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PubMed2000

Expectations of analgesia do not affect spinal nociceptive R-III reflex activity: an experimental study into the mechanism of placebo-induced analgesia.

The purpose of this study was to investigate whether placebo analgesia is mediated by the release of beta-endorphin. In addition to subjective pain reports, we included an objective physiological parameter of nociception reflected by the opioid sensitive nociceptive R-III reflex. Placebo consisted of strong suggestions of pain relief and an intravenous injection of saline. Forty minutes after placebo, either the opioid antagonist naloxone or saline was administered intravenously without subjects noticing (hidden). Sixty healthy males, aged 18-30 years, voluntarily participated in this study. Subjects were randomized into one of four groups: group 1 received placebo and hidden naloxone, group 2 received hidden naloxone only, group 3 received placebo and hidden saline and group 4 received hidden saline only. Pain was induced by electrical stimulation of the sural nerve and evaluated with a visual analogue scale (VAS). In addition, changes in the magnitude of the nociceptive R-III reflex activity were assessed. We determined to what extent R-III reflex activity and subjective pain reports were decreased by placebo and we investigated whether these placebo-induced changes in reflex activity and subjective pain reports were naloxone reversible. Furthermore, we measured the degree of association between pain relief as measured on VAS and changes in R-III reflex activity. Finally, the role of beta-endorphin was assessed by measuring plasma endorphin levels before and after the administration of placebo. This study could not demonstrate a placebo effect as measured on VAS and R-III responses. The administration of placebo did not appear to have an effect on the release of beta-endorphins. Consistently, the antagonizing effects of naloxone were negligible. A subgroup analysis of those who did show a placebo response as indicated on the VAS did not support the supposition that beta-endorphin is released due to placebo suggestion. It is suggested that intensified stimuli and a more effective procedure to induce placebo analgesia (e.g. conditioning) may produce a proper placebo effect.

Adolescent↗
PubMed2003

Placebo response and antidepressant clinical trial outcome.

Placebo response magnitude is suspected to affect the outcome of antidepressant clinical trials. To evaluate this, 52 randomized, double-blind, placebo-controlled clinical trials obtained from the FDA were examined to correlate placebo response magnitude with trial outcome. The magnitude of symptom reduction, percentage mean change from baseline in the Hamilton Depression Rating Scale (HAM-D), was assessed for patients assigned to placebo or an antidepressant. Correlation coefficients between symptom reduction with placebo and antidepressants and between symptom reduction with placebo and magnitude of advantage of antidepressants over placebo were assessed. A statistically significant positive correlation was seen between placebo and antidepressant response magnitude (r =.40, p <.001) and between placebo response magnitude and the advantage of antidepressants over placebo (r = -.592, p <.0001). Only 21.1% of antidepressant treatment arms in trials with high placebo response (>30% mean change from baseline) showed statistical superiority over placebo compared with 74.2% in trials with a low placebo response (< or =30). Response magnitude varies and has an important effect on antidepressant clinical trials, illustrating the need for a placebo arm to determine if the trial was sensitive to treatment differences and highlighting the dangers of cross-study comparisons.

Antidepressive Agents↗
PubMed2004

Pretreatment neurophysiological and clinical characteristics of placebo responders in treatment trials for major depression.

RATIONALE: High placebo response rates are a confound in treatment trials for major depressive disorder (MDD). A method for prospective identification of placebo responders could enhance the efficiency of clinical trials. OBJECTIVE: The objective was to identify the neurophysiological, symptomatic, and cognitive characteristics of subjects who were likely to respond to placebo in clinical trials for MDD. METHODS: Fifty-one subjects with MDD were treated in clinical trials with either fluoxetine ( n=24) or venlafaxine ( n=27) versus placebo. All subjects underwent pretreatment assessment with quantitative electroencephalographic (QEEG) power and cordance, as well as symptom ratings and neuropsychological testing. After a 1-week single-blind placebo lead-in, subjects were randomized to double-blind placebo controlled treatment with a medication or placebo. At the end of 8 weeks, the blind was broken and treatment response assessed. Response was defined by a final Hamilton Depression Rating Scale score of </=10. RESULTS: Of the medication-treated and placebo-treated subjects, 52% (13/25) and 38% (10/26) responded. Placebo responders had lower pretreatment frontocentral cordance in the theta frequency band than all other subjects ( P<0.006) and medication responders in particular ( P<0.004). Placebo responders also had faster cognitive processing time, as assessed by neuropsychological testing, and lower reporting of late insomnia ( P<0.03). Exploratory examination of a multiple variable model for predicting placebo response was conducted using logistic regression, in which these three pretreatment measures accurately identified 97.6% of eventual placebo responders. CONCLUSIONS: These findings suggest that combined clinical, neurophysiological, and cognitive assessments of prospective subjects for clinical trials may be useful for identifying MDD subjects who are likely to show robust response to placebo. Prospective validation of these results in a larger, independent sample of subjects is necessary to establish the reliability and usefulness of this method for prospective identification of placebo responders.

Adult↗
PubMed1994

Utility and reliability of placebo infusion in the evaluation of patients with seizures.

Placebo infusions are occasionally used to elicit psychogenic seizures. How frequently placebo infusions elicit patients' typical events, atypical and potentially confusing events, or even epileptic seizures is not known. We report the results of placebo infusions during video EEG in 68 patients who also had events recorded without placebo. A single investigator administered a saline placebo that was represented to the patient as an activating substance. We compared the events recorded without placebo with events recorded with placebo. Twenty patients had only epileptic seizures without placebo; with placebo, two of 20 (10%) had their typical epileptic seizures and three of 20 (15%) had atypical nonepileptic events. Forty patients had only psychogenic seizures without placebo; with placebo, 33 of 40 (82%) had their typical psychogenic seizures and three of 40 (8%) had atypical events. Eight patients had both psychogenic and epileptic seizures without placebo; with placebo, four of eight had their typical psychogenic seizures. Thus, placebo infusion elicits typical psychogenic events in most patients with psychogenic seizures, but atypical events or epileptic seizures may occur in a minority and lead to incorrect diagnosis.

Adult↗
PubMed2000

Objective changes in motor function during placebo treatment in PD.

OBJECTIVE: To examine the frequency, temporal development, and stability of objectively derived motor changes during placebo treatment in PD and to define the clinical domains and demographic groups most affected. BACKGROUND: Placebo effects are documented in neurology, but the timing and specific disabilities most susceptible to changes during placebo treatment in PD have not been examined. METHODS: The authors examined the placebo-treated group from a randomized, multicenter, placebo-controlled clinical trial of monotherapy ropinerole in PD patients without motor fluctuations. In 105 patients, they evaluated placebo-associated effects on the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS), dividing the motor examination into four categories: tremor, bradykinesia, rigidity, and gait/balance/midline functions. The motor UPDRS and its subscales were compared over time (at baseline and at 4, 12, and 24 weeks) using Wilcoxon's signed rank test. They applied a rigorous definition of placebo-associated improvement as an improvement over baseline score in motor UPDRS of at least 50% or a change in at least two motor items at any one visit by > or =2 points. RESULTS: During the 6-month study, 16% of subjects improved on placebo treatment. The prevalence of response was steady (8 to 9%) at any one visit without a predominance of an early effect. No patient showed a placebo-associated improvement on all visits. All domains of parkinsonian disability were subject to placebo-associated improvement, with a trend toward more response in bradykinesia and rigidity than in tremor or gait/balance/midline function. Gender, age, disease duration, and baseline disability score did not influence the likelihood of improvement in association with placebo treatment. CONCLUSION: Based on a rigorous definition of placebo-associated improvement, prominent improvements in objective measures of PD disability occur during clinical trials. Because placebo-associated improvements occur throughout a 6-month trial, placebo-controlled studies in PD should be at least 6 months to capture early as well as late improvements.

Aged↗
PubMed2004

Efficacy and tolerability of sustained-release tramadol in the treatment of symptomatic osteoarthritis of the hip or knee: a multicenter, randomized, double-blind, placebo-controlled study.

BACKGROUND: Opioid analgesics may be a useful alternative in patients with osteoarthritis who have not responded to first-line treatment with acetaminophen and in whom nonsteroidal anti-inflammatory drugs are contraindicated, ineffective, or poorly tolerated. OBJECTIVE: This study compared the efficacy and tolerability of tramadol LP 200 mg, a new once-daily,sustained-release formulation, with those of placebo in patients with osteoarthritis of the hip or knee. METHODS: In this multicenter, double-blind, placebo-controlled, parallel-group study, patients with osteoarthritis of the hip or knee (European League Against Rheumatism criteria) were randomized to receive either tramadol LP 200 mg once daily or placebo for 14 days. The primary efficacy end point was the change from baseline to the end of the study in scores on the Huskisson visual analog scale for pain. Secondary end points were change in the Lequesne functional discomfort index, global efficacy assessed by the patient and the investigator, time to improvement, and use of acetaminophen as rescue analgesic medication. Global tolerability was assessed by both patients and investigators at the end of the study The number and severity of adverse events occurring during the study and for 2 weeks thereafter were also recorded. RESULTS: Two hundred thirty patients (167 women, 63 men) were evaluable for efficacy and safety Demographic data for the tramadol and placebo groups were as follows: mean (SD) age, 67.1 (7.1) and 66.4 (92) years, respectively; female sex, 72.1% and 73.1%; and mean body weight, 74.7 (13.6) and 74.6 (14.8) kg. All patients were white. The completer analysis included 197 patients (85 tramadol, 112 placebo). Pain was significantly reduced in the tramadol LP group compared with the placebo group on day 7 (P = 0.002) and day 14 (P = 0.010). In the patient's assessment of global efficacy, 77.6% (66) of the tramadol LP group reported improvement by day 14, compared with 59.8% (67) of the placebo group; in the investigator's assessment, the efficacy of tramadol LP was rated very good or good for 612% (52) of patients, compared with 30.4% (34) for placebo. Improvement was reported before day 7 in 882% (75) of patients in the tramadol LP group, compared with 65.2% (73) in the placebo group (P = 0.021); the mean time from the initiation of treatment to reported improvement was 3 days for tramadol LP and 6 days for placebo (P < 0.001). Rates of response (defined as > or =30% pain reduction between days 0 and 14) were 64.7% (55) for tramadol LP and 50.0% (56) for placebo (P = 0.039); no rescue medication was used by 60.0% (51) of the tramadol LP group and 36.6% (41) of the placebo group (P - 0.001). One or more adverse event was reported by 45.0% (50) of the tramadol LP group, compared with 193% (23) of the placebo group (P < 0.001). As would be expected with an opiate agonist such as tramadol, the most common adverse events with this agent involved the gastrointestinal system (nausea, 22.5% [25] of patients; vomiting, 17.1% [19]) and the central nervous system (somnolence, 11.7% [13]). CONCLUSIONS: In this study, tramadol LP 200 mg was significantly more effective than placebo in alleviating pain in patients with osteoarthritis of the hip or knee. It appeared to be relatively well tolerated for an opioid compound.

Aged↗
PubMed1997

Efficacy of 24-week monotherapy with acarbose, metformin, or placebo in dietary-treated NIDDM patients: the Essen-II Study.

PURPOSE: To compare the therapeutic potential of acarbose, metformin, or placebo as first line treatment in patients with non-insulin-dependent diabetes mellitus (NIDDM). PATIENTS AND METHODS: Ninety-six patients with NIDDM (35-70 years of age, body mass index (BMI) < or = 35 kg/m2, insufficiently treated with diet alone, glycated hemoglobin (HbA1c; 7% to 11%) were randomized into 3 groups and treated for 24 weeks with acarbose, 3 x 100 mg/day, or metformin, 2 x 850 mg/day, or placebo. Efficacy, based on HbA1c (primary efficacy criterion), fasting blood glucose (BG) and insulin, 1 hour postprandial BG and insulin (after standard meal test), postprandial insulin increase, plasma lipid profile, and tolerability, based on subjective symptoms and laboratory values were determined every 6 weeks. Analysis of covariance was performed for endvalues with adjustment on baseline values. Ninety-four patients were valid for efficacy evaluation. RESULTS: Both active drugs showed the same improvement of efficacy criteria compared with placebo. Baseline adjusted means at endpoint were as follows: BG, fasting and 1 hour postprandial, 9.2 mM and 10.9 mM with placebo, 7.6 mM and 8.7 mM with acarbose, and 7.8 mM and 9.0 mM with metformin; HbA1c was 9.8% with placebo, 8.5% with acarbose, and 8.7% with metformin. Comparisons: acarbose versus placebo and metformin versus placebo were statistically significant, but not acarbose versus metformin. No effect on fasting insulin could be observed. Relative postprandial insulin increase was 1.90 with placebo, 1.09 with acarbose, and 1.03 with metformin. Comparisons: acarbose versus placebo and metformin versus placebo were statistically significant, but not acarbose versus metformin. With respect to lipid profile, acarbose was superior to metformin. Low-density lipoprotein (LDL)/high-density lipoprotein (HDL) cholesterol ratio increased by 14.4% with placebo, was unchanged with metformin, but decreased by 26.7% with acarbose. Comparisons: acarbose versus placebo and acarbose versus metformin were statistically significant, but not metformin versus placebo. Slight body weight changes were observed with acarbose (-0.8 kg) and metformin (-0.5 kg), but not with placebo. Acarbose led to mild or moderate intestinal symptoms in 50% of the patients within the first 4 weeks, but in only 13.8% of the patients within the last 4 weeks. CONCLUSIONS: Acarbose and metformin are effective drugs for the first line monotherapy of patients with NIDDM. With respect to plasma lipid profile, especially HDL cholesterol, LDL cholesterol and LDL/HDL cholesterol ratio acarbose may be superior to metformin.

Acarbose↗
PubMed1996

INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group.

OBJECTIVE: To determine the safety and efficacy of BAY x 1351, a murine monoclonal antibody to recombinant human tumor necrosis factor (TNF)-alpha, in patients with sepsis. DESIGN: An international, multicenter, prospective, placebo-controlled trial in patients with sepsis, stratified into shock/nonshock groups. SETTING: Forty acute clinical care facilities in 14 countries. PATIENTS: Of the 564 patients enrolled in the study, 553 patients received study drug or placebo. INTERVENTIONS: Patients received 15 mg/kg or 3 mg/kg of BAY x 1351, or placebo, as a single intravenous infusion. MEASUREMENTS AND MAIN RESULTS: The patients were well matched for severity of illness and for risk factors known to influence the outcome of sepsis. There was no difference in 28-day mortality rates between groups (placebo group 66 [39.5%] of 167;3 mg/kg group 57 [31.5%] of 181; 15 mg/kg group 87 [42.4%] of 205). Approximately 9 months after this study had begun, an interim safety examination of NORASEPT, a North American Sepsis Trial using the same monoclonal antibody, indicated that there was no benefit to patients in the nonshock group and further enrollment of these nonshock septic patients into INTERSEPT was stopped. The analysis therefore focused on the 420 patients in shock. The primary efficacy variable was the 28-day, all-cause mortality rate: placebo group 57 (42.9%) of 133; 3-mg/kg group 51 (36.7%) of 139; and 15-mg/kg group 66 (44.6%) of 148 (not significant). Two secondary efficacy variables were identified prospectively: shock reversal and frequency of organ failures. Life-table analysis showed that in patients who survived 28 days, there was a more rapid reversal of shock in both treatment groups compared with placebo (15-mg/kg group vs. placebo group log-rank statistic p = .007, 3-mg/kg group vs. placebo group p = .01). Similarly, in patients surviving 28 days, there was a significant delay in the time to the onset of first organ failure (log rank 15 mg/kg vs. placebo p = .03, 3 mg/kg vs. placebo p = .07), and more patients in the placebo group developed at least one organ failure: 15-mg/kg group 33 (40.2%) of 82; 3-mg/kg group 39 (44.3%) of 88; and placebo group 45 (59.2%) of 76 (15 mg/kg vs. placebo p = .03, 3 mg/kg vs. placebo p = .06). No significant adverse events were associated with the monoclonal antibody treatment. CONCLUSIONS: INTERSEPT provides additional clinical data implicating TNF-alpha as an integral mediator of septic shock. The study suggested a possible role for anti-TNF antibody as adjunctive therapy, but this possibility requires confirmation by another clinical trial.

APACHE↗
PubMed2003

Impact of placebo assignment in clinical trials of Parkinson's disease.

Informed consent procedures in placebo-controlled trials are developed to ensure that subjects entering studies clearly understand the possibility of placebo assignment. The extent of patient understanding and the impact of learning that they were assigned placebo treatment have not been extensively studied. By using a standardized questionnaire, we interviewed 50 consecutive placebo-treated patients from 14 placebo-controlled clinical trials of Parkinson's disease (PD) after completion of their involvement. All patients interviewed understood that their study contained a placebo arm. All had hoped to receive the study drug rather than placebo, and more than half the subjects believed they had improved clinically during their placebo exposure. Positive impressions of enrollment in placebo-controlled trials were more frequent than negative, included helping to advance science (86%); liking the experience, education, and attention associated with the clinical trial (90%); and participating in research for the benefit of other patients as well as for themselves (80%). If another placebo-controlled trial was offered, 88% expressed that they would possibly, likely, or definitely be interested in enrollment. PD patients clearly understand the concept of placebo-controlled trials they complete them, but they are inaccurate in assessing whether they received placebo treatment. Although most wish they received the active compound being tested, the overall view of participation in placebo-controlled trials is viewed very positively by PD patients.

Aged↗
PubMed2002

Moderators of placebo response to antipsychotic treatment in patients with schizophrenia: a meta-regression.

RATIONALE: Variation in placebo response within and among clinical trials involving patients with schizophrenia can substantially affect conclusions about the efficacy of new antipsychotic medications. Therefore, it is of great importance to identify factors that moderate response to placebo in such trials. OBJECTIVE: The objective of this meta-regression analysis was to estimate the effect of potential moderators of placebo response in randomized, short-term clinical trials involving patients with schizophrenia, schizoaffective disorder or schizophreniform disorder. METHODS: Mean placebo response and potential moderators were extracted from 35 placebo-controlled, randomized trials of antipsychotic medications in patients with schizophrenia. Placebo response was defined as the absolute change in the Brief Psychiatric Rating Scale total score. Fixed-effects meta-regression was used to investigate between-trial variation in placebo response. RESULTS: Trial duration accounted for a substantial proportion of the between-trial variation in response (27%), with greater improvement on placebo observed in shorter trials. Other variables showed insufficient variation across trials to permit any inferences regarding their relationships with placebo response. CONCLUSIONS: Placebo-controlled trials of short duration (<6-8 weeks) are vulnerable to substantial placebo response. Recruiting patients with more severe pathology to mitigate placebo response does not appear to offer benefits and may even be counterproductive. Meta-analyses based on individual patient data offer the potential for much more detailed and inferentially sound exploration of factors affecting placebo response and are highly recommended.

Adult↗
PubMed2000

Placebo-associated blood pressure response and adverse effects in the treatment of hypertension: observations from a Department of Veterans Affairs Cooperative Study.

BACKGROUND: The use of placebo in clinical trials has been vigorously debated. Placebo control may be useful in disease states, such as stage 1 and stage 2 hypertension as defined by the Sixth Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC VI), in which response rates for placebo are high or close to response rates for effective therapies, or when established interventions have significant adverse effects. OBJECTIVE: To compare rates for the control of blood pressure and adverse effects of placebo vs active treatment in patients with stage 1 and stage 2 hypertension. METHODS: This study is a randomized controlled trial evaluating the blood pressure response and adverse effects of placebo vs 6 active treatments administered in 15 Veterans Affairs hypertension centers. The 1292 subjects of the Veterans Affairs Cooperative Study receiving single-drug therapy for hypertension were randomly allocated to receive treatment with 1 of 6 active drugs (n= 1105) or placebo (n=187). Treatment success was defined as maintaining a diastolic blood pressure of less than 95 mm Hg for at least 1 year. We compared treatment success rates for the control of blood pressure and adverse effects of placebo vs active treatment. Using the Kaplan-Meier method, we also compared rates of discontinuation from placebo vs active drug treatment over time as a result of adverse drug effects and blood pressure exceeding safety limits. RESULTS: At the end of the titration phase, 58 patients who were treated with placebo (31%) achieved a goal diastolic blood pressure lower than 90 mm Hg and 57 (30%) achieved success at 1 year. Older white patients who received placebo had a success rate of 38% vs 23% to 27% for the other age-race subgroups. The rates of discontinuation as a result of adverse drug effects were 13% for patients receiving placebo vs 12% for patients receiving active treatment (P=.40). The rates of discontinuation for blood pressure being too high were 14% for patients receiving placebo vs 7% for patients receiving active treatment (P=.01). CONCLUSIONS: Placebo control provides an important benchmark for both efficacy and adverse effects. It continues to have an appropriate place in certain therapeutic trials, particularly those involving the treatment of stage 1 and stage 2 hypertension.

Adult↗
PubMed2005

Placebo effects in developmental disabilities: implications for research and practice.

Recent clinical trials of secretin in children with autism showed robust placebo effects and no benefit of secretin over placebo. This article explores the reasons for the observed placebo effects, focusing on the heightening of positive expectancy by media attention and by the sensory experiences associated with intravenous injections. Comparisons are drawn with research involving other novel treatments and other clinical populations of children with developmental disabilities and neurobehavioral disorders. Research regarding mechanisms of placebo effects is reviewed, including patient and clinician attributes, expectancy effects, participation effects, changes in caregiver behavior, and conditioning. New evidence regarding the biological basis of placebo effects is briefly presented. Since placebo effects are ubiquitous and may operate by a variety of mechanisms, research design is critical in designing clinical trials and in evaluating other outcomes research. Measurement issues important for research in developmental disabilities are emphasized. Ethical concerns have been raised regarding the use of placebo in clinical research, but current analysis suggests that placebo controls are necessary and defensible on ethical grounds, if certain conditions are met. The study of placebo effects ("placebology") holds great promise as a new area of research in therapeutics. The author's research in the potential augmentation of stimulant effects in children with attention deficit/hyperactivity disorder (ADHD) by adding placebo in open label is briefly presented. The placebo has always been integral to the practice of medicine, but advances in scientific medicine and medical ethics have diminished the role and use of placebo in practice. An innovative approach to the ethical use of placebo is proposed.

Child↗
PubMed1989

Placebo responses to cocaine administration in humans: effects of prior administrations and verbal instructions.

Subjective and physiological responses of eight male cocaine-using research volunteers were studied after a double-blind saline infusion (placebo) was given when subjects were instructed that a cocaine infusion might be given. Cardiovascular and subjective responses to placebo were similar in pattern and direction, though of lesser magnitude, than after a 40 mg cocaine infusion. These placebo responses were compared to responses after an earlier saline infusion condition in which subjects were instructed prior to the infusion that they would receive saline (instructed placebo). The design was thus meant to test for the effects of instructions on placebo responses to cocaine. Heart rates at baseline (pre-infusion) were significantly higher in the placebo than in the instructed placebo condition. Similar trends were found for elevated baseline placebo responses on two subjective effects measures. A comparison with an initial placebo session prior to the placebo and instructed placebo conditions described above provided evidence for conditioning of placebo responses on diastolic blood pressure and heart rate. The present results suggest that verbal instructions, as well as conditioning in the laboratory, could contribute to the observed placebo responses to cocaine infusions.

Adult↗
PubMed1996

Variation in the placebo effect in randomised controlled trials of analgesics: all is as blind as it seems.

The objective was to investigate the relationship between pain relief scores produced by placebo and by active interventions in randomised controlled trials (RCTs). Individual patient categorical pain relief scores from 5 placebo-controlled single-dose parallel-group RCTs in acute postoperative pain were used to calculate the percentage of the maximum possible pain relief score (%maxTOTPAR) for the different treatments. One hundred and thirty of the 525 patients in the 5 trials had a placebo. Individual patients' scores with placebo varied from 0 to 100% of the maximum possible pain relief. The proportion who obtained more than 50% of the maximum possible pain relief with placebo varied from 7% to 37% across the trials; with the active drugs the variation was from 5 to 63%. Mean placebo scores were related to the mean score for the active treatments in each study; the higher the mean active score, the higher the mean placebo score. This relationship disappeared when median values were used. Medical folklore has it that the amount of relief obtained with placebo is one-third of the maximum possible (and does not vary), and that one-third of patients respond to placebo. The results show that the amount of relief obtained with placebo varies considerably between patients, that 38% of patients obtained more than 10% of the maximum possible relief, and 16% obtained greater than 50%. In double-blind, randomised parallel-group studies of high quality placebo scores should not vary. Despite these conditions being met the placebo scores did vary. The previous explanation, of a relationship between the mean placebo scores and the mean scores for the active treatments was not supported.

Analgesics↗
PubMed2004

Placebo-controlled continuation treatment with mirtazapine: acute pattern of response predicts relapse.

Pattern of response to antidepressants has been proposed as a method to identify patients whose improvement is more likely due to drug vs those whose improvement on drug is more likely to be a placebo effect. It is hypothesized that those with 'true-drug initial response pattern' are most likely to benefit from continuation treatment. The relationship between acute patterns of response and subsequent placebo-controlled continuation treatment with the antidepressant mirtazapine is examined. A total of 410 outpatients were treated openly with mirtazapine for 8-12 weeks. Patients who remitted in the acute phase were randomized to continue the same dose of mirtazapine or switched to placebo. Acute phase responders were classified as 'placebo initial response pattern' (early responders and nonpersistent responders) and 'true-drug initial response pattern' (delayed and persistent responders). Of those with a 'true-drug initial response pattern,' 10/40 (25.0%) relapsed with continuation mirtazapine, and 23/41 (56.1%) relapsed when switched to placebo. The difference (31.1%) is significant. Of those with a 'placebo initial response pattern,' 5/36 (13.9%) relapsed with continuation mirtazapine, and 12/39 (30.8%) relapsed with placebo substitution. This difference (16.9%) is not statistically significant. Moreover, the relapse rate for 'true-drug initial response pattern' patients switched to placebo (56.1%) was also significantly greater than for 'placebo initial response pattern' patients switched to placebo (30.8%). It has been suggested that patients with late onset and persistence are more likely to have improved because of drug. This hypothesis gains support from this study because of the different relapse rates of 'true-drug' responders on drug and placebo. The low relapse rate for patients with an acute placebo pattern switched to placebo suggests specific drug effect played a smaller role in their initial improvement.

Adult↗
PubMed2001

Credibility of a newly designed placebo needle for clinical trials in acupuncture research.

OBJECTIVE: To test the credibility of a newly designed placebo needle for acupuncture research. DESIGN: Analysis of data on credibility of true and placebo interventions of a randomised, placebo-controlled, patient- and evaluator-blind clinical trial. PATIENTS AND SETTING: The study was carried out at a university department for physical medicine and rehabilitation. 68 patients (age 48.1 +/- 14.1 years, mean +/- SD) fulfilling the criteria of the International Headache Society for tension-type headache were enrolled into the study. INTERVENTIONS: Group 1 (treatment) was assigned to traditional needle placement and manipulation, whereas in group 2 (control) a new placebo device was used. OUTCOME PARAMETERS: After the first treatment with real or placebo acupuncture, patients were asked to fill in a questionnaire on credibility. In addition, after 3 or 4 treatments, patients were asked for the feeling of needle insertion and deqi. RESULTS: No difference between real and placebo acupuncture was detected with respect to the credibility of the treatment (p > 0.05). Needle insertion was recognised in all patients in the real acupuncture group and in all but 4 patients of the placebo group (p < 0.05). deqi was reported by 84% of patients in the real acupuncture group and by 34% of patients in the placebo group (p < 0.001). CONCLUSION: Acupuncture with the placebo needle device described here is of high credibility, and does not differ from that of real acupuncture treatment. However, to achieve comparable prick sensations in both treatment conditions, careful training with the placebo needle is needed. Furthermore, from these results arise new questions with respect to the placebo response of placebo needles. Further investigations are warranted to test if placebo needles are active controls.

Acupuncture Therapy↗
PubMed2005

The therapeutic effect of clinical trials: understanding placebo response rates in clinical trials--a secondary analysis.

BACKGROUND AND PURPOSE: Placebo response rates in clinical trials vary considerably and are observed frequently. For new drugs it can be difficult to prove effectiveness superior to placebo. It is unclear what contributes to improvement in the placebo groups. We wanted to clarify, what elements of clinical trials determine placebo variability. METHODS: We analysed a representative sample of 141 published long-term trials (randomized, double-blind, placebo-controlled; duration > 12 weeks) to find out what study characteristics predict placebo response rates in various diseases. Correlational and regression analyses with study characteristics and placebo response rates were carried out. RESULTS: We found a high and significant correlation between placebo and treatment response rate across diseases (r = .78; p < .001). A multiple regression model explained 79% of the variance in placebo variability (F = 59.7; p < 0.0001). Significant predictors are, among others, the duration of the study (beta = .31), the quality of the study (beta = .18), the fact whether a study is a prevention trial (beta = .44), whether dropouts have been documented (beta = -.20), or whether additional treatments have been documented (beta = -.17). Healing rates with placebo are lower in the following diagnoses; neoplasms (beta = -.21), nervous diseases (beta = -.10), substance abuse (beta = -.14). Without prevention trials the amount of variance explained is 42%. CONCLUSION: Medication response rates and placebo response rates in clinical trials are highly correlated. Trial characteristics can explain some portion of the variance in placebo healing rates in RCTs. Placebo response in trials is only partially due to methodological artefacts and only partially dependent on the diagnoses treated.

Data Interpretation, Statistical↗
PubMed2004

[Placebo test in the diagnostics of pseudoepileptic seizures in children and adolescents].

THE AIM OF THE STUDY: The psychogenic pseudoepileptic seizures can be provoked by suggestion and by placebo test. This is the possibility that differentiates them with epileptic seizures, if there is a chance to record with video EEG. In the developmental age the intravenous placebo tests are willingly used, moreover the oral placebo has probably the same effectiveness. The Aim of the study was to determined the effectiveness of oral placebo in provoking psychogenic paroxysm and bioelectrical brain disorders in children with pseudoepileptic seizures. We also evaluated the effectiveness of placebo in provoking epileptic seizures in children with coexisting epilepsy. MATERIAL: The placebo was given to 30 among 40 children with pseudoseizures which was diagnosed with video EEG. There were 36 girls and 4 boys aged 8 to 18 years (average 13 years) hospitalised in the Department of Neurology in Kraków between 2002-2004. The most frequent type of paroxysm were syncope which needed to be diagnosed, fainting, headache, dizziness, paroxysmal abdominal pain and visual disorders. In 15/40 children with paroxysmal nonepileptic events the epileptic seizures were coexisting. METHODS: Pseudoepileptic seizures were provoked even by the video EEG monitoring, suggestion, hyperventilation and placebo probe. For deepening the assessment of the EEG pattern beside the hyperventilation reactions test of open and closed eye and photostimmulation were used. During the placebo probe video EEG was done with voice recording and analyses of the synchrony of clinic and EEG pattern. RESULTS: Among 30 children with pseudoepileptic seizures after placebo in 20 paroxysm during recording were observed. The character of the paroxysm was similar to the previous history. More frequently were observed behavioural and visual disorders and rare syncope. No epileptic seizures were developed by placebo. 19/30 children with clinically positive and negative placebo test, developed paroxysmal bioelectric activity. CONCLUSION: The oral placebo test was clinically effective in diagnosis of the pseudoepileptic events in 2/3 children. It developed paroxysmal EEG pattern in children with clinically positive and also with negative placebo test.

Adolescent↗