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PloS One 2014Surveys of doctors suggest that they use placebos and placebo effects clinically to help patients. However, patients' views are not well-understood. We aimed to identify...
BACKGROUND
Surveys of doctors suggest that they use placebos and placebo effects clinically to help patients. However, patients' views are not well-understood. We aimed to identify when and why placebo-prescribing in primary care might be acceptable and unacceptable to patients.
METHODS
A purposive diverse sample of 58 English-speaking adults (18 men; aged 19-80 years) participated in 11 focus groups. Vignettes describing doctors prescribing placebos in primary care were used to initiate discussions. Data were analyzed inductively.
RESULTS
Participants discussed diverse harms and benefits of placebo-prescribing for individual patients, carers, healthcare providers, and society. Two perspectives on placebo-prescribing were identified. First, the "consequentialist" perspective focused on the potential for beneficial outcomes of placebo-prescribing. Here, some participants thought placebos are beneficial and should be used clinically; they often invoked the power of the mind or mind-body interactions. Others saw placebos as ineffective and therefore a waste of time and money. Second, the "respecting autonomy" perspective emphasized the harms caused by the deceptive processes thought necessary for placebo-prescribing. Here, participants judged placebo-prescribing unacceptable because placebo-prescribers deceive patients, thus a doctor who prescribes placebos cannot be trusted and patients' autonomy is compromised. They also saw placebo-responders as gullible, which deterred them from trying placebos themselves. Overall, the word "placebo" was often thought to imply "ineffective"; some participants suggested alternative carefully chosen language that could enable doctors to prescribe placebos without directly lying to patients.
CONCLUSIONS
Negative views of placebos derive from beliefs that placebos do not work and/or that they require deception by the doctor. Positive views are pragmatic in that if placebos work then any associated processes (e.g. mechanisms, deception) are deemed unimportant. Public education about placebos and their effects is warranted and research to identify optimal ways of harnessing placebo effects in clinical practice is needed.
Topics: Adult; Aged; Aged, 80 and over; Female; Focus Groups; Humans; Male; Middle Aged; Patients; Placebo Effect; Placebos; Treatment Outcome; Young Adult
PubMed: 25006673
DOI: 10.1371/journal.pone.0101822 -
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 -
Indian Journal of Pharmacology 2016Multidrug-resistant tuberculosis (MDR-TB) is associated with significant morbidity and mortality. Bedaquiline is the first drug approved for treating MDR-TB. (Review)
Review
BACKGROUND
Multidrug-resistant tuberculosis (MDR-TB) is associated with significant morbidity and mortality. Bedaquiline is the first drug approved for treating MDR-TB.
OBJECTIVES
We performed a systematic review and meta-analysis to summarize the totality of all available evidence on the efficacy of bedaquiline for the management of MDR-TB.
MATERIALS AND METHODS
We searched the following PubMed and Cochrane Registry of Clinical Trials. Randomized controlled trials (RCTs) with a parallel design comparing bedaquiline versus any treatment for the management of MDR-TB in adults were eligible for inclusion. Data were pooled under a random effects model.
RESULTS
Two trials published as three manuscripts with a total of 207 patients were included. As per the Cochrane risk of bias tool, majority of parameter were labeled as high or unclear risk of bias. Bedaquiline compared with placebo was associated with a statistically significant decrease in time to conversion of positive sputum culture to negative at 8 and 24 weeks with a significant increase in mortality on long-term follow-up. There was no difference in completion rates between bedaquiline and placebo.
CONCLUSION
Bedaquiline is an effective treatment modality for MDR-TB but needs to be balanced against significant mortality. Future Phase 3 RCTs are needed to make a conclusive recommendation.
Topics: Antitubercular Agents; Diarylquinolines; Humans; Placebos; Randomized Controlled Trials as Topic; Tuberculosis, Multidrug-Resistant
PubMed: 27127322
DOI: 10.4103/0253-7613.178839 -
The Cochrane Database of Systematic... Sep 2020Antisocial personality disorder (AsPD) is associated with rule-breaking, criminality, substance use, unemployment, relationship difficulties, and premature death.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Antisocial personality disorder (AsPD) is associated with rule-breaking, criminality, substance use, unemployment, relationship difficulties, and premature death. Certain types of medication (drugs) may help people with AsPD. This review updates a previous Cochrane review, published in 2010.
OBJECTIVES
To assess the benefits and adverse effects of pharmacological interventions for adults with AsPD.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, 13 other databases and two trials registers up to 5 September 2019. We also checked reference lists and contacted study authors to identify studies.
SELECTION CRITERIA
Randomised controlled trials in which adults (age 18 years and over) with a diagnosis of AsPD or dissocial personality disorder were allocated to a pharmacological intervention or placebo control condition.
DATA COLLECTION AND ANALYSIS
Four authors independently selected studies and extracted data. We assessed risk of bias and created 'Summary of findings tables' and assessed the certainty of the evidence using the GRADE framework. The primary outcomes were: aggression; reconviction; global state/global functioning; social functioning; and adverse events.
MAIN RESULTS
We included 11 studies (three new to this update), involving 416 participants with AsPD. Most studies (10/11) were conducted in North America. Seven studies were conducted exclusively in an outpatient setting, one in an inpatient setting, and one in prison; two studies used multiple settings. The average age of participants ranged from 28.6 years to 45.1 years (overall mean age 39.6 years). Participants were predominantly (90%) male. Study duration ranged from 6 to 24 weeks, with no follow-up period. Data were available from only four studies involving 274 participants with AsPD. All the available data came from unreplicated, single reports, and did not allow independent statistical analysis to be conducted. Many review findings were limited to descriptive summaries based on analyses carried out and reported by the trial investigators. No study set out to recruit participants on the basis of having AsPD; many participants presented primarily with substance abuse problems. The studies reported on four primary outcomes and six secondary outcomes. Primary outcomes were aggression (six studies) global/state functioning (three studies), social functioning (one study), and adverse events (seven studies). Secondary outcomes were leaving the study early (eight studies), substance misuse (five studies), employment status (one study), impulsivity (one study), anger (three studies), and mental state (three studies). No study reported data on the primary outcome of reconviction or the secondary outcomes of quality of life, engagement with services, satisfaction with treatment, housing/accommodation status, economic outcomes or prison/service outcomes. Eleven different drugs were compared with placebo, but data for AsPD participants were only available for five comparisons. Three classes of drug were represented: antiepileptic; antidepressant; and dopamine agonist (anti-Parkinsonian) drugs. We considered selection bias to be unclear in 8/11 studies, attrition bias to be high in 7/11 studies, and performance bias to be low in 7/11 studies. Using GRADE, we rated the certainty of evidence for each outcome in this review as very low, meaning that we have very little confidence in the effect estimates reported. Phenytoin (antiepileptic) versus placebo One study (60 participants) reported very low-certainty evidence that phenytoin (300 mg/day), compared to placebo, may reduce the mean frequency of aggressive acts per week (phenytoin mean = 0.33, no standard deviation (SD) reported; placebo mean = 0.51, no SD reported) in male prisoners with aggression (skewed data) at endpoint (six weeks). The same study (60 participants) reported no evidence of difference between phenytoin and placebo in the number of participants reporting the adverse event of nausea during week one (odds ratio (OR) 1.00, 95% confidence interval (CI) 0.06 to 16.76; very low-certainty evidence). The study authors also reported that no important side effects were detectable via blood cell counts or liver enzyme tests (very low-certainty evidence). The study did not measure reconviction, global/state functioning or social functioning. Desipramine (antidepressant) versus placebo One study (29 participants) reported no evidence of a difference between desipramine (250 to 300 mg/day) and placebo on mean social functioning scores (desipramine = 0.19; placebo = 0.21), assessed with the family-social domain of the Addiction Severity Index (scores range from zero to one, with higher values indicating worse social functioning), at endpoint (12 weeks) (very low-certainty evidence). Neither of the studies included in this comparison measured the other primary outcomes: aggression; reconviction; global/state functioning; or adverse events. Nortriptyline (antidepressant) versus placebo One study (20 participants) reported no evidence of a difference between nortriptyline (25 to 75 mg/day) and placebo on mean global state/functioning scores (nortriptyline = 0.3; placebo = 0.7), assessed with the Symptom Check List-90 (SCL-90) Global Severity Index (GSI; mean of subscale scores, ranging from zero to four, with higher scores indicating greater severity of symptoms), at endpoint (six months) in men with alcohol dependency (very low-certainty evidence). The study measured side effects but did not report data on adverse events for the AsPD subgroup. The study did not measure aggression, reconviction or social functioning. Bromocriptine (dopamine agonist) versus placebo One study (18 participants) reported no evidence of difference between bromocriptine (15 mg/day) and placebo on mean global state/functioning scores (bromocriptine = 0.4; placebo = 0.7), measured with the GSI of the SCL-90 at endpoint (six months) (very low-certainty evidence). The study did not provide data on adverse effects, but reported that 12 patients randomised to the bromocriptine group experienced severe side effects, five of whom dropped out of the study in the first two days due to nausea and severe flu-like symptoms (very low-certainty evidence). The study did not measure aggression, reconviction and social functioning. Amantadine (dopamine agonist) versus placebo The study in this comparison did not measure any of the primary outcomes.
AUTHORS' CONCLUSIONS
The evidence summarised in this review is insufficient to draw any conclusion about the use of pharmacological interventions in the treatment of antisocial personality disorder. The evidence comes from single, unreplicated studies of mostly older medications. The studies also have methodological issues that severely limit the confidence we can draw from their results. Future studies should recruit participants on the basis of having AsPD, and use relevant outcome measures, including reconviction.
Topics: Adult; Aggression; Alcohol-Related Disorders; Amantadine; Antisocial Personality Disorder; Anxiety; Bromocriptine; Desipramine; Female; Humans; Male; Middle Aged; Nortriptyline; Phenytoin; Placebos; Psychotropic Drugs; Randomized Controlled Trials as Topic
PubMed: 32880105
DOI: 10.1002/14651858.CD007667.pub3 -
Arquivos de Gastroenterologia 2020Inflammatory bowel disease comprises two distinct conditions - Crohn's disease and ulcerative colitis - which can be treated with immunomodulators. A non-neglectable... (Review)
Review
Inflammatory bowel disease comprises two distinct conditions - Crohn's disease and ulcerative colitis - which can be treated with immunomodulators. A non-neglectable proportion of these patients will need biologic therapy, and many patients under biologic treatment will experience either primary or secondary failure. As a consequence, clinical trials evaluating new therapeutic alternatives are being developed. These trials share common features, such as being controlled with placebo. Placebo use in clinical trials is a matter of intense debate. Those who support placebo use highlight the methodologic advantages placebo-controlled trials have. Those against placebo use argue that it would be against ethical principles in clinical research to expose a patient to placebo when a valid therapeutic alternative exists. In this review, we summarize the existing arguments for and against the use of placebo in the context of inflammatory bowel disease research. We finally suggest that it is very likely that in the near future inflammatory bowel disease trials will no longer be controlled with a placebo arm, but instead they will be non-inferiority trials with an active comparator.
Topics: Clinical Trials as Topic; Colitis, Ulcerative; Crohn Disease; Humans; Placebos
PubMed: 32294741
DOI: 10.1590/S0004-2803.202000000-15 -
Current Opinion in HIV and AIDS Jan 2016We discuss selected statistical issues in the design and analysis of preexposure prophylaxis (PrEP) trials. The general principles may inform thinking for other... (Review)
Review
PURPOSE OF REVIEW
We discuss selected statistical issues in the design and analysis of preexposure prophylaxis (PrEP) trials. The general principles may inform thinking for other interventions in HIV prevention.
RECENT FINDINGS
To date, four different designs have been used to determine the effectiveness of PrEP: randomized, double-blind, placebo-controlled; randomized, open-label, immediate or delayed access; nonrandomized comparison of HIV incidence according to the level of drug detected; comparison of the observed HIV incidence to the expected rate using historical control data. Open-label trials of PrEP, which assess public health effectiveness, complement the placebo-controlled trials which established the biological efficacy of TDF/FTC. Future trials of PrEP will be highly challenging to design since a no PrEP group is difficult to justify and the natural control regimen, TDF/FTC, is highly efficacious.
SUMMARY
Standard statistical paradigms for noninferiority trials should be reconsidered for evaluating alternative PrEP regimens.
Topics: Administration, Oral; Anti-HIV Agents; Biostatistics; Chemoprevention; Clinical Trials as Topic; Disease Transmission, Infectious; Double-Blind Method; HIV Infections; Humans; Placebos; Pre-Exposure Prophylaxis
PubMed: 26545264
DOI: 10.1097/COH.0000000000000218 -
Nature Communications Mar 2021The brain systems underlying placebo analgesia are insufficiently understood. Here we performed a systematic, participant-level meta-analysis of experimental functional... (Meta-Analysis)
Meta-Analysis
The brain systems underlying placebo analgesia are insufficiently understood. Here we performed a systematic, participant-level meta-analysis of experimental functional neuroimaging studies of evoked pain under stimulus-intensity-matched placebo and control conditions, encompassing 603 healthy participants from 20 (out of 28 eligible) studies. We find that placebo vs. control treatments induce small, widespread reductions in pain-related activity, particularly in regions belonging to ventral attention (including mid-insula) and somatomotor networks (including posterior insula). Behavioral placebo analgesia correlates with reduced pain-related activity in these networks and the thalamus, habenula, mid-cingulate, and supplementary motor area. Placebo-associated activity increases occur mainly in frontoparietal regions, with high between-study heterogeneity. We conclude that placebo treatments affect pain-related activity in multiple brain areas, which may reflect changes in nociception and/or other affective and decision-making processes surrounding pain. Between-study heterogeneity suggests that placebo analgesia is a multi-faceted phenomenon involving multiple cerebral mechanisms that differ across studies.
Topics: Adult; Analgesia; Behavior; Brain; Female; Humans; Image Enhancement; Magnetic Resonance Imaging; Male; Nervous System; Pain; Placebos
PubMed: 33654105
DOI: 10.1038/s41467-021-21179-3 -
Annals of African Medicine 2017The use of control group in clinical trials has been universally acclaimed by researchers to effectively help discriminate between the actual effects of an intervention... (Review)
Review
The use of control group in clinical trials has been universally acclaimed by researchers to effectively help discriminate between the actual effects of an intervention and those arising from other factors. However, the choice of the control that provided both scientific and ethical acceptability among researchers has been a source of intense debate. We conducted a literature search on the use of placebo and active controls in clinical trials and X-ray the arguments for and against both choices in randomized control trials and concluded by highlighting the scenarios where the use of placebo is justified.
Topics: Antipsychotic Agents; Biomedical Research; Ethics, Medical; Humans; Mental Disorders; Placebos; Randomized Controlled Trials as Topic
PubMed: 28671148
DOI: 10.4103/aam.aam_211_16 -
The Cochrane Database of Systematic... Nov 2020This is an update of a Cochrane Review first published in 2005. Blepharospasm is the second most common form of focal dystonia. It is a disabling disorder, characterised... (Meta-Analysis)
Meta-Analysis
BACKGROUND
This is an update of a Cochrane Review first published in 2005. Blepharospasm is the second most common form of focal dystonia. It is a disabling disorder, characterised by chronic, intermittent or persistent, involuntary eyelid closure, due to spasmodic contractions of the orbicularis oculi muscles. Currently, botulinum toxin type A (BtA) is considered the first line of therapy for this condition.
OBJECTIVES
To compare the efficacy, safety, and tolerability of BtA versus placebo in people with blepharospasm.
SEARCH METHODS
We searched Cochrane Movement Disorders' Trials Register, CENTRAL, MEDLINE, Embase, reference lists of included articles, and conference proceedings. We ran all elements of the search, with no language restrictions, in July 2020.
SELECTION CRITERIA
Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtA versus placebo in adults with blepharospasm.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed records, selected included studies, extracted data using a paper pro forma, and evaluated the risk of bias. We resolved disagreements by consensus, or by consulting a third review author. We performed meta-analyses using a random-effects model, for the comparison of BtA versus placebo, to estimate pooled effects and corresponding 95% confidence intervals (95% CI). We did not carry out any prespecified subgroup analyses. The primary efficacy outcome was improvement on any validated symptomatic rating scale. The primary safety outcome was the proportion of participants with any adverse event.
MAIN RESULTS
We included three RCTs, assessed at low to moderate overall risk of bias, which randomised 313 participants with blepharospasm. Two studies excluded participants with poorer prior responses to BtA treatment, therefore, they included an enriched population with a higher probability of benefiting from this therapy. All trials were industry-funded. All RCTs evaluated the effect of a single BtA treatment session. BtA resulted in a moderate to large improvement in blepharospasm-specific severity, with a reduction of 0.93 points on the Jankovic Rating Scale (JRS) severity subscale at four to six weeks after injection (95% confidence interval (CI) 0.61 to 1.25; I² = 9%) compared to placebo. BtA was also resulted in a moderate to large improvement in blepharospasm-specific disability and blepharospasm-specific involuntary movements at four to six weeks after injection (disability: 0.69 JRS disability subscale points, 95% CI 0.18 to 1.19; I² = 74%; blepharospasm-specific involuntary movements: standardised mean difference (SMD) 0.79, 0.31 to 1.27; I² = 58%) compared to placebo. BtA did not show a risk of adverse events (risk ratio (RR) 1.18, 95% CI 0.87 to 1.60; I² = 0%). However, BtA increased the risk of vision complaints and eyelid ptosis (vision complaints: RR 5.73, 95% CI 1.79 to 18.36; I² = 51%; eyelid ptosis: RR 4.02, 95% CI 1.61 to 10.00; I² = 39%). There was no distinction between BtA and placebo in the number of participants who dropped out of the trial. A single trial estimated the duration of effects to be 10.6 weeks (range 6.1 to 19.1). We found no evidence supporting the existence of a clear dose-response relationship with BtA. We found no data reporting the impact of BtA on health-related quality of life, or the development of secondary non-responsiveness.
AUTHORS' CONCLUSIONS
We are moderately certain that a single BtA treatment resulted in a clinically relevant reduction of blepharospasm-specific severity and disability, and have low certainty that it is well tolerated, when compared with placebo. There is low-certainty evidence that people treated with BtA are not at an increased risk of developing adverse events, though BtA treatment likely increases the risk of visual complaints and eyelid ptosis. There are no data from RCTs evaluating the effectiveness and safety of repeated BtA injection cycles. There is no evidence from RCTs to allow us to draw definitive conclusions on the optimal treatment intervals and doses, or the impact on quality of life.
Topics: Bias; Blepharospasm; Botulinum Toxins, Type A; Dose-Response Relationship, Drug; Female; Humans; Male; Neuromuscular Agents; Placebos; Randomized Controlled Trials as Topic
PubMed: 33211907
DOI: 10.1002/14651858.CD004900.pub3 -
The Cochrane Database of Systematic... Jul 2016Cough in children is a commonly experienced symptom that is associated with increased health service utilisation and burden to parents. The presence of chronic (equal to... (Review)
Review
BACKGROUND
Cough in children is a commonly experienced symptom that is associated with increased health service utilisation and burden to parents. The presence of chronic (equal to or more than four weeks) cough in children may indicate a serious underlying condition such as inhaled foreign body or bronchiectasis. Codeine (and derivative)-based medications are sometimes used to treat cough due to their antitussive properties. However, there are inherent risks associated with the use of these medications such as respiratory drive suppression, anaesthetic-induced anaphylaxis, and addiction. Metabolic response and dosage variability place children at increased risk of experiencing such side effects. A systematic review evaluating the quality of the available literature would be useful to inform management practices.
OBJECTIVES
To evaluate the safety and efficacy of codeine (and derivatives) in the treatment of chronic cough in children.
SEARCH METHODS
We searched the Cochrane Airways Group Register of Trials, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1946 to 8 June 2016), EMBASE (1974 to 8 June 2016), the online trials registries of the World Health Organization and ClinicalTrials.gov, and the bibliographic references of publications. We imposed no language restrictions.
SELECTION CRITERIA
We considered studies eligible for analysis when: the participant population included children aged less than 18 years with chronic cough (duration equal to or more than four weeks at the time of intervention); and the study design evaluated codeine or codeine-based derivatives against placebo through a randomised controlled trial.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the search results to determine eligibility against a standardised criteria, and we had a pre-planned method for analysis.
MAIN RESULTS
We identified a total of 556 records, of which 486 records were excluded on the basis of title and abstract. We retrieved the remaining 70 references in full to determine eligibility. No studies fulfilled the inclusion criteria of this review, and thus we found no evidence to support or oppose the use of codeine or derivatives as antitussive agents for chronic cough in children.While chronic cough is not the same as acute cough, systematic reviews on the use of codeine efficacy for acute cough in children conclude an overall lack of evidence to support or oppose the use of over-the-counter cough and cold medications containing codeine (or derivatives) for treatment of acute cough in children. The lack of sufficient evidence to support the use of these medications has been consistently reaffirmed by medical experts in international chronic cough guidelines and by governing medical and pharmaceutical authorities in the USA, Europe, Canada, New Zealand, and Australia. Due to the lack of sufficient evidence to support efficacy, and the known risks associated with use - in particular the increased risks for children - these medications are now not recommended for children less than 12 years of age and children between 12 to 18 years with respiratory conditions.
AUTHORS' CONCLUSIONS
This review has highlighted the absence of any randomised controlled trials evaluating codeine-based medications in the treatment of childhood chronic cough. Given the potential adverse events of respiratory suppression and opioid toxicity, national therapeutic regulatory authorities recommend the contraindication of access to codeine in children less than 12 years of age. We suggest that clinical practice adhere to clinical practice guidelines and thus refrain from using codeine or its derivatives to treat cough in children. Aetiological-based management practices continue to be advocated for children with chronic cough.
Topics: Antitussive Agents; Child; Chronic Disease; Codeine; Cough; Humans; Placebos
PubMed: 27405706
DOI: 10.1002/14651858.CD011914.pub2