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PubMed1998

Does the Choice of Placebo Determine the Results of Clinical Studies on Acupuncture?

OBJECTIVE: To establish whether the choice of the placebo treatment used may influence the outcomes of clinical trials on acupuncture or not. DESIGN: A meta-analysis of outcomes according to the choice of the placebo. Attention was focused on the placebo design of 117 clinical, controlled trials found after an extensive search. Studies comparing acupuncture to no treatment or a reference treatment were discarded from the analysis. A set of 90 publications could be classified into one of two groups: i) Clinical studies with sham acupuncture as placebo, which consists of needling outside the meridian, but near to classical acupoints. This group of 45 trials was classified as energetic placebo model (EPM). ii) 45 studies using a placebo treatment consisting of needling within a segmental zone far enough away from the active points were classified as neurophysiological or metameric placebo model (MPM). In both groups of studies the proportions of significant results and the distribution of outcomes characterized by nonsignificant results with improvements greater than 35% in both groups of patients were assessed by the chi-square test. RESULTS: The proportion of meaningful results was significantly higher in the MPM group [73.33% (33/45)], while only 33.33% (15/45) of such results were found in the EPM group (p < 0.03). In the EPM group 24/30 studies showed nonsignificant results with improvements greater than 35% in both groups of patients, while in the MPM group only 20% (6/30) of studies with this outcome could be observed (p < 0.05). CONCLUSION: Studies using EPM as placebo failed more frequently to show any differences between real acupuncture and placebo treatment than those using MPM as placebo. On the other hand, sham acupuncture appears almost as active as 'real' acupuncture. These results suggest that the design and the way of performing the placebo procedure determine the outcome, i. e. success or failure of a clinical trial in obtaining differences among the patients groups, in case they actually exist.

Journal Article↗
PubMed1983

Familiarization session and placebo control in EEG studies of drug effects.

The need for a familiarization session and for a placebo session for each subject in pharmaco-EEG studies was examined. The data from 18 crossover studies of 22 substances at 33 doses in 112 subjects was used: 371 drug sessions, 195 placebo sessions and 53 familiarization sessions. The left occipital to vertex signal was quantified using power spectral density analyses. EEG changes under different conditions were compared using the spectral difference index. Less EEG change from baseline was found after placebo in the first session than after placebo in later sessions. Drug effects were defined by comparisons to placebo effects in the same subjects (related samples analyses) and to placebo effects in other subjects in the data base (independent samples analyses). Decisions using the two analyses were in accord for 27 substance doses: 20 were found active, 7 inactive. For one substance, the related samples analysis indicated drug activity, while the independent samples analysis did not (just below criterion). For five other substances, the related samples analyses did not distinguish drug and placebo sessions, while the independent samples analyses showed lesser EEG changes after drug than after placebo. First-session findings support the need for a familiarization session in pharmaco-EEG studies. Placebo findings indicate that past placebo session data are adequate for deciding whether a drug has CNS activity, without the necessity of a placebo session for each subject.

Adult↗
PubMed1999

Treatment of premature ejaculation with paroxetine hydrochloride as needed: 2 single-blind placebo controlled crossover studies.

PURPOSE: We evaluate the efficacy of paroxetine hydrochloride as needed for the treatment of premature ejaculation. MATERIALS AND METHOD: Study 1 comprised 26 potent men with a mean age of 39.5 years with premature ejaculation who were randomized to receive 20 mg. oral paroxetine (group A) or placebo (group B) as needed 3 to 4 hours before planned intercourse in a controlled single-blind crossover trial. Study 2 comprised 42 potent men with a mean age of 40.5 years with premature ejaculation who were randomized to receive 10 mg. paroxetine daily for 3 weeks and then 20 mg. paroxetine as needed (group C) for 4 weeks or placebo daily for 3 weeks and then placebo as needed (group D) for 4 weeks. RESULTS: Mean pretreatment ejaculatory latency time was 0.3 minute for study 1. At 4 weeks mean ejaculatory latency time was 3.2 minutes in the paroxetine as needed and 0.45 in the placebo as needed phase for group A (p < 0.001), and 0.6 in the placebo as needed and 3.5 in the paroxetine as needed phase for group B (p < 0.001). There were no adverse effects with paroxetine or placebo in study 1. Mean pretreatment ejaculatory latency time was 0.5 minute for study 2. At 3 weeks mean ejaculatory latency time was 4.3 minutes in the paroxetine daily and 5.8 in the paroxetine as needed phase, and 0.9 in the placebo daily and 0.6 in the placebo as needed phase for group C (p < 0.001). At 3 weeks mean ejaculatory latency time was 0.8 minutes in the placebo daily and 1.1 in the placebo as needed phase, and 3.3 in the paroxetine daily and 6.1 in the paroxetine as needed phase for group D (p < 0.001). Adverse effects in 7 of 42 men (17%) given paroxetine daily included an ejaculation in 3, anorexia in 1, gastrointestinal upset in 3 and reduced libido in 2. Mean ejaculatory latency time was greater in the paroxetine as needed phase of study 2 than that of study 1 (p < 0.05), suggesting that ejaculatory control achieved with paroxetine as needed is significantly better if patients are initially treated with the drug daily. CONCLUSIONS: Paroxetine appears to be superior to placebo in the pharmacological treatment of premature ejaculation when administered on a chronic or as needed basis.

Adult↗
PubMed2002

Multicenter prospective, randomized, double-masked, placebo-controlled study of Rheopheresis to treat nonexudative age-related macular degeneration: interim analysis.

OBJECTIVE: To evaluate the safety and efficacy of Rheopheresis blood filtration to treat intermediate- to late-stage preangiogenic age-related macular degeneration (AMD) with soft drusen. DESIGN: Multicenter, prospective, randomized, double-masked, placebo-controlled clinical trial. PARTICIPANTS: First 43 randomized patients (28 Rheopheresis and 15 placebo-control patients) with available baseline and 3-month postbaseline best corrected visual acuity (BCVA) measurements and intermediate- to late-stage preangiogenic AMD with multiple large soft drusen and elevated serum levels of targeted macromolecules. INTERVENTION: Patients were randomly assigned to receive eight Rheopheresis or eight placebo procedures over 10 weeks. MAIN OUTCOME MEASURES: ETDRS BCVA measurements at baseline, 3, 6, 9, and 12 months postbaseline. RESULTS: In primary eyes, the mean LogMAR line difference between Rheopheresis and placebo-control eyes was 1.6 lines at 12 months postbaseline; the difference was significant throughout the first posttreatment year (P = .0011, repeated measures analysis). Thirteen percent of Rheopheresis compared with 0% of placebo-control eyes had a > or = 3-line improvement in BCVA at 12 months postbaseline. Four percent of Rheopheresis compared with 18% of placebo-control eyes had a > or = 3-line loss in BCVA. The subgroup of patients whose primary eyes had baseline BCVA worse than 20/40 demonstrated a mean LogMAR difference between Rheopheresis and placebo-control eyes equaling 3.0 lines at 12 months postbaseline; the difference was significant throughout the first posttreatment year (P = .0014, repeated measures analysis). Sixteen percent of Rheopheresis compared with 0% of the placebo-control eyes had a > or = 3-line improvement in BCVA at 12 months postbaseline. Five percent of Rheopheresis compared with 29% of placebo-control eyes had a > or = 3-line loss in BCVA. Fifty-eight percent of Rheopheresis eyes improved to 20/40 or better, compared with 14% of placebo-control eyes. No serious treatment-related adverse events were observed. CONCLUSIONS: Rheopheresis demonstrated statistically significant and clinically relevant effects on BCVA when compared with placebo controls for the 12-month study interval. Untreated patients with BCVA worse than 20/40 with intermediate- to late-stage preangiogenic AMD, soft drusen, and elevated blood factors were at risk for substantial visual loss. A sample size larger than 43 patients is important to provide a basis for widespread adoption of novel therapeutic options for AMD such as Rheopheresis. Therefore, enrollment to 150 patients is continuing.

Aged↗
PubMed1994

Double-blind comparison of lansoprazole, ranitidine, and placebo in the treatment of acute duodenal ulcer. Lansoprazole Study Group.

OBJECTIVES: To study in a double-blind controlled manner the effects of lansoprazole 15 mg or 30 mg daily compared with ranitidine 300 mg once daily and placebo in the relieving of symptoms and healing of acute duodenal ulceration. METHODS: Two hundred eighty patients with duodenal ulcer entered in to the study from 30 centers. They were randomized in a double-blind manner into four groups with 80 patients entered into each active treatment group and 40 patients into the placebo group. Endoscopy was performed at 2- and 4-wk intervals to assess healing. Symptom relief was recorded, serum gastrin levels were measured, and gastric mucosal biopsies were obtained to evaluate for the presence of acute and chronic inflammation, the presence of neoplasia, and the extent of gastric endocrine growth at the time of endoscopy. RESULTS: After 4 wk of treatment using per protocol analysis, 19 of 40 (47.5%) patients receiving placebo had healed compared with 55 of 78 (70.5%) receiving ranitidine (p < 0.05 vs. placebo), 61 of 76 (80.3%) receiving lansoprazole 30 mg (p < 0.05 vs. placebo), and 72 of 78 (92.3%) receiving lansoprazole 15 mg (p < 0.05 vs. placebo and ranitidine). In patients with evaluable data, lansoprazole 30 mg and ranitidine produced greater relief of night-time symptoms and lansoprazole 15 mg produced greater relief of both day- and night-time symptoms than did placebo after 4 wk of treatment. Ranitidine increased fasting serum gastrin levels (22%; p < 0.05 vs. placebo), whereas both lansoprazole regimens produced more marked rises in serum gastrin (54% and 60%; p < 0.05 vs. placebo and ranitidine). Lansoprazole 15 mg and 30 mg also increased the density of antral G-cells (105.8% and 128.80%; p < 0.05 vs. baseline) and greater curvature Grimelius-positive cells (20.33% and 28.8%; p < 0.05 vs. baseline); there were no increases in the density of antral EC- or D-cells, and there was no alteration of gastric endocrine growth as judged by the Solcia classification. Both ranitidine and lansoprazole were associated with decreased antral Helicobacter pylori density accompanied, in the lansoprazole groups, by decreased antral inflammation scores. All antisecretory regimens were associated with increased inflammatory scores in the greater curvature. CONCLUSIONS: In acute duodenal ulceration, treatment with lansoprazole 15 and 30 mg produced 4-wk healing rates and symptom relief superior to those produced by placebo and the 15-mg dose similar to those produced by placebo. The 15-mg dose of lansoprazole was also superior to ranitidine in healing duodenal ulcer after 4 wk of therapy.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1998

Use of pattern analysis to predict differential relapse of remitted patients with major depression during 1 year of treatment with fluoxetine or placebo.

BACKGROUND: Delayed and persistent ("true drug") improvement characterizes the response to antidepressant medication. Early or nonpersistent ("placebo") benefit is typical of a placebo response. The prediction was that patients with a true drug response would sustain their benefit best if they continued to receive the drug and that patients with a placebo response would have an equivalent prognosis whether they continued to receive the drug or were switched to placebo. METHODS: Patients with major depression who met the study's response criteria (a modified Hamilton Depression Rating Scale score < or =7 and failure to meet major depression criteria after each of the last 3 weeks following 12 to 14 weeks of treatment with fluoxetine hydrochloride, 20 mg/d) were enrolled in a 50-week randomized placebo substitution trial during which the return of depressive symptoms defined relapse. The timing and persistency of response during initial treatment defined true drug or placebo response patterns. RESULTS: Patients with a true drug response pattern relapsed significantly more frequently if they were switched to placebo than if they continued to receive fluoxetine (P<.001 for weeks 12-26, P<.005 for weeks 26-50, and P<.41 for weeks 50-62). Patients with a placebo response pattern had an equivalent outcome whether maintained on fluoxetine therapy or placebo (P< .20 for weeks 12-26, test invalid for weeks 26-50, and P<.67 for weeks 50-62). Patients with a placebo response pattern relapsed more often when they continued to receive fluoxetine than patients with a true drug response pattern (P<.01 for weeks 12-26, P<.10 for weeks 26-50, and P<.36 for weeks 50-62). CONCLUSIONS: These findings confirm that pattern analysis validly differentiates true drug from nonspecific initial responses and extend its use to the continuation and maintenance phases of treatment for depression. Investigations into the mechanisms of antidepressant activity might best be limited to those that can account for delayed efficacy. Fluoxetine's efficacy during the continuation and maintenance phases of treatment may be limited to patients with a true drug pattern of initial response.

Adolescent↗
PubMed2006

How prior experience shapes placebo analgesia.

Some studies indicate that placebo analgesia is stronger when pre-conditioning with effective analgesic treatments is performed, thereby suggesting that the placebo response is a learning phenomenon. Here we further tested this hypothesis in order to better understand when and how previous experience affects the placebo analgesic response. To do this, we used a conditioning procedure whereby the intensity of painful stimulation was reduced surreptitiously, so as to make the subjects believe that an analgesic treatment was effective. This procedure induced strong placebo responses after minutes, and these responses, albeit reduced, lasted up to 4-7 days. In addition, in a second group of subjects we repeated the same conditioning procedure 4-7 days after a totally ineffective analgesic treatment, and found that the placebo responses were remarkably reduced compared to the first group. Thus we obtained small, medium and large placebo responses, depending on several factors, such as the previous positive or negative experience of an analgesic treatment and the time lag between the treatment and the placebo responses. We also ran extinction trials, and found that these effects did not undergo extinction in a time span of several minutes. These findings indicate that placebo analgesia is finely tuned by prior experience and these effects may last, albeit reduced, several days. These results emphasize that the placebo effect is a learning phenomenon in which many factors come into play, and may explain the large variability of the placebo responses that is found in many studies.

Adult↗
PubMed1998

Placebo therapy of benign prostatic hyperplasia: a 25-month study. Canadian PROSPECT Study Group.

OBJECTIVE: To analyse the efficacy, correlations and adverse-event profile of placebo therapy from the initial placebo run-in period to beyond 2 years of treatment. PATIENTS AND METHODS: The effects of placebo therapy on prostate size, maximum urinary flow rate (Qmax) and symptoms were analysed, and adverse drug experiences documented, for a period of 25 months in 303 patients randomized to the placebo arm of a controlled trial evaluating finasteride in the treatment of BPH (the Canadian PROSPECT study). RESULTS: For all variables, the values during follow-up were significantly different from baseline (P < or = 0.001). Transrectal ultrasonography confirmed a progressive increase in prostate volume over 25 months (+8.4%) but Qmax improved for the first 5 months (to 1.4 mL/s over baseline) and remained 1.0 mL/s more than baseline at 25 months. The total symptom score improved by -2.9 points in the first 2 months on placebo and was ultimately 2.3 points below baseline at 25 months. The extent of the placebo response for symptoms (r=0.08, P=.180) and Qmax (r=0.04, P=0.550) was independent of age, but the response correlated with the initial severity of symptoms (r= -0.394, P < or = 0.001) and initial Qmax (r= -0.134, P=0.023). Patients with a prostate of < or = 40 mL had a clinically more important placebo response than those with larger prostates. In all, 246 patients (81.2%) reported adverse events thought to be secondary to placebo therapy. The most common complaint was urogenital (40.3%), specifically impotence (6.3%) and decreased libido (6.3%); 13.2% of patients discontinued placebo therapy because of significant adverse reactions. CONCLUSIONS: Placebo therapy rapidly produces a significant improvement in Qmax and symptoms of BPH but also causes clinically important adverse effects. The beneficial effect fades but remains after 2 years.

Aged↗
PubMed1991

[Placebos: aspects in medical history and approaches to definition].

The historic roots of the term placebo, its development from religious to secular use and finally its establishment as a medical terminus at the end of the 18th century are described. After the first and rare placebo publications in the 30ties and 40ties a sudden increase in the number of published placebo articles took place since 1950. In the following decades the progress in experimental placebo investigations was overwhelming and placebo phenomena more and more became a subject of scientific inquiry in its own. An overview of the experimental results of this period concerning the efficacy and toxicity of placebo interventions is given. Existing attitudes and prejudices to placebos are confronted with hard data from empirical studies. In particular the 'myth of the non-specificity of placebos' will be critical reviewed and reconsidered. Finally, after a short retrospective view to placebo definitions in medical dictionaries since the 19th century the actual controversy between pharmacological and general placebo definitions is outlined. Two modern definitory propositions of Shapiro and Morris, 1978, and Brody, 1980, are presented and discussed in detail.

Germany↗
PubMed1990

[Ethical and legal aspects of the use of placebos in research and practice].

The discussion of ethical and legal problems concerning placebo application is suggested as an essential constituent of modern placebo research. Implications of distinctions between inadvertent and intended placebo applications and between single case and sample applications of placebos are examined. Implicit hypotheses of placebo applicators (investigators, practitioners) on the indications and contra-indications of placebos are confronted with empirical data which are still limited, however. Differentiation between several levels of information given the placebo recipient about the real nature of the placebo application is suggested and pro and contra of each level will be discussed in detail. In the following ethical and legal aspects of placebo application in practice (with clinical patients) and in research (sample tests) are elaborated. Finally actual issues of law concerning placebo applications in the Federal Republic of Germany are discussed.

Clinical Trials as Topic↗
PubMed2000

The placebo effect and white coat effect in isolated systolic hypertension and systo-diastolic hypertension.

It is well recognised from many clinical trials that there is a blood pressure lowering effect when placebo is administered to patients with essential hypertension ("placebo effect"). The reduction in blood pressure, however, may also be partly due to loss of the alerting response ("white coat effect") as a result of familiarisation with the clinical environment. To investigate the hypothesis that there may be a more marked placebo effect and white coat effect in isolated systolic hypertension (ISH) compared with systo-diastolic hypertension (SDH), we studied 78 patients with hypertension: 34 had ISH and 44 patients had SDH. The 34 patients with ISH were older (68.7 vs 54.9 years), had a higher SBP (192.2 vs 169.6 mmHfg) and lower DBP (85.5 vs 102.0 mmHg) when compared to patients with SDH. Amongst the patients with ISH, there were no significant changes in mean blood pressures pre-placebo (paired t-test, p = NS). In the placebo period, there was a significant reduction in systolic blood pressures at all three points, and a significant reduction in diastolic blood pressures after 2 and 3 months placebo (paired t-test, p < 0.05). There was a mean reduction in mean systolic blood pressure at visit 1 by 5.2%, visit 2 by 5.1% and visit 3 by 4.6%, when compared to mean pre-placebo systolic blood pressures (p < 0.05). The mean reduction in diastolic blood pressure was 5.8% at visit 2 and 3.5% at visit 3, when compared to mean pre-placebo diastolic blood pressure (p < 0.05). At the 4-week visit after receiving placebo, the mean systolic blood pressure decreased by 9.4 mmHg (p = 0.003) and mean diastolic blood pressure by 2.7 mmHg (p = NS) in the patients with ISH. In patients with SDH, there were no statistically significant changes in recorded BP readings following the introduction of placebo. We suggest blood pressures in some patients with ISH may settle with careful follow up and initiation of treatment in these patients could potentially be delayed for at least 3 months, as therapy may not prove necessary.

Adult↗
PubMed1996

Placebo response in anxiety disorders.

OBJECTIVE: To review literature on placebo response in anxiety, to discuss sources and levels of placebo response in various anxiety disorders, and to suggest methods to prevent high placebo response rates in clinical research trials. DATA SOURCE: Data from scientific literature were identified using a MEDLINE search, and were extracted and summarized for this review. STUDY SELECTION: Representative findings were selected from clinical and epidemiologic studies, review articles, letters to the editor, book chapters, and proceedings. DATA EXTRACTION: Data from English-language reports of studies on humans were included. Only the most representative conclusions drawn from review articles were used. DATA SYNTHESIS: Anxiety disorders in general are thought to be extremely susceptible to a variety of influences, including patient characteristics and environmental variables. Reported placebo response levels in clinical studies of anxiolytics for generalized anxiety disorder and panic disorder vary widely, with a tendency to be rather high, although studies in social phobia and obsessive compulsive disorder appear to have consistently low placebo response rates. Comparisons of anxiety studies with studies of other indications, such as depression, show similar overall placebo response rates. To determine efficacy, drug response rates and placebo response rates must be clearly differentiated. CONCLUSIONS: Examination of the literature suggests that placebo response rates in studies of anxiolytics are influences by a number of factors, including both endogenous and exogenous variables. High placebo response rates may mask true drug response rates and may result from poor study design or lack of procedural standardization. The use of certain design methods may help to prevent high placebo response rates in anxiolytic clinical trials.

Anxiety Disorders↗
PubMed2002

Placebo response in studies of major depression: variable, substantial, and growing.

CONTEXT: Intense debate persists about the need for placebo-controlled groups in clinical trials of medications for major depressive disorder (MDD). There is continuing interest in the development of new medications, but because effective antidepressants are already available, ethical concerns have been raised about the need for placebo groups in new trials. OBJECTIVE: To determine whether the characteristics of placebo control groups in antidepressant trials have changed over time. DATA SOURCES AND STUDY SELECTION: We searched MEDLINE and PsychLit for all controlled trials published in English between January 1981 and December 2000 in which adult outpatients with MDD were randomly assigned to receive medication or placebo. Seventy-five trials met our criteria for inclusion. DATA EXTRACTION: Data were extracted from the articles by 2 of the authors and discrepancies were resolved via discussion and additional review by a third author. DATA SYNTHESIS: The mean (SD) proportion of patients in the placebo group who responded was 29.7% (8.3%) (range, 12.5%-51.8%). Most studies examined more than a single active medication, and, in the active medication group with the greatest response, the mean (SD) proportion of patients responding was 50.1% (9.0%) (range, 31.6%-70.4%). Both the proportion of patients responding to placebo and the proportion responding to medication were significantly positively correlated with the year of publication (for placebo: n = 75; r = 0.45; 95% confidence interval [CI], 0.25-0.61; P<.001; for medication: n = 75; r = 0.26; 95% CI, 0.03-0.46; P =.02). The association between year of publication and response rate was more statistically robust for placebo than medication. CONCLUSIONS: The response to placebo in published trials of antidepressant medication for MDD is highly variable and often substantial and has increased significantly in recent years, as has the response to medication. These observations support the view that the inclusion of a placebo group has major scientific importance in trials of new antidepressant medications and indicate that efforts should continue to minimize the risks of such studies so that they may be conducted in an ethically acceptable manner.

Adult↗
PubMed2004

Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes.

BACKGROUND: Hot flushes and night sweats are common symptoms experienced by menopausal women. Hormone therapy (HT), containing oestrogens alone or oestrogens together with progestogens in a cyclic or continuous regimen, is often recommended for their alleviation. OBJECTIVES: To examine the effect of oral HT compared to placebo on these vasomotor symptoms and the risk of early onset side-effects. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders Group and Subfertility Group trials register (searched May 2002). This register is based on regular searches of MEDLINE, EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, the handsearching of 20 relevant journals and conference proceedings, and searches of several key grey literature sources. We also contacted all relevant pharmaceutical companies, The Journal of the International Menopause Society and Climacteric. SELECTION CRITERIA: Double-blind, randomised, placebo-controlled trials of oral HT for at least three months duration. DATA COLLECTION AND ANALYSIS: Study quality and outcome data were assessed independently. Random effects models were considered appropriate due to the variety of trial methodologies. The meta-analyses were explored for sensitivity to trial quality and therapy duration. Symptom frequency and severity were assessed separately, together with withdrawals and side-effects. Frequency data were analysed using the Weighted Mean Difference (WMD) between treatment and placebo outcomes. For severity data, odds ratios were estimated from the proportional odds model. From 115 references originally identified, 24 trials meeting the selection criteria were included in the review. Study participants totaled 3,329. Trial duration ranged from three months to three years. MAIN RESULTS: There was a significant reduction in the weekly hot flush frequency for HT compared to placebo (WMD -17.92, 95% CI -22.86 to -12.99). This was equivalent to a 75% reduction in frequency (95% CI 64.3 to 82.3) for HT relative to placebo. Symptom severity was also significantly reduced compared to placebo (OR 0.13, 95% CI 0.07 to 0.23). Withdrawal for lack of efficacy occurred significantly more often on placebo therapy (OR 10.51, 95% CI 5.00 to 22.09). Withdrawal for adverse events, commonly breast tenderness, oedema, joint pain and psychological symptoms, was not significantly increased (OR 1.25, 95% CI 0.83 to 1.90), although the occurrence of any adverse events was significantly increased for HT (OR 1.41, 95% CI 1.00 to 1.99). In women who were randomised to placebo treatment, a 57.7% (95% CI 45.1 to 67.7) reduction in hot flushes was observed between baseline and end of study. REVIEWERS' CONCLUSIONS: Oral HT is highly effective in alleviating hot flushes and night sweats. Therapies purported to reduce such symptoms must be assessed in blinded trials against a placebo or a validated therapy because of the large placebo effect seen in well conducted randomised controlled trials, and also because during menopause symptoms may fluctuate and after menopause symptoms often decline. Withdrawals due to side-effects were only marginally increased in the HT groups despite the inability to tailor HT in these fixed dose trials. Comparisons of hormonal doses, product types or regimens require analysis of trials with these specific "within study" comparisons.

Administration, Oral↗
PubMed2003

Placebo treatment versus no treatment.

BACKGROUND: Placebo interventions are often believed to improve patient reported and observer reported outcomes, but this belief is not based on evidence from randomised trials that compare placebo with no treatment. OBJECTIVES: To assess the effect of placebo interventions. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (The Cochrane Library, issue 3, 1998), MEDLINE (Jan 1966 to Dec 1998), EMBASE (Jan 1980 to Dec 1998), Biological Abstracts (Jan 1986 to Dec 1998), PsycLIT (Jan 1887 to Dec 1998). Experts on placebo research were contacted and references in the included trials were read. SELECTION CRITERIA: Randomised placebo trials with a no-treatment control group investigating any health problem were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. MAIN RESULTS: Outcome data were available in 114 out of 130 included trials, investigating 40 clinical conditions. Outcomes were binary in 32 trials (3795 patients) and continuous in 82 (4730 patients). We found no statistically significant pooled effect of placebo in studies with binary outcomes, relative risk 0.95 (95 per cent confidence interval 0.88 to 1.02). The pooled relative risk for subjective (patient reported) outcomes was 0.95 (0.86 to 1.05) and for objective (observer reported) outcomes 0.91 (0.80 to 1.04). There was statistically significant heterogeneity (P < 0.03), but no evidence of sample size bias (P = 0.56). We found an overall positive effect of placebo treatments in trials with continuous outcomes, standardised mean difference -0.28 (95 per cent confidence interval -0.38 to -0.19). The standardised mean difference for subjective outcomes was -0.36 (-0.47 to -0.25), whereas no statistically significant effect was found for objective outcomes, standardised mean difference -0.12 (-0.27 to 0.03). There was statistically significant heterogeneity (P < 0.001), and evidence of sample size bias (P = 0.05). There was no statistically significant effect of placebo interventions in eight out of nine clinical conditions investigated in three trials or more (nausea, relapse in prevention of smoking and depression, overweight, asthma, hypertension, insomnia and anxiety), but confidence intervals were wide. There was a modest apparent analgesic effect of placebo interventions, standardised mean difference -0.27 (-0.40 to -0.15), but also a substantial risk of bias. REVIEWER'S CONCLUSIONS: There was no evidence that placebo interventions in general have clinically important effects. A possible moderate effect on subjective continuous outcomes, especially pain, could not be clearly distinguished from bias.

Humans↗
PubMed1998

Oral iloprost treatment in patients with Raynaud's phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study.

OBJECTIVE: To evaluate the efficacy and tolerability of an oral preparation of iloprost, a prostacyclin analog, in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (scleroderma). METHODS: A multicenter, randomized, parallel-group, placebo-controlled double-blind study was performed at university and community-based medical centers. Patients were randomly assigned to receive either 50 microg of iloprost orally twice daily or an identical gelatin-coated capsule containing placebo for 6 weeks. Outcome measures included average total daily duration of RP attacks, average number of RP attacks, and RP condition scored via a standardized daily diary. RESULTS: Three hundred eight patients with scleroderma (272 women, 36 men, mean age 49 years [range 18-80]) were enrolled. One hundred fifty seven were assigned to receive iloprost and 151 to receive placebo. One hundred forty-three patients in the iloprost group (91.1%) and 144 in the placebo group (95.4%) completed the 6-week treatment phase. Fifteen of these treated patients (8 iloprost, 7 placebo) failed to complete all of the followup visits. The mean reduction in the average duration of attacks from baseline to week 5-6 was 24.32 minutes in the iloprost group and 34.34 minutes in the placebo group (P = 0.569). Likewise, the mean reduction from baseline to week 5-6 in the daily frequency of attacks was 1.02 in the iloprost group and 0.83 in the placebo group (P = 0.459). The Raynaud's condition score, a patient-completed assessment of the severity of RP attacks, was reduced by 1.32 in the iloprost group and 1.00 in the placebo group (P = 0.323). The lack of significant difference between treatment groups did not change when a variety of factors, including use of other vasodilators, duration of disease, classification of scleroderma (limited versus diffuse), or number of baseline digital ulcers were taken into account. Premature withdrawal from the study due to adverse events occurred in 10 patients (6.4%) in the iloprost group and 3 (2.0%) in the placebo group (P = 0.058). CONCLUSION: Oral iloprost at a dosage of 50 microg twice daily is no better than placebo for management of RP secondary to scleroderma, either during 6 weeks of treatment or during 6 weeks of posttreatment followup.

Administration, Oral↗
PubMed2004

Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial.

OBJECTIVE: Tumor necrosis factor (TNF) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis (RA). We investigated the ability of adalimumab, a human anti-TNF monoclonal antibody, to inhibit the progression of structural joint damage, reduce the signs and symptoms, and improve physical function in patients with active RA receiving concomitant treatment with methotrexate (MTX). METHODS: In this multicenter, 52-week, double-blind, placebo-controlled study, 619 patients with active RA who had an inadequate response to MTX were randomized to receive adalimumab 40 mg subcutaneously every other week (n = 207), adalimumab 20 mg subcutaneously every week (n = 212), or placebo (n = 200) plus concomitant MTX. The primary efficacy end points were radiographic progression at week 52 (total Sharp score by a modified method [TSS]), clinical response at week 24 (improvements of at least 20% in the American College of Rheumatology core criteria [ACR20]), and physical function at week 52 (disability index of the Health Assessment Questionnaire [HAQ]). RESULTS: At week 52, there was statistically significantly less radiographic progression, as measured by the change in TSS, in the patients receiving adalimumab either 40 mg every other week (mean +/- SD change 0.1 +/- 4.8) or 20 mg weekly (0.8 +/- 4.9) as compared with that in the placebo group (2.7 +/- 6.8) (P < or = 0.001 for each comparison). In addition, there were statistically significant changes in the components of the TSS. At week 24, ACR20 responses were achieved by 63% and 61% of patients in the adalimumab 40 mg every other week and 20 mg weekly groups, respectively, versus 30% of patients in the placebo group (P < or = 0.001 for each comparison). At week 52, ACR20 responses were achieved by 59% and 55% of patients taking adalimumab 40 mg every other week and 20 mg weekly, respectively, versus 24% of patients taking placebo (P < or = 0.001 for each comparison). At week 52, physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo (mean change in HAQ score -0.59 and -0.61, respectively, versus -0.25; P < or = 0.001 for each comparison). A total of 467 patients (75.4%) completed 52 weeks of treatment. Adalimumab was generally well tolerated. Discontinuations occurred in 22.0% of adalimumab-treated patients and in 30.0% of placebo-treated patients. The rate of adverse events (both serious and nonserious) was comparable in the adalimumab and placebo groups, although the proportion of patients reporting serious infections was higher in patients receiving adalimumab (3.8%) than in those receiving placebo (0.5%) (P < or = 0.02), and was highest in the patients receiving 40 mg every other week. CONCLUSION: In this 52-week trial, adalimumab was more effective than placebo at inhibiting the progression of structural joint damage, reducing the signs and symptoms, and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX.

Activities of Daily Living↗
PubMed2003

A comparison of antidepressant trials using active and inert placebos.

In placebo-controlled antidepressant trials, there are concerns that the double blind may be breached, which may bias results. Some trials have therefore used placebos containing active substances in order to mimic the side effects of antidepressants. This study set out to examine the impact of 'unblinding' by comparing the results of a meta-analysis of a sample of trials using ordinary inert placebos with a meta-analysis of trials using active placebos. An a priori sub-group analysis of trials conducted with inpatients and outpatients was carried out. Quality was assessed using a quality assessment instrument and meta-regression analysis was conducted to explore heterogeneity. Results of meta-analysis did not differ between trials using active placebos and trials using inert ones. However, results were strongly influenced by two large trials. When these were excluded trials using inert placebos showed greater antidepressant-placebo differences than trials using active placebos. There was very high heterogeneity especially among trials using inert placebos. Meta-regression analysis showed the only significant predictor of outcome was whether trials were conducted with inpatients or outpatients. Sub-group analysis showed significant differences between antidepressants and any type of placebo in trials conducted with outpatients but not in inpatient trials. Lack of data, heterogeneity and the influence of large studies limited the analysis. The integrity of the double blind design, its effect on results and the heterogeneity between studies, require further exploration in antidepressant trials.

Antidepressive Agents↗