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PubMed2004

The biochemical bases of the placebo effect.

A great variety of medical conditions are subject to the placebo effect. Although there is mounting evidence to suggest that the placebo effect is related to the expectation of clinical benefit, little is still known about the biochemical bases underlying placebo responses. Positron emission tomography studies have recently shown that the placebo effect in Parkinson's disease, pain, and depression is related to the activation of the limbic circuitry. The observation that placebo administration induces the release of dopamine in the ventral striatum of patients with Parkinson's disease suggests a link between the placebo effect and reward mechanisms. In addition to Parkinson's disease, the placebo-reward model may also apply to other disorders. However, the relative contribution of the different neurotransmitters and neuropeptides that are known to be involved in modulating the activity of the limbic system may be disease-specific. Thus, while the placebo-induced clinical benefit observed in Parkinson's disease would mostly reflect the release of dopamine in the dorsal striatum, the activation of opioid and serotonin pathways could be particularly implicated in mediating placebo responses encountered in pain and depression, respectively.

Biochemical Phenomena↗
PubMed1983

Partial antagonism of placebo analgesia by naloxone.

Thirty subjects were given a placebo (intravenous saline), which was described as a known pain killer, once a week for 3 consecutive weeks. Experimental ischemic arm pain was produced prior to the placebo and again 1 h later. In a double blind procedure, half of the subjects received 10 mg of naloxone after placebo; the remaining subjects received naloxone vehicle. In addition to the placebo session, there were control and naloxone sessions each week to determine the normal changes in pain and the effect of naloxone on the pain, respectively, when no placebo was given. Significant placebo-induced analgesia was demonstrated, and a group of consistent placebo responders was identified. Although naloxone alone had no effect on the experimental pain, naloxone diminished the analgesic effectiveness of the placebo, suggesting that endogenous opioids are involved in producing placebo-induced analgesia.

Adult↗
PubMed2004

The effect of previous treatment experience and incontinence severity on the placebo response of stress urinary incontinence.

OBJECTIVE: The placebo response associated with stress urinary incontinence (SUI) is sizeable but poorly understood. The aim of this study was to examine the relationship between previous treatment experience and baseline urinary incontinence severity with placebo response. STUDY DESIGN: Nine hundred twenty-one women ages 24 to 83 years received placebo in 4 12-week randomized trials evaluating duloxetine for SUI in 16 countries in Africa, Australia, Europe, and North and South America. Incontinence episode frequency (IEF) was calculated before and after randomization with entries from subject-completed real-time diaries. At baseline, subjects reported on their experience with previous continence surgery and with current pelvic floor muscle training (PFMT) with standardized questions. Analyses included Pearson correlations and the Wilcoxon two-sample test, and were based on intent-to-treat principles. RESULTS: The placebo group averaged 17 IEF per week at baseline. Fifty-five percent of placebo-treated subjects averaged >or=14 IEF/wk, 11.8% had previous continence surgery, and 16.5% currently performed PFMT. The overall median decrease in IEF with placebo was 33%, but ranged from 11% to 57% for individual countries. The placebo response was lower in women with more severe SUI (29.6% vs 36.4%, P=.07), in those who had previous continence surgery (25.0% vs 33.3%, P=.26), and for those using PFMT (23.6% vs 33.3%, P=.02). There was a significant positive correlation (rho=.44; P <.0001) between the placebo response within a country and that country's use rate for PFMT. CONCLUSION: Treatment naivete and less severe incontinence are associated with an increased placebo response in clinical trials for stress urinary incontinence, although this difference was statistically significant only for PFMT.

Adrenergic Uptake Inhibitors↗
PubMed2006

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

OBJECTIVE: The efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy were assessed in patients with type 2 diabetes and inadequate glycemic control (glycosylated hemoglobin [HbA(1c)] > or =7% and < or =10%) while receiving a stable dose of pioglitazone. METHODS: This was a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel group study in patients aged > or =18 years (ClinicalTrials. gov NCT00086502). At screening, all patients began a diet/exercise program that continued throughout the study period. Patients taking antihyperglycemic therapy other than pioglitazone underwent a washout of this therapy and entered an 8- to 14-week open-label pioglitazone dose-titration/stabilization period. Patients with an HbA(1c) > or =7% and < or =10% at the end of this period entered a 2-week, single-blind, placebo run-in period (total duration of run-in period, up to 21 weeks). Patients who had been receiving pioglitazone monotherapy (30 or 45 mg/d) and had an HbA(1c) > or =7% and < or =10% entered the 2-week, single-blind, placebo run-in period directly. Thus, at the time of randomization, all patients were receiving ongoing pioglitazone (30 or 45 mg/d). Patients were randomized in a 1:1 ratio to receive sitagliptin 100 mg once daily or placebo for 24 weeks. The primary efficacy end point was the change from baseline in HbA(1c) at week 24. Secondary efficacy end points included the change from baseline in fasting plasma glucose (FPG), insulin, and proinsulin; the Homeostasis Model Assessment beta-cell function and insulin-resistance indexes; the proinsulin/ insulin ratio; the Quantitative Insulin Sensitivity Check Index; the percent changes from baseline in selected lipid parameters; the proportion of patients meeting the American Diabetes Association HbA(1c), goal of <7.0%; the proportion of patients requiring metformin rescue therapy; and the time to the initiation of rescue therapy. RESULTS: One hundred seventy-five patients were randomized to receive sitagliptin, and 178 were randomized to receive placebo. The mean (SD) baseline HbAlc value was 8.1% (0.8) in the sitagliptin group and 8.0% (0.8) in the placebo group. After 24 weeks, sitagliptin added to pioglitazone therapy was associated with significant reductions compared with placebo in HbA(1c) (between-treatment difference in least squares [LS] mean change from baseline. -0.70 %; 95 % CI, -0.85 to -0.54; P < 0.001) and FPG (-17.7 mg/dL; 95% CI, -24.3 to -11.0; P < 0.001). Mean HbA(1c) values at end point were 7.2% (0.9) and 7.8% (1.1) in the respective treatment groups, and the proportions of patients reaching a target HbA(1c) of <7.0% were 45.4% and 23.0% (P < 0.001). Significant reductions in fasting serum proinsulin levels and the proinsulin/insulin ratio were seen with sitagliptin treatment compared with placebo (both, P < 0.01). Sitagliptin was generally well tolerated, with no increased risk of hypoglycemia compared with placebo (2 vs 0 patients, respectively).

Aged↗
PubMed2006

Double-blind, placebo-controlled homeopathic pathogenetic trials: symptom collection and analysis.

BACKGROUND: Homeopathic pathogenetic trials (provings) are fundamental to homeopathy. Since most of the data from available provings have not been statistically evaluated, it is unclear how specific reported symptoms are and how they differ from those reported by people taking placebo. METHOD: We combine and analyse data from two different homeopathic pathogenic trials--including 10 and 11 provers, respectively, and both including 30% placebo-to test the null hypothesis that there is no significant difference between the number of symptoms in placebo and verum groups. RESULTS: The principal results were: Placebo reported less symptoms than verum groups. Symptom distribution according to predefined classes (common symptoms increased in intensity and/or duration-, cured, old, new and exceptional) was statistically different between placebo and verum group at a high level of significance (P<0.001). Compared to verum, placebo provers reported less new and old but more common (increased in duration or intensity) symptoms. Within repertory categories, other differences were detected. The two groups differ in terms of the duration of each symptom and kinetics of symptoms: most symptoms were more persistent in verum than in placebo groups and verum provers recorded a decreasing number of symptoms with time. Placebo provers did not show such a temporal pattern. CONCLUSIONS: If confirmed by other studies these results would demonstrate the non-equivalence between homeopathic medicines in high dilution and placebo and contribute to the improvement of proving methodology and evaluation.

Double-Blind Method↗
PubMed2005

A controlled trial of placebo versus real acupuncture.

UNLABELLED: We sought to determine whether a novel method of placebo acupuncture can be differentiated by subjects from real acupuncture treatment. A single-blind, randomized, controlled clinical trial with an independent observer was performed. Forty-nine healthy subjects over the age of 18 years were randomly assigned to one of 2 experimental groups: 24 subjects received real acupuncture, and 25 subjects received placebo acupuncture. Placebo acupuncture was performed by administering a blunted acupuncture needle through a foam pad at the Large Intestine 4 acupoint. The blunted needle touched but did not penetrate the skin. Real acupuncture was performed by administering an acupuncture needle through a foam pad at the Large Intestine 4 acupoint. The needle pricked and penetrated the skin to a depth of 10 to 20 mm. A simple questionnaire followed, asking whether the subject believed they received real or placebo acupuncture. Twenty-two (88%) of the 25 subjects who received placebo acupuncture believed they received real acupuncture. Nineteen (79.2%) of the 24 subjects who received real acupuncture correctly determined they received real acupuncture. The Fisher exact test showed an insignificant difference between real and placebo acupuncture treatments (P = .463). Subjects were not able to differentiate between real or placebo acupuncture, thereby validating this novel method of administering placebo acupuncture as a good control for acupuncture-naive patients. PERSPECTIVE: The method of placebo acupuncture herein described is a valid control for acupuncture research involving acupuncture-naive patients.

Acupuncture Analgesia↗
PubMed2004

Uncovering the hidden placebo effect in deep-brain stimulation for Parkinson's disease.

OBJECTIVE: To determine the magnitude of the placebo effect in deep-brain stimulation (DBS) for Parkinson's disease (PD). BACKGROUND: The placebo effect in PD is related to the expectation of clinical benefit. Changes in expectation occurring in DBS crossover studies can be used to estimate the associated placebo effect. For example, the response to active-DBS is predicted to be greater in patients who have previously experienced the effect of placebo-DBS than in those without such an experience. METHODS: Data were obtained by searches of Medline and PubMed using three keywords: Parkinson's disease, deep-brain stimulation, and crossover study. Between-group comparisons of the effect of active-DBS were performed by t-test and analysis of covariance. RESULTS: Data on 126 PD patients were available for analysis. These patients participated in a multicenter, two-period, placebo-controlled crossover study on the efficacy of DBS for PD. As predicted, active-DBS was found to be more effective when preceded by placebo-DBS (i.e. in the high expectation group) than when not (i.e. in the lower expectation group). The estimated magnitude of the placebo effect in DBS was equivalent to 39% of the magnitude of the effect of active-DBS. CONCLUSIONS: There is a prominent placebo effect associated with DBS in PD. Crossover studies may be useful for estimating the placebo effect in other medical conditions.

Analysis of Variance↗
PubMed1997

A randomized double-blind placebo controlled study of azelastine nasal spray in children with perennial rhinitis.

One hundred and twenty five children (median age 8.71 years) suffering from perennial allergic rhinitis were treated in a randomized, double-blind, parallel group study comparing azelastine nasal spray 0.14 mg/nostril twice daily (0.56 mg/day) and placebo nasal spray. Medication was given for a period of 6 weeks which followed a 2 week placebo washout period in all patients. Subjects were aged between 5 and 12 and were skin prick positive to either house dust mites and/or cat or dog dander. Concomitant anti allergic treatment was not permitted during the study. Severity of rhinitis symptoms was scored daily by the child or his/her parents on a diary card using a visual analogue scale (VAS) for each evaluated symptom: 0, absent-100, could not be worse. Mean weekly scores were calculated. Symptoms evaluated were: sneezing, nasal blockage, nasal itch and rhinorrhea. In addition, at each clinic visit the investigator evaluated symptoms using a verbal score of 0, no symptom-3, severe. Compared to the baseline, for each of the six study weeks, the reduction in the VAS scores for all four symptoms was statistically greater for the azelastine group compared to the placebo group. The investigator's assessment at clinic visits bore out these results. Both azelastine nasal spray and placebo were well tolerated, no serious adverse events were reported. During the treatment phase of the study a total of 36 adverse events were reported by 25 patients (azelastine 10, placebo 15). The most frequently occurring events were pharyngitis (azelastine 5, placebo 3), cough (azelastine 3, placebo 1) and bronchitis (azelastine 1, placebo 3). In conclusion, azelastine has been shown to be effective in the treatment of perennial rhinitis in children aged 5-12 years and to be superior to placebo in the relief of all symptoms assessed, namely sneezing, nasal blockage, nasal itch and rhinorrhea.

Child↗
PubMed1998

A randomized, double-blind, placebo-controlled, parallel-group, multicenter trial of four doses of tasosartan in patients with essential hypertension. Tasosartan Investigator's Group.

Tasosartan, a new, long-acting, nonpeptide angiotensin II receptor antagonist was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial at 21 sites in the United States and Canada. After a 2-week, placebo washout qualification period, 278 patients (187 men/91 women) with a mean age of 53.4+/-9.5 years (range, 30 to 70 years) and a baseline sitting diastolic blood pressure (DBP) of 95 to 114 mm Hg were randomly assigned to receive placebo (n = 56), or 10 mg (n = 57), 30 mg (n = 55), 100 mg (n = 55), or 300 mg (n = 55) tasosartan for 4 weeks. The treatment period was followed by a 2-week washout period. Ambulatory blood pressure (BP) monitoring was performed at the end of the placebo washout period and after at least 4 weeks of double-blind treatment. Clinically significant placebo-adjusted differences in baseline sitting systolic blood pressure (SBP)/DBP were observed in the 10 mg (5/3 mm Hg), 30 mg (5/4 mm Hg), 100 mg (10/7 mm Hg) and 300 mg (10/7 mm Hg) dose groups (P < .05). A dose-response relationship (P < .001) was observed within 1 to 2 weeks of treatment initiation and was maintained throughout the double-blind period. Discontinuation of tasosartan therapy was not associated with rebound hypertension. Moreover, significant (P < .05) placebo-adjusted differences in ambulatory SBP/DBP and a significant dose-response relationship (P < .001) were observed with all tasosartan dosages during the 24-h, daytime, and nighttime periods. Placebo-adjusted trough-to-peak ratios ranged from 87% to 100% for ambulatory SBP and 64% to 81% for DBP. In general, no significant differences were observed between the tasosartan treatment groups and the placebo group in the incidence of adverse events. Headache incidence was significantly lower in the 300 mg dose group than the placebo group. In conclusion, tasosartan at dosages of 10, 30, 100, or 300 mg given once daily produced a significant and dose-related reduction in both clinic and ambulatory BP that was maintained over the 24-h period. Tasosartan was generally well tolerated.

Adult↗
PubMed2001

Randomized, placebo-controlled, double-blind study of a cytomegalovirus-specific monoclonal antibody (MSL-109) for prevention of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation.

MSL-109 is a monoclonal antibody specific to the cytomegalovirus (CMV) glycoprotein H with high neutralizing capacity. In a prospective, randomized, double-blind study, allogeneic hematopoietic stem cell transplantation (HSCT) recipients with positive donor and/or recipient serology for CMV before transplantation received either 60 mg/kg MSL-109 (n = 59), 15 mg/kg MSL-109 (n = 60), or placebo (n = 60) intravenously every 2 weeks from day -1 until day 84 after transplantation. CMV pp65 antigenemia, CMV-DNA load in plasma, and viremia by culture were tested weekly. Primary end points were development of pp65 antigenemia at any level and/or viremia for which ganciclovir was given. There was no statistically significant difference in CMV pp65 antigenemia or viremia among patients in the 60-mg group (pp65 antigenemia, 47%; viremia, 15%), the 15-mg group (52%; 23%), and the placebo group (45%; 17%). There was also no difference in maximum levels of pp65 antigenemia, time to clearance of pp65 antigenemia after start of ganciclovir, CMV disease, invasive bacterial and fungal infections, time to neutrophil and platelet engraftment, acute graft-versus-host disease, days of hospitalization, and overall survival rate among the 3 groups. However, a subgroup analysis of CMV-seronegative recipients with a seropositive donor (D+/R-) showed a transiently improved survival rate by day 100 in MSL-109 recipients (mortality: 60-mg group, 1/13; 15-mg group, 1/12; placebo group, 6/10 [P = .02 for 60-mg versus placebo groups; P = .08 for 15-mg versus placebo groups]); by the end of follow-up, the difference was no longer statistically significant. The improved survival rate in D+/R- patients could not be attributed to a reduction in CMV disease; however, MSL-109 was associated with improved platelet engraftment and less grade III to IV acute graft-versus-host disease in this subgroup. In a subgroup analysis of CMV-seropositive recipients of MSL-109 (D+/R+ and D-/R+), overall mortality was increased compared to that of the placebo group (P = .12 for the 60-mg versus placebo groups, P = .05 for the 15-mg versus placebo groups, and P = .04 for the dose levels combined versus placebo). MSL-109 was well tolerated and no immune response to the drug was observed. Thus, MSL-109 was safe but did not reduce CMV infection in allogeneic HSCT recipients. The transient survival advantage seen early after transplantation in CMV D+/R- patients and the negative effect on survival in seropositive patients remain unexplained. Thus, there is no evidence that MSL-109 is beneficial in CMV-seropositive HSCT recipients.

Adult↗
PubMed2005

Defining the predictors of the placebo response in irritable bowel syndrome.

BACKGROUND AND AIMS: We sought to determine the components of irritable bowel syndrome (IBS) clinical trials that correlate with higher levels of placebo response. METHODS: We performed a systematic review of placebo-controlled trials in patients with IBS to assess which variables correlate with a higher placebo response. Placebo responses for global symptom improvement and for decreased abdominal pain were assessed. Univariate and multiple linear regression analyses were conducted. RESULTS: Higher rates of global improvement correlated with frequency of administration of study intervention ( r = .31, P = .03), duration of the study ( r = .28, P = .04), and overall treatment effect of the active agent being studied ( r = .33, P = .02). Higher rates of decreased abdominal pain correlated with the frequency of intervention ( r = .39, P = .02) and overall treatment effect ( r = .40, P = .01), whereas lower placebo response rates correlated with year of the study ( r = -.36, P = .03), median age ( r = -.38, P = .04), and duration of study run-in period ( r = -.33, P = .04). On multivariate analysis, global improvement in the placebo group was associated significantly with intervention frequency ( P = .0079), overall treatment response ( P = .0031), and parallel study design ( P = .0044). Decreased abdominal pain was associated significantly with frequency of intervention ( P = .0061) and overall treatment response ( P = .0128). CONCLUSIONS: In IBS studies, higher placebo response rates correlated with frequency of the intervention and with overall treatment effect of the active agent being studied. In designing IBS trials, it may be possible to minimize placebo response by less frequent dosing. In treating patients with IBS, it may be possible to harness the placebo response and maximize therapeutic response rates by more frequent dosing.

Clinical Trials as Topic↗
PubMed1985

Conditioned placebo responses.

Following earlier animal research, we attempt to condition placebo effects in human subjects. Four groups of 8 voluntary subjects were told that the experimenters would test a powerful new analgesic cream over three sessions by assessing its ability to reduce experimentally induced pain. The analgesic cream was, in fact, a placebo. In the first session all subjects were tested with and without the cream to assess their placebo response. In the second session, to condition two groups (with differing stimulation levels) to experience pain relief in response to the placebo, we repeatedly paired a reduction in nocioceptive stimulation with placebo administration. (Subjects were unaware that stimulation levels were manipulated). To condition the other two groups (with different stimulation levels) to experience an exacerbation of the pain, we paired an increase in nocioceptive stimulation with placebo administration. In the third session, all subjects were again tested for placebo response. Results suggested that placebo responses are conditionable in the laboratory in both a positive and negative direction. The clinical implications of a learning theory of placebo behavior are discussed.

Administration, Topical↗
PubMed2005

Goal activation, expectations, and the placebo effect.

Motivational factors receive little attention in current theories of the placebo effect. Reasons for this position are reviewed, and an argument is made for reconsidering the influence of motivation on the placebo effect. The authors hypothesize that nonconscious goals alter reactions to a placebo expectation. Specifically, the authors predict that the placebo effect is most likely to occur when individuals have a goal that can be fulfilled by confirmation of the placebo expectation. The authors tested this notion in 5 experiments. The results demonstrate the role of motivation in the placebo effect across a variety of symptom domains and via 4 different goal activation techniques. Moreover, this moderating effect occurred for both positive and negative placebo expectations, across different placebo effect measures, and in brief laboratory experiments as well as in lengthier studies. It is argued that theories regarding the placebo effect should incorporate motivational factors.

Analysis of Variance↗
PubMed1992

Nizatidine versus placebo in active benign gastric ulcer disease: an eight-week, multicenter, randomized, double-blind comparison. The Nizatidine Benign Gastric Ulcer Disease Study Group.

STUDY OBJECTIVE: To determine if 150 mg nizatidine twice daily or 300 mg nizatidine at bedtime are similarly effective and to compare each dose with placebo in healing benign gastric ulcers and relieving peptic ulcer symptoms. METHODS: This study was a randomized, double-blind, placebo-controlled parallel comparison. The study was conducted at 74 gastroenterology and internal medicine clinics in the United States and Canada. Four hundred fifty-six patients with active benign gastric ulcer documented by endoscopy participated in the study. On the basis of a computer-generated randomization list, patients were assigned sequentially to receive either 150 mg nizatidine twice daily (n = 151), 300 mg nizatidine once daily at bedtime and identically appearing placebo capsules in the morning (n = 153), or placebo capsules twice daily (n = 152). Treatment lasted for 8 weeks unless healing was documented by endoscopy after 4 weeks. Antacid tablets (aluminum hydroxide, magnesium hydroxide, simethicone combination) were supplied for relief of symptoms. MEASUREMENTS AND MAIN RESULTS: Both doses of nizatidine significantly improved healing rates at 8 weeks compared with placebo. Daytime and nighttime symptom severity was improved by both nizatidine regimens at end point (p less than 0.015 versus placebo, two-tailed test). Antacid use was similar for all groups in the end point analysis. Patient well-being was significantly better in patients treated with nizatidine than in patients in the placebo group ((p less than 0.04, two-tailed test). No clinically significant differences in the incidence of adverse clinical or laboratory events were noted. CONCLUSION: Nizatidine, 300 mg at bedtime and 150 mg twice daily, resulted in greater healing of benign gastric ulcers than placebo treatment after 8 weeks. Relief of the symptoms of gastric ulcer was significantly better in the patients receiving nizatidine treatment versus placebo treatment.

Capsules↗
PubMed1992

Classic conditioning and placebo effects in crossover studies.

OBJECTIVE: To find evidence of classically conditioned placebo effects in a placebo-controlled crossover drug study. Specifically, we tested a prediction of the conditioning model that the placebo response will be greater after drug exposure than before. METHODS: Twenty-four patients with mild to moderate essential hypertension and no contraindications to atenolol participated in the study. The study design required randomized assignment to one of three groups: placebo followed by 50 mg atenolol daily, followed by no treatment, each for 1 week; atenolol followed by placebo; and atenolol followed by nothing (to show residual drug effects). Twice-daily blood pressure measurements were made by patients at home; once-weekly measurements of blood pressure and heart rate were made by a research nurse. RESULTS: Before drug treatment, there were no differences in the antihypertensive responses of patients taking placebo and patients taking nothing (difference, 0.98 mm Hg; 95% confidence interval, -0.98 to 2.93). After atenolol treatment, placebo treatment produced a significantly greater antihypertensive response than no treatment (difference, -6.09 mm Hg; 95% confidence interval, -11.81 to -0.38). Thus the placebo response after atenolol administration was more than a residual drug effect. Similar patterns were observed for heart rate but not for blood pressure readings taken in the office. CONCLUSIONS: These observations are consistent with a conditioning model of placebo effects. These findings warrant further investigation in larger studies and in other disease models.

Adult↗
PubMed2001

The efficacy and safety of sc alniditan vs. sc sumatriptan in the acute treatment of migraine: a randomized, double-blind, placebo-controlled trial.

This double-blind, placebo-controlled, parallel-group, multicentre, multinational, phase-III trial was designed to assess the efficacy and safety of a single subcutaneous injection of placebo, 2 doses of alniditan (1.4 mg and 1.8 mg) and 6 mg of sumatriptan in subjects with acute migraine. A total of 114 investigators from 13 different countries screened 2021 subjects. In total 924 patients were treated with placebo (157), alniditan 1.4 mg (309), alniditan 1.8 mg (141) and sumatriptan 6 mg (317). The lower number of subjects in the alniditan 1.8 mg group is due to the termination of this trial arm after the incidence of a serious adverse event and a subsequent protocol amendment. The number of subjects who were pain free at 2 h (primary endpoint) was: 22 (14.1%) with placebo, 174 (56.3%) with alniditan 1.4 mg, 87 (61.7%) with alnditan 1.8 mg and 209 (65.9%) with sumatriptan 6 mg. Alniditan 1.4 mg was significantly better (P < 0.001) than placebo and sumatriptan was significantly better (P = 0.015) than alniditan 1.4 mg. The number of responders (reduction of headache severity from moderate or severe headache before treatment to mild or absent at 2 h), was 59 (37.8%) on placebo, 250 (80.9%) on alniditan 1.4 mg, 120 (85.1%) on alniditan 1.8 mg, and 276 (87.1%) on sumatriptan. Response was significantly higher (P < 0.001) with alniditan 1.4 mg than with placebo, and significantly lower (P = 0.036) with alniditan 1.4 mg than with sumatriptan. Recurrence rates were: 22 (37.3%) with placebo, 87 (34.8%) with alniditan 1.4 mg, 35 (29.2%) with alniditan 1.8 mg and 108 (39.1%) with sumatriptan. Adverse events occurred in 577/924 (62.4%) subjects, i.e. in 62/157 (39.5%) with placebo, 214/309 (69.3%) with alniditan 1.4 mg, 91/141 (64.5%) with alniditan 1.8 mg and 210/317 (66.2%) with sumatriptan 6 mg. Sumatriptan was significantly better than alniditan 1.4 mg for pain free at 2 h. The difference, however, was small and clinically not important. For alniditan, a dose-dependent adverse event relationship was seen. The safety profile of alniditan 1.4 mg was similar to that of sumatriptan.

Acute Disease↗
PubMed1997

Inhibition of intragastric acidity in healthy subjects dosed with ranitidine 75 mg: a comparative study with cimetidine and placebo.

BACKGROUND: Despite the widespread use of over-the-counter H2-receptor antagonists little is known about their duration of action on human gastric acid secretion. There are studies reporting inhibitory effects for up to 9 h post-dose but few data beyond this period. METHODS: Profiles of 20-h intragastric acidity were measured simultaneously in 24 healthy subjects who were dosed (at 12.30 h) with either ranitidine 75 mg, cimetidine 200 mg or placebo in a three-way crossover study, according to a standard protocol. Five-millilitre aliquots of gastric juice were aspirated half-hourly during the day (0-10 h post-dose) and hourly overnight (10-20 h post-dose). pH was measured to three decimal places with a glass electrode. Weighted intragastric acidity (AUC/time) was calculated for both day- and night-times using 2.5-h intervals during the day and 5-h intervals at night. Statistical analysis was by ANOVA. RESULTS: The results are expressed as mean weighted intragastric acidity (mmol/L). (i) Daytime (0-10 h post-dose): when dosed with placebo the weighted intragastric acidity was 31.03, decreasing to 10.37 (P < 0.001 vs. placebo) and 16.23 (P < 0.001 vs. placebo) when treated with ranitidine and cimetidine, respectively. Ranitidine inhibited weighted intragastric acidity to a greater degree than cimetidine (P < 0.001) during this period. (ii) Night-time (10-20 h post-dose): when dosed with placebo the weighted intragastric acidity was 21.36 decreasing to 16.65 (P < 0.001 vs. placebo) when dosed with ranitidine and remaining unchanged at 20.03 (P = 0.886 vs. placebo) when dosed with cimetidine. Ranitidine inhibited weighted intragastric acidity to a greater degree than cimetidine (P = 0.010) during this period. A sub-analysis of the two 5-h intervals showed that compared to placebo, ranitidine inhibited weighted intragastric acidity significantly in the 10-15 h period. However, its effect in the 15-20 h period did not differ from placebo. CONCLUSIONS: In healthy subjects, the inhibitory effect of ranitidine 75 mg on intragastric acidity can be detected 10-15 h after an oral dose. By contrast, the inhibitory effect of cimetidine 200 mg seems to be restricted to the first 10 h.

Adult↗
PubMed2005

[Mechanisms of placebo effect and of conditioning: neurobiological data in human and animals].

A placebo is a sham treatment such as pill, liquid, injection, devoid of biological activity and used in pharmacology as a control for the activity of a drug. In many cases, this placebo induces biological or psychological effects in the human. Two theories have been proposed to explain the placebo effect: the conditioning theory which states that the placebo effect is a conditioned response, and the mentalistic theory for which the patient expectation is the primary basis of the placebo effect. The mechanisms involved in these processes are beginning to be understood through new techniques of investigation in neuroscience. Dopamine and endorphins have been clearly involved as mediators of the placebo effect. Brain imaging has demonstrated that the placebo effect activates the brain similarly as the active drug and in the same brain area. This is the case for a dopamine placebo in the Parkinson'disease, for analgesic-caffeine- or antidepressor-placebo in the healthy subject. It remains to be understood how conditioning and expectancy are able to activate, in the brain, memory loops that reproduce the expected biological response.

Animals↗