2014 that were identified during an earlier systematic review of benefits and harms of placebo-controlled surgical trials published in 2014.
RESULTS
63 trials were included in the review. The main problem reported in many trials was a very slow recruitment rate, mainly due to the difficulty in finding eligible patients. Existing placebo trials were funded equally often from commercial and non-commercial sources. General anaesthesia or sedation was used in 41% of studies. Among the reviewed trials, 81% were double-blinded, and 19% were single-blinded. Across the reviewed trials, 96% (range 50-100%) of randomised patients completed the study. The withdrawal rate during the study was similar in the surgical and in the placebo groups.
CONCLUSIONS
This review demonstrated that placebo-controlled surgical trials are feasible, at least for procedures with a lower level of invasiveness, but also that recruitment is difficult. Many of the presumed challenges to undertaking such trials, for example, funding, anaesthesia or blinding of patients and assessors, were not reported as obstacles to completion in any of the reviewed trials.
Topics: Anesthesia, General; Feasibility Studies; Humans; Placebos; Randomized Controlled Trials as Topic; Surgical Procedures, Operative
PubMed: 27008687
DOI: 10.1136/bmjopen-2015-010194 -
The Cochrane Database of Systematic... Apr 2018Panic disorder is characterised by repeated, unexpected panic attacks, which represent a discrete period of fear or anxiety that has a rapid onset, reaches a peak within... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Panic disorder is characterised by repeated, unexpected panic attacks, which represent a discrete period of fear or anxiety that has a rapid onset, reaches a peak within 10 minutes, and in which at least four of 13 characteristic symptoms are experienced, including racing heart, chest pain, sweating, shaking, dizziness, flushing, stomach churning, faintness and breathlessness. It is common in the general population with a lifetime prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions. Amongst pharmacological agents, the National Institute for Health and Care Excellence (NICE) and the British Association for Psychopharmacology consider antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), as the first-line treatment for panic disorder, due to their more favourable adverse effect profile over monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). Several classes of antidepressants have been studied and compared, but it is still unclear which antidepressants have a more or less favourable profile in terms of effectiveness and acceptability in the treatment of this condition.
OBJECTIVES
To assess the effects of antidepressants for panic disorder in adults, specifically:1. to determine the efficacy of antidepressants in alleviating symptoms of panic disorder, with or without agoraphobia, in comparison to placebo;2. to review the acceptability of antidepressants in panic disorder, with or without agoraphobia, in comparison with placebo; and3. to investigate the adverse effects of antidepressants in panic disorder, with or without agoraphobia, including the general prevalence of adverse effects, compared to placebo.
SEARCH METHODS
We searched the Cochrane Common Mental Disorders' (CCMD) Specialised Register, and CENTRAL, MEDLINE, EMBASE and PsycINFO up to May 2017. We handsearched reference lists of relevant papers and previous systematic reviews.
SELECTION CRITERIA
All double-blind, randomised, controlled trials (RCTs) allocating adults with panic disorder to antidepressants or placebo.
DATA COLLECTION AND ANALYSIS
Two review authors independently checked eligibility and extracted data using a standard form. We entered data into Review Manager 5 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details and settings. Primary outcomes included failure to respond, measured by a range of response scales, and treatment acceptability, measured by total number of dropouts for any reason. Secondary outcomes included failure to remit, panic symptom scales, frequency of panic attacks, agoraphobia, general anxiety, depression, social functioning, quality of life and patient satisfaction, measured by various scales as defined in individual studies. We used GRADE to assess the quality of the evidence for each outcome MAIN RESULTS: Forty-one unique RCTs including 9377 participants overall, of whom we included 8252 in the 49 placebo-controlled arms of interest (antidepressant as monotherapy and placebo alone) in this review. The majority of studies were of moderate to low quality due to inconsistency, imprecision and unclear risk of selection and performance bias.We found low-quality evidence that revealed a benefit for antidepressants as a group in comparison with placebo in terms of efficacy measured as failure to respond (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.66 to 0.79; participants = 6500; studies = 30). The magnitude of effect corresponds to a number needed to treat for an additional beneficial outcome (NNTB) of 7 (95% CI 6 to 9): that means seven people would need to be treated with antidepressants in order for one to benefit. We observed the same finding when classes of antidepressants were compared with placebo.Moderate-quality evidence suggested a benefit for antidepressants compared to placebo when looking at number of dropouts due to any cause (RR 0.88, 95% CI 0.81 to 0.97; participants = 7850; studies = 30). The magnitude of effect corresponds to a NNTB of 27 (95% CI 17 to 105); treating 27 people will result in one person fewer dropping out. Considering antidepressant classes, TCAs showed a benefit over placebo, while for SSRIs and serotonin-norepinephrine reuptake inhibitor (SNRIs) we observed no difference.When looking at dropouts due to adverse effects, which can be considered as a measure of tolerability, we found moderate-quality evidence showing that antidepressants as a whole are less well tolerated than placebo. In particular, TCAs and SSRIs produced more dropouts due to adverse effects in comparison with placebo, while the confidence interval for SNRI, noradrenergic reuptake inhibitors (NRI) and other antidepressants were wide and included the possibility of no difference.
AUTHORS' CONCLUSIONS
The identified studies comprehensively address the objectives of the present review.Based on these results, antidepressants may be more effective than placebo in treating panic disorder. Efficacy can be quantified as a NNTB of 7, implying that seven people need to be treated with antidepressants in order for one to benefit. Antidepressants may also have benefit in comparison with placebo in terms of number of dropouts, but a less favourable profile in terms of dropout due to adverse effects. However, the tolerability profile varied between different classes of antidepressants.The choice of whether antidepressants should be prescribed in clinical practice cannot be made on the basis of this review.Limitations in results include funding of some studies by pharmaceutical companies, and only assessing short-term outcomes.Data from the present review will be included in a network meta-analysis of psychopharmacological treatment in panic disorder, which will hopefully provide further useful information on this issue.
Topics: Adult; Agoraphobia; Antidepressive Agents; Humans; Numbers Needed To Treat; Panic Disorder; Patient Dropouts; Placebos; Randomized Controlled Trials as Topic; Treatment Failure
PubMed: 29620793
DOI: 10.1002/14651858.CD010676.pub2