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PubMed1999

Placebo--efficacy and adverse effects in controlled clinical trials.

UNLABELLED: The therapeutic efficacy of placebo in a series of diseases has long been known. It is less well known, however, that treatment with placebo can also produce significant adverse drug reactions. Therefore, the placebo drug reactions from controlled trials were studied for the first time systematically. METHOD: The efficacy and the safety of placebos were investigated using patient and drug data pooled from randomized, placebo-controlled, multicentre studies in five different groups of indications covering the therapeutic areas of cardiology (nisoldipine), neurology/psychiatry (nimodipine/ipsapirone), metabolism (acarbose) and gastroenterology (hydrotalcite). RESULTS: The efficacy of placebo was clear, and varied not only between the five indication groups but also within them. Whereas placebo, unlike active treatment, produced hardly any improvement in symptoms in patients with severe stroke, it was as effective as active treatment in patients with mild neurological deficits, producing an improvement of about 50%. In patients with angina pectoris, placebo produced an increase in exercise tolerance (treadmill walking time to onset of ST-segment depression and angina attacks) of about 10% on average, compared with about 22% under active treatment (nisoldipine). In diabetes therapy, placebo produced no improvement in fasting and postprandial blood glucose levels compared with active treatment (acarbose), and also had no effect on HbA1C values. ADVERSE EFFECTS OF PLACEBO: Adverse drug reactions were observed under treatment with placebo. The frequency and type of placebo-induced adverse reactions also varied between indication groups. For example, typical cardiovascular effects such as tachycardia were observed in the control group. The placebo side effect profile was largely similar to the side effect profile of the active treatment. Some adverse drug reactions (such as "dry mouth" in patients with generalized anxiety syndromes) were observed more frequently under placebo than under active treatment. CONCLUSIONS: Treatment with placebo is frequently effective and cannot therefore be considered as "non-treatment". Placebo effects can only be quantified by direct comparison with "non-treatment". Like active treatment, treatment with placebo is frequently accompanied by adverse drug reactions. Placebo adverse effects are often disease- and active treatment-specific. The effects and adverse effects of a placebo need to be known before the effects of active treatment in controlled clinical trials can be assessed. The mechanisms of placebo effects are many and varied (e.g. endorphin release, conditioning). Since the use of drugs without regard to evidence-based medicine (prescription of drugs without proven efficacy = pseudoplacebos) may clearly also result in serious adverse effects, such practice may not only be non-beneficial but may even be harmful.

Controlled Clinical Trials as Topic↗
PubMed1999

[Placebo effect in clinical trials].

BACKGROUND: It is well known that placebos evoke a variety of effects in the human body. It is less known that placebo medication can produce adverse drug reactions (ADRs). METHOD: The efficacy and, as the main topic, the tolerability were investigated from an international clinical data pool on placebo-controlled randomized multicenter studies of 5 different groups of indications. The therapeutic areas analyzed were neuropsychiatry (nimodipine, ipsapirone), cardiology (nisoldipine), metabolism (acarbose) and gastroenterology (hydrotalcit). RESULTS: The placebo efficacy was evident and varied not only in comparison to 5 indication groups analyzed, but also within them. Placebo showed for example hardly an effect on the symptomatology of stroke patients with a severe neurological deficit in comparison to verum while there was a 50% improvement in symptoms following placebo application in patients with a mild stroke. In angina patients exercise tolerance increased under placebo by 10% (time to onset of ST segment depression and symptoms of angina) while verum showed a 22% improvement. In diabetes placebo had no effect as compared to baseline and to a verum on blood glucose and HbA1C. ADRs could be observed under placebo treatment. The frequency and kind of placebo-induced ADRs varied also between the indication groups, i.e. typical CV side-effects were observed in CV controls. The placebo ADR profile was similar to the reference drug also. Some ADRs were reported even more frequently under placebo than under verum, like "dry mouth" in patients with general anxiety status. CONCLUSIONS: Placebo therapy is frequently effective and is not a "non-therapy". Placebo effects can be shown only by direct comparison with a "non-therapy". A placebo therapy is frequently accompanied by adverse drug reactions (ADRs) just as a verum therapy. Placebo ADRs are frequently illness- and verum-specific. Effects and ADRs of placebo therapy must be known, to judge the effect of verum medication in controlled clinical trials. The mechanisms of placebo effects are manifold (e.g. endorphine release, conditioned learning). Since placebo therapy outside of evidence-based medicine (use of drugs without proven efficacy = pseudoplacebos) may potentially also cause serious side effects, the use may not only be useless but also harmful.

Clinical Trials as Topic↗
PubMed2001

The double-blind variable placebo lead-in period: results from two antidepressant clinical trials.

The 1-week single-blind placebo lead-in has long been a standard in double-blind psychopharmacology clinical trials. Although a lead-in period is often necessary (e.g., to receive laboratory results before randomization), some authors have demonstrated that the standard single-blind placebo lead-in's performance was similar to having a lead-in in which placebo was not administered. The single-blind placebo lead-in did not decrease postrandomization placebo response, nor did it increase drug-placebo differences. To eliminate a higher percentage of placebo responders before randomization and to reduce potential biases in baseline ratings, the authors designed and implemented two depression studies with a double-blind variable placebo lead-in period. In these designs, both the patients and personnel at the investigative sites were blinded to the length of the placebo lead-in period and the start of the active treatment period. Approximately 28% of the patients in the double-blind placebo lead-in studies met criteria to be placebo lead-in responders, as compared with fewer than 10% from two single-blind placebo lead-in studies conducted in a similar time frame. Although all patients continued in the study (including placebo lead-in responders), the primary efficacy analysis prospectively excluded double-blind placebo lead-in responders. Analysis of postrandomization changes revealed that double-blind placebo lead-in responders, even when continuing to receive placebo treatment, maintained their response. At the study endpoint, these placebo lead-in responders had significantly lower severity scores than their counterparts who were not lead-in responders. The prospective removal of lead-in responders thus resulted in an increase in mean endpoint placebo group severity scores. This resulted in an increased drug-placebo treatment difference in one of the two studies but had no effect on the treatment difference in the other study.

Antidepressive Agents↗
PubMed2000

[Placebo effects and adverse effects in clinical trials].

BACKGROUND: It is well known that placebos evoke a variety of effects in the human body. It is less known that placebo medication can produce adverse drug reactions (ADRs). METHOD: The efficacy and, as the main topic, the tolerability were investigated from an international clinical data pool on placebo-controlled randomized multicenter studies of 5 different groups of indications. The therapeutic areas analyzed were neuropsychiatry (nimodipine, ipsapirone), cardiology (nisoldipine), metabolism (acarbose) and gastroenterology (hydrotalcit). RESULTS: The placebo efficacy was evident and varied not only in comparison to 5 indication groups analyzed, but also within them. Placebo showed for example hardly an effect on the symptomatology of stroke patients with a severe neurological deficit in comparison to verum while there was a 50% improvement in symptoms following placebo application in patients with a mild stroke. In angina patients exercise tolerance increased under placebo by 10% (time to onset of ST segment depression and symptoms of angina) while verum showed a 22% improvement. In diabetes placebo had no effect as compared to baseline and to a verum on blood glucose and HbA1C. ADRs could be observed under placebo treatment. The frequency and kind of placebo-induced ADRs varied also between the indication groups, i.e. typical CV side-effects were observed in CV controls. The placebo ADR profile was similar to the reference drug also. Some ADRs were reported even more frequently under placebo than under verum, like "dry mouth" in patients with general anxiety status. CONCLUSIONS: Placebo therapy is frequently effective and is not a "non-therapy". Placebo effects can be shown only by direct comparison with a "non-therapy". A placebo therapy is frequently accompanied by adverse drug reactions (ADRs) just as a verum therapy. Placebo ADRs are frequently illness- and verum-specific. Effects and ADRs of placebo therapy must be known, to judge the effect of verum medication in controlled clinical trials. The mechanisms of placebo effects are manifold (e.g. endorphine release, conditioned learning). Since placebo therapy outside of evidence-based medicine (use of drugs without proven efficacy = pseudoplacebos) may potentially also cause serious side effects, the use may not only be useless but also harmful.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of botulinum toxin type A (BoNT-A; BOTOX, Allergan, Inc.) for the prophylactic treatment of chronic daily headache (CDH). BACKGROUND: Several open-label and small controlled trials suggest that BoNT-A may be effective in the prophylactic treatment of headache. DESIGN AND METHODS: This was an 11-month, randomized double-blind, placebo-controlled study of BoNT-A for the treatment of patients aged 18 to 65 years old with 16 or more headache days per 30 days conducted at 13 North American study centers. Following a 30-day screening period and a 30-day, single-blind, placebo-response period to identify placebo responders, eligible patients from both the placebo responder and placebo nonresponder groups were injected with BoNT-A or placebo every 90 days and assessed every 30 days for 9 months, a period encompassing three treatment cycles. The primary efficacy measure was the change from baseline in the frequency of headache-free days in a 30-day period for the placebo nonresponder group at day 180, the chosen efficacy time point. The secondary efficacy measure was the proportion of patients with a decrease from baseline of 50% or more in the frequency of headache days per 30-day period for the placebo nonresponder group at day 180. The change from baseline in the frequency of headaches (per 30-day period), the proportion of patients with a decrease from baseline of 50% or greater in the frequency of headaches per 30-day period, acute medication use, and adverse events were also assessed. RESULTS: Of 571 patients assessed over the baseline period, 355 (mean age, 43.5 years; 300/355 [84.5%] female) were enrolled and randomized. At the end of the placebo run-in period, 279 patients (79%) were classified as placebo nonresponders and 76 patients (21%) as placebo responders. Subsequently, patients were randomized within each group to receive either BoNT-A or placebo. In the placebo nonresponder stratum, the mean number of headache-free days at baseline was 5.8 (+/-4.7) for BoNT-A- versus 5.5 (+/-4.7) for placebo-treated patients. At day 180, placebo nonresponders treated with BoNT-A had an improved mean change from baseline of 6.7 headache-free days per 30-day period compared to a mean change from baseline of 5.2 headache-free days for placebo-treated patients. The between-group difference of 1.5 headache-free days favored BoNT-A treatment, although the difference between the groups was not statistically significant. However, a statistically significant difference was observed at day 180 endpoint for the secondary efficacy measure. A significantly higher percentage of BoNT-A patients had a decrease from baseline of 50% or greater in the frequency of headache days per 30-day period at day 180 (32.7% vs. 15.0%, P=.027). Also, the mean change from baseline in the frequency of headaches per 30-day period at day 180 was -6.1 for BoNT-A patients vs. -3.1 for the placebo patients (P=.013). Only 4 of 173 BoNT-A patients (2.3%) discontinued the study due to adverse events. The majority of treatment-related adverse events were transient and mild to moderate in severity. CONCLUSIONS: BoNT-A treatment resulted in patients having, on average, approximately seven more (1 week) headache-free days compared to baseline. Although at the primary time point (day 180) the BoNT-A treatment resulted in a 1.5 between-group difference compared to placebo, this difference was not statistically significant. The treatment met secondary efficacy outcome measures, including the percentage of patients experiencing a 50% or more decrease in the frequency of headache days, in addition to statistically significant reductions in headache frequency. BoNT-A was also well tolerated in patients with CDH.

Adolescent↗
PubMedDate not supplied

Worsening of depressive symptoms prior to randomization in clinical trials: a possible screen for placebo responders?

A common practice in depression trials is to exclude patients whose depressive symptoms improve between Screen and Baseline evaluations under the assumption that they are more likely to respond to placebo. The present study investigated this contention by examining the relationship between pre-randomization changes in Hamilton depression rating scale (HAMD) scores to post-randomization placebo response and drug-placebo separation. Four randomized, double-blind, placebo-controlled trials (active medication=fluoxetine or paroxetine) were conducted in outpatients with Major Depressive Disorder using a novel design in which a depressive severity inclusion criterion (HAMD >/= 22) was utilized only at Screen. Patients with no change or minimal (1 point) improvement on the HAMD between Screen and Baseline had the lowest placebo response and the best drug-placebo separation. Patients with pre-randomization improvement of 2 points or greater had moderately higher placebo response and poorer drug-placebo separation. Patients who worsened between Screen and Baseline showed the highest placebo response and the poorest drug-placebo separation. There were no obvious differences in demographic variables between the groups which could account for the findings. In our original analyses 3/4 studies failed to show significant drug-placebo separation. When only patients with no change or pre-randomization improvement of 1 point were used in the analyses, 3/4 studies showed significant drug-placebo separation while the other study approached significance, p < 0.07. These results suggest that pre-randomization changes in HAMD scores may predict post-randomization placebo response and drug-placebo separation. Further, pre-randomization increases in HAMD scores (i.e., worsening) may be the best predictor of heightened placebo responding and poor drug placebo separation.

Adolescent↗
PubMed1999

The long-term effects of placebo in patients with chronic schizophrenia.

BACKGROUND: It has been hypothesized that placebo periods may increase long-term morbidity for patients with schizophrenia. In this study, the long-term effect of a placebo period was evaluated in a group of relatively treatment-refractory patients with chronic schizophrenia. METHODS: This retrospective study examined behavioral rating scores for 127 patients with chronic schizophrenia who were placed in a double-blind placebo study on the inpatient units of the National Institute of Mental Health Neuropsychiatric Research Hospital. Patients were rated daily with the Psychiatric Symptom Assessment Scale (PSAS), an extended and anchored version of the Brief Psychiatric Rating Scale (BPRS). At the end of the placebo phase, most patients were placed on haloperidol. Pre-placebo baseline PSAS ratings were compared with, first, discharge ratings and second, post-placebo ratings. To determine expected variability in the course of illness, patients in the placebo group were compared with patients hospitalized during the same time period, but who did not enter the placebo study. RESULTS: By discharge, ratings for placebo patients had returned to baseline. Post-placebo ratings were quite variable. Although many of the placebo patients had returned to baseline by day 3 of the post-placebo phase, others had not returned to baseline by post-placebo day 42. PSAS Total Scores for patients who left the study early were no different at baseline, placebo, or through post-placebo day 35 compared with patients who completed the study. CONCLUSIONS: The results indicate that given a sufficiently lengthy recovery period, patients with chronic schizophrenia who go through a placebo phase return to baseline, but that the speed with which they attain that recovery is highly variable.

Adult↗
PubMed2005

Two replicate randomized, double-blind, placebo-controlled trials of the time to onset of pain relief in the acute treatment of migraine with a fast-disintegrating/rapid-release formulation of sumatriptan tablets.

BACKGROUND: The gastric stasis that commonly accompanies migraine headache may impair absorption of conventional oral tablets in the stomach. A fast-disintegrating/rapid-release formulation of sumatriptan has been developed to enhance tablet disintegration and drug dispersion and potentially improve absorption. OBJECTIVE: Two studies were conducted comparing the time to onset of relief from moderate or severe migraine pain with the fast-disintegrating/rapid-release formulation of sumatriptan tablets 50 and 100 mg and placebo. METHODS: These were 2 identically designed randomized, double-blind, parallel-group studies. Sumatriptan 50 or 100 mg or placebo was taken on an outpatient basis to treat a single moderate or severe migraine attack. Using a personal digital assistant, patients recorded the time of dosing and the time at which pain severity reached none or mild (ie, pain relief) or none (ie, pain free) in real time so that the time to onset of relief could be measured as a continuous variable. Onset of relief was defined as the earliest time point at which a statistically significant difference in pain relief compared with placebo was achieved and maintained through 2 hours after dosing. Before dosing and at pre-determined time points after dosing, patients also provided an assessment of migraine pain as none, mild, moderate, or severe. At a clinic visit within 1 week after treatment of the migraine attack, patients were queried about adverse events. For each adverse event, investigators recorded whether study medication was considered the cause. Data analyses were undertaken for each study individually and, in post hoc analyses of the primary and key secondary end points, on pooled data from both studies. RESULTS: The 2 studies comprised 2696 patients: 902 received sumatriptan 50 mg, 902 received sumatriptan 100 mg, and 892 received placebo. Patients' mean age ranged from 40.2 to 40.8 years across treatment groups, and most patients were female (83%-87%) and white (92%-93%). In the analysis of pooled data, sumatriptan tablets provided significantly more effective pain relief compared with placebo as early as 20 minutes after dosing with the 100-mg dose and as early as 30 minutes after dosing with the 50-mg dose (P < or = 0.05). Similar results were observed for the individual studies: in study 1, sumatriptan tablets were significantly more effective than placebo at 25 minutes with the 100-mg dose and at 50 minutes with the 50-mg dose; in study 2, sumatriptan tablets were significantly more effective than placebo at 17 minutes for the 100-mg dose and at 30 minutes for the 50-mg dose (P < or = 0.05). In the pooled data, the cumulative percentages of patients with pain relief by 2 hours after dosing were 72% for the 100-mg dose and 67% for the 50-mg dose, compared with 42% for placebo (P < or = 0.001, both sumatriptan doses vs placebo). The cumulative percentages of patients with a pain-free response by 2 hours were 47% for the 100-mg dose, 40% for the 50-mg dose, and 15% for placebo (P < or = 0.001, both sumatriptan doses vs placebo). In the individual studies, significantly more patients receiving either sumatriptan dose were migraine free 2 hours after dosing and had sustained pain relief and a sustained pain-free response over 24 hours compared with placebo (P < or = 0.001, both sumatriptan doses vs placebo). The only drug-related adverse events reported in >2% of patients in any treatment group in either study were nausea (both studies: 3% sumatriptan 100 mg, 2% sumatriptan 50 mg, 1% placebo) and paresthesia (study 1: <1% sumatriptan 100 mg, <1% sumatriptan 50 mg, 0% placebo; study 2: 3% sumatriptan 100 mg, 1% sumatriptan 50 mg, <1% placebo). CONCLUSIONS: In these studies, sumatriptan tablets in a fast-disintegrating/rapid-release formulation were effective for the acute treatment of moderate to severe migraine pain, were generally well tolerated, and achieved an onset of pain relief as early as 20 minutes for 100 mg and as early as 30 minutes for 50 mg.

Adult↗
PubMed1999

A study to test the effectiveness of placebo Reiki standardization procedures developed for a planned Reiki efficacy study.

Reiki is one type of alternative therapy that is increasing in popularity. It is advocated by its practitioners as a precise method for connecting universal life energy with the body's innate process of healing through hands-on techniques. The claim of Reiki practitioners is that Reiki reduces a variety of physical problems and improves psychospiritual well-being. There are abundant anecdotal records that support the previous claim, and a few pioneer scientific studies are starting to emerge. Although the Reiki research in totality supports the anecdotal records, the absence of randomized and placebo-controlled trials precludes the interpretation of the outcomes as resulting from specific effects as opposed to placebo effects plus natural history. Authorities in the field indicate that researchers interested in placebo-controlled studies should have the placebo treatment look exactly like the real intervention in every respect. Because no studies could be found in the literature that tested standardization procedures for real and placebo Reiki, the decision was made to conduct one. The purpose of this study was to test the standardization procedures developed by our research team for placebo Reiki, before going ahead and conducting our planned full-scale randomized and placebo-controlled Reiki efficacy study. This study used a 4-round, crossover experimental design in which 20 blinded subjects (12 students, 4 breast cancer survivors, and 4 observers) were exposed to a combination of 2 interventions (Reiki plus Reiki, or placebo plus placebo, or Reiki plus placebo, or placebo plus Reiki); and were then asked to evaluate the interventions using a self-administered questionnaire. The blinded observers were used in round number 4. Two real Reiki practitioners in the Usui system were chosen first, then 2 placebo practitioners who closely resembled them were recruited. The placebo practitioners were trained in Reiki by the study Reiki Master and the principal investigator, but were not initiated. The belief in Reiki is that only practitioners that are initiated could give Reiki, thus making it possible to have a placebo arm in efficacy studies. The findings of the study indicate that the developed standardization procedures were successful because none of the final participants in round 4 (4 breast cancer patients and 4 observers) could differentiate between the identity of placebo and Reiki practitioners. The qualitative comments expressed by the participants further con-firmed the quantitative data. It was concluded based on these findings that it is safe to go ahead and conduct the planned randomized 3-arm Reiki efficacy clinical trial. It is recommended that scholars interested in Reiki research could incorporate our techniques to strengthen their designs by adding a placebo arm.

Acupressure↗
PubMed1996

Repeated measurements of non-invasive ambulatory blood pressure: distinction between reproducibility and the proper effect of placebo.

OBJECTIVE: To determine whether non-invasive ambulatory blood pressure is more reproducible and less affected by the placebo treatment than are clinic blood pressure measurements. METHOD: Thirty-four essential hypertensive outpatients were randomly allocated after a 4-week preselection period in two groups in a cross-over study design. One group received placebo for 4 weeks while the other formed the control group (reproducibility), then the treatments were exchanged for another 4 weeks. Clinic and ambulatory blood pressures were measured at three different times for each patient, namely bnefore the random allocation to groups and at the end of each period, using a mercury sphygmomanometer and 24 h non-invasive ambulatory blood pressure monitoring. RESULTS: Administration of placebo was accompanied by a significant reduction in systolic and diastolic clinic blood pressures (by 3.4+/-13 and 3.6+/-8 mmHg, respectively), but not in 24 h, daytime and night-time blood pressures. Circadian hourly blood pressure and heart rate curves were virtually superimposable. In the 13 placebo responder patients selected on the basis of clinic blood pressure, placebo decreased the clinic blood pressure and also reduced systolic and diastolic ambulatory blood pressures, mainly during the day period (by 5.2+/-6.2 and 4.89+/-7.8 mmHg, respectively). This effect is specific and related to the placebo administration because repetition of the measurements without any treatment showed no significant difference. To characterize at baseline the placebo responder patients, comparison with the non-placebo responders showed lower baseline values of ambulatory systolic blood pressure recorded during 24 h daytime and night-time in the placebo responder group. CONCLUSION: The 24 h ambulatory blood pressure average is not affected by placebo in the present group of patients but that a placebo effect occurs mainly during the daytime in patients who decreased their clinic blood pressure under placebo (placebo responders); the placebo-induced reduction in blood pressure is related to a specific effect of placebo and is independent from any alerting reaction or reproducibility hypothesis. This study clearly indicates the necessity of including placebo and ambulatory blood pressure monitoring in the therapeutic and pharmacological trials of antihypertensive drugs.

Journal Article↗
PubMed2006

The placebo effect for gastroenterology: tool or torment.

Placebo generally has a negative connotation both in clinical practice and in clinical trials. In this report the nature of placebo is explored in general and in relation to gastrointestinal diseases. The goodness of placebo is highlighted. PubMed was searched for articles and commentaries on placebo and for systematic reviews on placebo. Selected placebo-controlled trials in gastroenterology were reviewed. There are 5 key components impacting the placebo response: patient characteristics, practitioner characteristics, practitioner-patient interaction, the nature of the illness being treated, and the treatment being applied and the setting in which it is applied. There are also a number of factors that constitute the placebo response and likely all apply to some extent. These include the natural history of the condition, a regression to the mean (accounting for fluctuation in measurements over time), other time effects (ie, patient learning to cope, practitioner gaining expertise), unidentified parallel interventions (ie, change in habits or exogenous stress), the placebo effect of the administered agent being compared with placebo, and the physiologic effects of the placebo. In summary, there are positive aspects to placebo. Clinicians treating patients with gastrointestinal diseases can harness aspects of the placebo response to improve patient outcomes. Clinical trial planners can harness aspects of the placebo response to design disease-specific trials that can minimize the placebo response.

Animals↗
PubMed1999

Placebo medication use in patient care: a survey of medical interns.

The use of placebo medication, long recognized by clinicians, often has serious practical implications, such as patient deception. Past evidence has suggested that resident physicians tend to misuse placebo medication. Interns from two consecutive years of a residency program were surveyed anonymously to assess their knowledge and use of placebos. Of the 74 interns surveyed, 44 (59%) were familiar with placebo use in patient care. Fifty percent of these interns familiar with placebo use had learned about placebos from another physician. All interns who had learned about placebos during their internships had learned from another physician, whereas interns who had gained their knowledge of placebos as medical students were as likely to have learned from the medical literature as they were to have learned from a physician (P = 0.027). Interns aware of placebo use were more likely to consider placebo administration for suspected, factitious pain (P = 0.022). The present study uncovered no relationship between interns' estimations of placebo efficacy and the utility they attributed to placebos in assessing a complaint of pain. This suggests that conceptual inconsistencies underlie their use of placebos. Interns often learn of placebos as medical students and are influenced by physician-mentors. Placebo use in patient care is an area of attention for medical educators.

Health Knowledge, Attitudes, Practice↗
PubMed2002

The contribution of suggestibility and expectation to placebo analgesia phenomenon in an experimental setting.

This study reports how placebo analgesia was produced by conditioning whereby the intensity of electric stimulation was surreptitiously reduced in order to examine the contribution of psychological factors of suggestibility and expectancy on placebo analgesia. This strategy was used in order to manipulate expectancy for pain reduction. The magnitudes of the placebo effects were estimated after a manipulation procedure and during experimental trials in which stimulus intensities were reset to original baseline levels. Individual differences in suggestibility, verbal expectancy for drug efficacy and manipulation procedure for pain reduction were tested as possible mediators of placebo analgesia. The following dependent variables were measured: (a) subjective expectancy for drug efficacy in pain relief, (b) expected pain intensity and unpleasantness, (c) concurrent pain intensity and unpleasantness and (d) remembered pain intensity and unpleasantness. Statistically significant placebo effects on sensory and affective measures of pain were obtained independently of the extent of the surreptitious lowering of stimulus strength during manipulation trials. The pairing of placebo administration with painful stimulation was sufficient to produce a generalized placebo analgesic effect. However, verbal expectancy for drug efficacy and individual differences in suggestibility were found to contribute significantly to the magnitude of placebo analgesia. The highest placebo effect was shown by the most pronounced reductions in pain ratings in highly suggestible subjects who received suggestions presumed to elicit high expectancy for drug efficacy. The results also demonstrated that placebo effects established on remembered pain were at least twice as great as those obtained on concurrent placebo effects. This was mainly because baseline pain was remembered as being much more intense than it really was. Moreover, remembered placebo effects, like the concurrent placebo effects, were highly correlated with expected pain scores obtained just after manipulation trials. These results indicate that multiple factors contribute to the placebo effect, including suggestibility, expectancy and conditioning, and that the judgement of placebo analgesia is critically determined by whether pain relief is assessed concurrently or after treatment.

Adult↗
PubMed1999

Prospective follow-up and pulmonary functions from a placebo-controlled randomized trial of ribavirin therapy in respiratory syncytial virus bronchiolitis. Ribavirin Study Group.

OBJECTIVE: To determine any long-term differences in adverse effects and pulmonary function between infants with respiratory syncytial virus and lower respiratory tract infection who were treated with ribavirin and a control group. STUDY DESIGN: Long-term follow-up included enumeration of episodes of respiratory illness, wheezing, and pneumonia and, ultimately, administration of pulmonary function tests (PFTs). Pulse oximetry was done at each visit. During the first 3 years we conducted follow-up in the fall and spring. In years 4 and 5 we conducted 1 visit per year. During years 5 through 7 we conducted PFTs, and starting with year 7 a methacholine chloride challenge was done if forced expiratory volume in 1 second (FEV1) was greater than 70% of predicted value. RESULTS: We prospectively enrolled (December 1983 to February 1985) in a randomized trial of ribavirin vs placebo children who were previously healthy, were premature, or had chronic pulmonary disease. One pulmonologist (R.F.; blinded) scored and interpreted the results of the PFTs. We studied 42 patients aged 1 to 33 months; 2 patients died (1 receiving ribavirin and 1 receiving placebo) and 5 patients receiving placebo were lost to follow-up; 35 patients (24 taking ribavirin and 11 taking placebo) attended 212 visits. Four patients were premature (3 in the ribavirin and 1 in the placebo group), and 3 of these had bronchopulmonary dysplasia (2 in the ribavirin and 1 in the placebo group). From years 1 to 3, there was more reactive airway disease, wheezing, and pneumonia in the placebo than in the ribavirin group (mean score, 22.3 for 12 placebo-treated patients vs. 15.8 for 23 ribavirin-treated patients; P = .07 by Kruskal-Wallis test); for all years, it was 22.0 for 11 placebo-treated patients vs. 16.0 for 22 ribavirin-treated patients (P = .10). After informed consent was given, 19 patients completed PFTs (13 receiving ribavirin and 6 receiving placebo); 7 of 13 ribavirin-treated patients (53%) had normal or mild PFT results vs. 0 of 6 placebo-treated patients (P = .04 by Fisher exact test). On methacholine challenge (7 ribavirin-treated patients and 5 placebo-treated patients), there was more reactivity in the placebo vs. the ribavirin group (exact P = .07). Scoring done by weighting for severity for 19 patients (13 ribavirin-treated patients and 6 placebo-treated patients) (even after correcting for asthma) showed a significant difference in favor of previously ribavirin-treated patients (exact P = .02). CONCLUSIONS: No outward effects were identified from ribavirin exposure. We observed no increase in reactive airway disease, wheezing, and pneumonia in the ribavirin compared with the placebo group. Weighted severity scores suggest long-term beneficial effect of ribavirin therapy; however, larger numbers should be evaluated.

Antiviral Agents↗
PubMed2002

Effects of transdermal estradiol delivered by a matrix patch on bone density in hysterectomized, postmenopausal women: a 2-year placebo-controlled trial.

This 2-year, double-masked, randomized, placebo-controlled trial was designed to evaluate the safety and efficacy in preventing bone loss in postmenopausal women of two doses of transdermal 17betaestradiol (estradiol) delivered by a matrix patch, compared with placebo. One hundred and sixty healthy, hysterectomized postmenopausal volunteers aged 40-60 years with serum estradiol levels < 20 pg/ml were started on treatment at four centers in The Netherlands. Every 6 months, bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine, non-dominant wrist and left hip, and markers of bone turnover were assessed in urine and serum. The treatment arms were: estradiol, 100 microg/day (E-100, n = 53), oestradiol, 50 microg/day (E-50, n = 54), placebo (P-100, placebo to E-100, n = 27 or P-50, placebo to E-50, n = 26). Treatment was continued for up to 2 years. After 24 months, BMD of the lumbar spine in the E-100 group differed by 7.7% [5.8-9.5%] (mean [95% confidence interval]) from the placebo group and showed a mean (s.e.m.) increase in BMD from baseline of 5.9% (0.69%). For the E-50 group the difference compared with placebo was 6.2% [4.4-8.0%] and the absolute increase was 4.5% (0.62%); in the placebo group, the absolute change was -2.3% (0.48%). In the total wrist, the changes were: E-100: difference compared with placebo 2.5% [1.5 3.6%], absolute increase 0.6% (0.3%); E-50: difference compared with placebo 2.9% [1.8-3.9%], absolute increase 0.7% (0.25%); and absolute change on placebo: -2.5% (0.35%). In the total hip, the changes were: E-100: difference compared with placebo 3.7% [2.2-5.2%], absolute increase 2.8% (0.5%); E-50: difference compared with placebo: 3.2% [1,8-4.7%], absolute change 2.4% (0.36%); and absolute change on placebo -1.4% (0.66%). Three markers of bone turnover--serum bone-specific alkaline phosphatase, serum osteocalcin and urinary CTX--fell significantly during the trial. Breast pain was reported by 8% of women on placebo, by 6% of women on E-50 and by 17% of women on E-100. Estradiol delivered by the E-50 matrix patch effectively reversed bone loss in hysterectomized postmenopausal women with few side-effects. The marginal additional gain in BMD with the higher dose may be offset by a more important side effect profile.

Administration, Cutaneous↗
PubMed2003

Efficacy of a low-dose regimen of cyclobenzaprine hydrochloride in acute skeletal muscle spasm: results of two placebo-controlled trials.

BACKGROUND: Cyclobenzaprine hydrochloride is a muscle relaxant that is effective in improving muscle spasm, reducing local pain and tenderness, and increasing range of motion in acute, painful musculoskeletal conditions. Sedation is the most common adverse event associated with its use at the usual dosage of 10 mg TID. Studies in healthy adults suggest that a lower dose may produce less sedation. Because cyclobenzaprine's duration of action is 4 to 6 hours, reducing the dosing frequency to 10 mg BID would create a potentially painful untreated interval between doses. The alternative is administration of a lower dose (eg, 5 or 2.5 mg) TID. OBJECTIVE: These studies were designed to assess the efficacy and tolerability of cyclobenzaprine 2.5, 5, and 10 mg TID compared with placebo in patients with acute musculoskeletal spasm. METHODS: In 2 randomized, double-blind, placebo-controlled, parallel-group trials conducted at primary care centers in the United States, adult patients with acute painful muscle spasm of the lumbar or cervical region were randomly assigned to receive treatment with 2.5, 5, or 10 mg cyclobenzaprine TID or placebo for 7 days (study 1: cyclobenzaprine 5 or 10 mg TID or placebo; study 2: cyclobenzaprine 2.5 or 5 mg TID or placebo). The primary efficacy measures were patient-rated clinical global impression of change, medication helpfulness, and relief from starting backache. Neither study included a nonsteroidal anti-inflammatory drug (NSAID) as an active control. Although physicians frequently prescribe an analgesic or NSAID in addition to cyclobenzaprine, these studies were not designed to assess whether adding cyclobenzaprine provides a benefit over that of an analgesic. RESULTS: One thousand four hundred five patients (737 study 1; 668 study 2), two thirds with low back pain and one third with neck pain, were randomized to treatment. Their mean age was 42 years, and approximately 89% were white. In both studies, patients receiving cyclobenzaprine 5 or 10 mg had significantly higher mean scores on the primary efficacy measures compared with those receiving placebo (study 1-P</=0.001 cyclobenzaprine 5 and 10 mg vs placebo, all measures at visits 2 and 3; study 2-P</=0.03 cyclobenzaprine 2.5 mg vs placebo, relief from starting backache on day 3 only; cyclobenzaprine 5 mg vs placebo, patient-rated clinical global impression of change, medication helpfulness, and relief from starting backache at visit 3 or day 7 only). On day 7, significantly more patients receiving cyclobenzaprine 5 or 10 mg reported relief compared with placebo recipients (P < 0.05 all cyclobenzaprine groups vs placebo). Onset of relief was apparent within 3 or 4 doses of the 5-mg regimen. In the subanalysis of the proportion of responders in the pooled 5-mg groups who did and did not report somnolence, a meaningful treatment effect was observed on all primary efficacy variables in patients who did not report somnolence, suggesting that efficacy was independent of sedation. Cyclobenzaprine was well tolerated. Somnolence and dry mouth, the most common adverse effects, were mild and dose related. Overall, >/= 1 adverse event was reported in 54.1%, 61.8%, and 35.4% of patients receiving cyclobenzaprine 5 or 10 mg or placebo, respectively, in study 1 and by 43.9%, 55.9%, and 35.4% of patients receiving cyclobenzaprine 2.5 or 5 mg or placebo, respectively, in study 2. Adverse events were the primary reason for discontinuation of treatment in the cyclobenzaprine 5- and 10-mg groups in both studies. In study 2, ineffectiveness of therapy was the main reason for discontinuation of therapy in the group receiving cyclobenzaprine 2.5 mg. CONCLUSIONS: Cyclobenzaprine 2.5 mg TID was not significantly more effective than placebo. The cyclobenzaprine 5- and 10-mg TID regimens were associated with significantly higher mean efficacy scores compared with placebo. Cyclobenzaprine 5 mg TID was as effective as 10 mg TID, and was associated with a lower incidence of sedation.

Acute Disease↗
PubMed1996

Fluconazole vs itraconazole-flucytosine association in the treatment of esophageal candidiasis in AIDS patients. A double-blind, multicenter placebo-controlled study. The Candida Esophagitis Multicenter Italian Study (CEMIS) Group.

STUDY OBJECTIVE: To assess the role and the therapeutic efficacy of fluconazole and itraconazole-flucytosine association compared with placebo, in the treatment of endoscopically diagnosed esophageal candidiasis in a selected population of AIDS patients. DESIGN: Double-blind, placebo-controlled study. SETTING: University Hospitals and AIDS Centers. PATIENTS: Eighty-five HIV-positive patients (53 men and 32 women; mean age, 28 years) at first episode of esophageal candidiasis diagnosed by endoscopy (grades I to II of Kodsi's endoscopic classification and grades I to IIa of Barbaro's clinical classification). All the patients selected for the study provided informed consent. INTERVENTIONS: The patients have been double blindly randomized in 3 groups of patients in relation to pharmacologic therapy: (1) the patients of the first group (n = 30) received fluconazole (3 mg/kg daily orally) and placebo (100 mg/kg/daily orally); (2) the patients of the second group (n = 30) received itraconazole (3 mg/kg daily orally) and flucytosine (100 mg/kg daily orally); and (3) the patients of the third group (n = 25) received placebo (3 mg/kg daily orally) and placebo (100 mg/kg daily orally). After 2 weeks of treatment, the patients previously randomized to receive placebo only were double blindly randomized to receive fluconazole+placebo or itraconazole+flucytosine. To evaluate the efficacy of pharmacologic therapy, clinical and endoscopic examinations were performed at weeks 2 and 4 and at the end of follow-up (3 months). RESULTS: At week 2, endoscopic cure (grade 0) was observed in 68.9% of the fluconazole+placebo group and in 72.4% of the itraconazole+flucytosine group (relative risk, 0.95; 95% confidence interval [CI], 0.68 to 1.33; p = 0.772); partial endoscopic response (grade I) was observed in 22.7% of the placebo group. Clinical cure (grade 0) was observed in 75.8% of fluconazole+placebo group and in 72.4% of itraconazole+flucytosine group (relative risk, 1.05; 95% CI, 0.77 to 1.42; p = 0.764), with a difference statistically significant for both treatments in comparison to placebo group (p < 0.001). Partial clinical response (grade I) was observed in 27.3% of the placebo group. At the end of follow-up, endoscopic cure was observed in 89.8% of the fluconazole+placebo group and in 94.8% of the itraconazole+flucytosine group (relative risk, 0.97; 95% CI, 0.83 to 1.08; p = 0.695). Clinical cure was observed in 94.8% of the fluconazole+placebo group and in 97.3% of the itraconazole+flucytosine group (relative risk, 0.97; 95% CI, 0.89 to 1.07; p = 0.981). CONCLUSIONS: The results of this study have demonstrated that both fluconazole and itraconazole+flucytosine association are efficacious in short-term treatment of esophageal candidiasis in AIDS patients with a statistically significant difference in comparison to placebo. Both therapeutic regimens demonstrated a good therapeutic efficacy, without statistically significant difference, between them, in the rate of endoscopic and clinical cure. Itraconazole+flucytosine association may represent an alternative therapeutic regimen for patients with fluconazole-resistant Candida esophagitis.

AIDS-Related Opportunistic Infections↗
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↗