Placebo and placebo effect

The word placebo appeared for the first time in an English medical dictionary in 1785. In French, it appeared much latter in 1958. This word defines an experimental tool used for rigourous evaluation of a specific effect of pharmacological treatment and the non specific effect of any therapy. The placebo effect is the strictly psychological or psychophysiological effect of a placebo. The two principal components of placebo effect as a pain killer, which has been extensively studied in this field, are positive expectancies of both the patient and the physician. Although the mechanisms of action of placebo effect are not well understood, results of several recent works are particularly interesting.     

Two bass scale factors and response to placebo and anxiolytic drugs

Two principal oblique factors are identified in the Bass Social Acquiescence Scale, a measure previously shown to correlate positively with placebo response and negatively with anxiolytic drug response. The two factors appeared very similar in separate analyses of data from samples of 941 psychiatric outpatients and 1,837 college students. Also, results are presented which indicate that one factor, tentatively labeled traditionalism, accounted for the empirically observed relationships to placebo and drug response in two clinical trials.     

Compensatory Responses to Placebo Vary with Presumed Personality “Risk” for Alcoholism and Drinking Habits

Physiological reactions of men who reported intoxication after consuming placebo beer were related to a personality index of presumed “risk” for alcoholism and drinking habits. Presumed personality “risk” varied with decreases in skin conductance. Those at higher “risk” showed a larger compensatory response. Drinking habits varied with decreases in skin temperature. Those who drank more showed larger changes. These results are consistent with work linking risk and compensatory responding, and support compensatory response theory. Nevertheless, these results were found only for a subset of subjects (24 of 81) who reported moderate intoxication after consuming the placebo, limiting generalizability.     

Situational factors contributing to the placebo effect

The influence of four variables (status of communicator of drug effects, attitude of dentist, attitude of dental technician, and message of drug effects) on the obtainment of placebo effects in an oral surgery clinic was investigated. Dependent variables were (1) rating of pain experienced from mandibular-block injection, (2) pre-post placebo state anxiety, and (3) pre-postplacebo fear of injection. Enthusiastic messages of drug effects produced statistically and clinically significant reductions in postplacebo fear of injection and state anxiety and markedly lower ratings of pain experienced during injection of local anesthetic. Although there was a strong tendency for positive placebo effects to occur when the dental staff was perceived as friendly and supportive, only the attitude factors obtained statistical significance. The status of the communicator accounted for very small portions of the variance.This investigation was conducted in the Oral Surgery Clinic of Ben Taub General Hospital, Houston, Texas     

Caffeine-associated stimuli elicit conditioned responses: an experimental model of the placebo effect

Rationale: A neutral stimulus repeatedly paired with administration of a drug may elicit a conditioned response. This process, termed pharmacological classical conditioning, may be important in the understanding of placebo effects. Objective: The unconditioned response to caffeine is increased physiological and psychological arousal. The present study investigated whether stimuli associated with the use of caffeine, i.e. the smell and taste of coffee, elicited a conditioned increase in arousal. It was also investigated whether conditioned arousal modulated the unconditioned arousal induced by caffeine. Methods: Twenty subjects who drank at least two cups of coffee per day were exposed to four conditions in a within-subjects design, where the subjects received coffee or orange juice crossed with placebo or 2 mg/kg caffeine. Dependent variables were skin conductance responses and startle reflexes to 85 dB noise bursts, skin conductance levels, blood pressure, heart rate, and subjective measures of arousal. Results: Both caffeine (caffeinated juice) and caffeine-associated stimuli (decaffeinated coffee) increased subjective and physiological arousal. When caffeine and caffeine-associated stimuli were presented together (caffeinated coffee), a non-significant tendency towards an additive effect of the conditioned arousal on the unconditioned arousal to caffeine was seen in some dependent variables. Conclusions: Presentation of caffeine-associated stimuli to caffeine-users elicited conditioned responses similar to the unconditioned drug response. Thus, presentation of caffeine-associated stimuli could be used as an experimental model of placebo effects. Received: 23 November 1998/Final version: 16 February 1999     

Expected effect of caffeine on motor performance predicts the type of response to placebo

Two experiments (N=56) investigated the relationship between subjects’ expectancies concerning the effect of caffeine on a motor skill, and the type of placebo response. Male subjects were assigned to four groups. Three groups expected to receive caffeine but received a placebo. Prior to the placebo, two of the groups received information about the effect of caffeine on a motor skill task which led one group E(+) to expect enhanced performance, and the other E(?) to expect impairment. The third placebo group received no information E(?). A control group E(0) received no beverage, so neither caffeine nor any effect on performance was expected. The expected type of effect predicted the type of placebo response displayed. Group E(+) displayed greater improvement under placebo than did group E(0), and group E(?) performed more poorly than those in group E(0). No placebo response was observed in group E(?). Placebo effects on mood were correlated with subjects’ predictions about the effect of caffeine on mood. The role of expectancies in response to placebos and psychoactive drugs is discussed.     

Expectations and placebo responses to caffeine-associated stimuli

Rationale To test the theory that expectations control placebo responses. Objective Subjects (n=20) were asked how much they expected their arousal to increase after one or two cups of coffee, and were subsequently exposed to one or two cups of decaffeinated coffee, or to caffeine equivalent to one or two cups of coffee (200 and 400 mg). The expectancy theory of placebo responses predicts a positive correlation between expectations and actual placebo responses. Methods Dependent variables were acoustic startle eyeblink and skin conductance responses, blood pressure and heart rate, and measures of subjective arousal. Results Caffeine increased startle eyeblink and skin conductance responses, as well as blood pressure and subjective arousal. Decaffeinated coffee increased startle eyeblink and skin conductance responses, but had no effect on subjective arousal, although the participants clearly expected increased subjective arousal after both one and two cups of coffee. However, there were significant correlations between the alertness expected after coffee, and the actual alertness recorded after decaffeinated coffee. Conclusions The main finding in this study was that relatively strong expectations about the effects of coffee did not generate placebo responses after administration of decaffeinated coffee. Expectations were dose dependent, whereas the placebo response was not. However, expected alertness after coffee predicted recorded alertness after coffee. In sum, the expectancy theory of placebo effects received only limited support.     

Experimental comparison between the effect of standardized trazodone-amitriptyline and placebo treatment in vitalized depressive patients

We are performing a double-blind trial with inward psychiatric patients. The indication for our psychotropic or psychotherapeutic intervention is mainly severe depression (=major depressive disorders DSM III). For a 3-week trial course trazodone (400 mg daily), amitriptyline (150 mg/die) or placebo capsules were given at random. All patients received the same type of cognitive behaviour therapy. The test battery consists of CGI, BPRS, HAMD, HAMA and AMDP; adverse drug reactions are documented as free reports (=freier Nebenwirkungsbericht). The interim results (until March 1987) will be presented. Our investigation indicates that it is probable that the trazodone treatment we used is equivalent to corresponding amitriptyline treatment.     

Pills and improvement: A study of placebo response in psychoneurotic outpatients

Summary The hypothesis that clinical improvement would be significantly correlated with number of daily placebo pills prescribed was supported for clinic and general practice patients but not for private psychiatric practice patients. Patients in the 3 treatment settings differed in other ways, particularly in treatment orientation, i.e., their awareness of having emotional problems and the most suitable treatment recommended for them by their physicians, as well as in social class. Treatment orientation was found not to account for the demonstrated pill effect, and social class differences, seen only in general practice, also did not appear to modify the relationship between pills and improvement within the entire patient sample.Our findings in this study have methodological as well as clinical implications. The fact that higher placebo intake levels resulted in reduced drug-placebo differences in improvement poses a practical problem for the clinical researcher, while the lack of placebo improvement observed at lower placebo intake levels indicates that 1 placebo pill per day is not a very effective agent in the symptomatic treatment of neurotic outpatients. Further research is needed to determine the optimal dosage for placebo therapy. Perhaps dosage intake norms, which probably vary within different treatment settings and social classes, represent a major factor influencing the pill effect on placebo response.This work was supported in full by USPHS Grants MH-08957-8.     

Predicting response to opiate antagonists and placebo in the treatment of pathological gambling

Rationale  Although opiate antagonists have shown promise in the treatment of pathological gambling (PG), individual responses vary. No studies have systematically examined predictors of medication treatment outcome in PG. Understanding clinical variables related to treatment outcome should help generate treatment algorithms for PG. Objective  We sought to identify clinical variables associated with treatment outcome in PG subjects receiving opiate antagonists. Materials and methods  Two hundred eighty-four subjects [137 (48.2%) women] with DSM-IV PG were treated in one of two double-blind placebo-controlled trials (16 weeks of nalmefene or 18 weeks of naltrexone). Gambling severity was assessed with the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS) with positive response defined as ≥35% reduction in PG-YBOCS score for at least 1 month by study endpoint. Depression, anxiety, and psychosocial functioning were included in stepwise logistic regression analyses designed to identify clinical factors independently associated with treatment response. Results  The clinical variable most strongly associated with a positive response to an opiate antagonist was a positive family history of alcoholism (p = 0.006). Among individuals receiving higher doses of opiate antagonists (i.e., nalmefene 50 or 100 mg/day or naltrexone 100 or 150 mg/day), intensity of gambling urges (PG-YBOCS urge subscale) was associated with a positive response on a trend level (p = 0.036). Among individuals receiving placebo, younger age was associated, on a trend level, with positive treatment outcome (p = 0.012). Conclusions  A family history of alcoholism appears to predict response to an opiate antagonist in PG. Future research is needed to identify specific factors (e.g., genetic) mediating favorable responses.     

The placebo–nocebo response: Controversies and challenges from clinical and research perspective

Placebo and nocebo responses fascinate, confuse, mystify and challenge. They are genuine social, cultural and psychobiological phenomena which can significantly modify the overall treatment outcome. The placebo–nocebo phenomenon represents a very good model for our better understanding the role of treatment context and how the words, indices, symbols and icons act on our brains. Placebo response is associated with reward expectancy and relief of anticipatory anxiety, while nocebo response is related to lack of reward/positive expectancy and to increase of anticipatory anxiety. Placebo–nocebo responses are mediated through changes in various cortico-subcortical networks and psychophysiological systems. In spite of many existing complementary theories and still growing research on placebo and nocebo response, the implementation of our current knowledge to benefit basic research, clinical trials and routine clinical practice is still so scarce.     

A meta-analysis of the placebo response in acute migraine and how this response may be influenced by some of the characteristics of clinical trials

Migraine is the most common cause of vascular headache and a highly prevalent illness. In the last 20 years, the discovery of new agents has increased clinical research on migraine. In most of clinical trials that have been conducted, the efficacy was established using a placebo as a control treatment. The objective of the study reported here was to analyse the response rate in patients who received a placebo as well as to determine how a number of the methodological factors may affect the effect of the placebo in clinical trials of acute migraine. Computer-based information searches were conducted on the Medline database. Data analysis included the outcomes 'pain relief', 'pain-free', 'associated symptoms', 'recurrence', 'patients' opinion' about pain relief and 'adverse events'. Administration route, study design and country in which the study was carried out were the methodological factors that were analyzed. Meta-analysis was computed using Mantel-Haenszel, and a total of 98 papers were considered in the final analysis. After 2 h, 28.6% of the patients of the placebo group improved and 8.8% were pain-free. The percentage of pain-free patients was the highest in the placebo and active drug groups in which the placebo or drug had been administered subcutaneously, in parallel design studies (vs. cross-over trials) and in studies performed in Europe (vs. North America). Adverse events in the placebo group were significantly higher in studies performed in North America. These data reinforce the need for knowing the magnitude of the placebo response in each specific situation during the planning of clinical trials on acute migraine.     

The expected drug and its expected effect interact to determine placebo responses to alcohol and caffeine

This study tested placebo responses in psychomotor performance when caffeine or alcohol was expected. Fifty male university students were assigned to one of four placebo groups or to a no-treatment control group. Two groups received placebo caffeine and two received placebo alcohol. Subjects performed 12 trials on a pursuit rotor task and performance was measured by the percent time on target. Then they received information about the expected drug effect on the task. One caffeine placebo group (C+) and one alcohol placebo group (A+) were led to expect enhanced performance on the task. The other caffeine placebo group (C–) and alcohol placebo group (A–) were led to expect impaired performance. Subjects subsequently performed 12 trials on the task. An interaction was obtained between the expected type of effect and the expected type of drug. The C+ group displayed superior performance compared to the C– group, and the reverse relationship was observed between the A+ and A– group. In addition, subjects led to expect alcohol-induced impairment (A–) performed better than subjects led to expect caffeine-induced impairment (C–). Subjects also reported greater motivation to resist impairment when they expected alcohol rather than caffeine. The research indicates that understanding and predicting placebo responses may require consideration of the drug that is expected as well as its expected effect.This work was supported in part by a Natural Sciences and Engineering Research Council of Canada Grant A8321 to the third author and by a grant from the Alcoholic Beverage Medical Research Foundation.     

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.From the Laboratory of Behavioral Pharmacology, UCLA Neuropsychiatric Institute, and the Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA.     

Clinical and experimental comparison of diazepam,chlorazepate and placebo

A double blind clinical evaluation of chlorazepate (dipotassium-7-chloro-5-phenyl-2,2-dihydroxy-3-carboxy-1,2-dihydro-2H-1,4-benzodiazepine), diazepam and placebo on a patient group of young students, mean age 25 years, is reported. Both drugs were significantly better than placebo and according to global assessment chlorazepate was superior to diazepam. An analysis of the main target symptom revealed better effects of chlorazepate on the following items: anxiety, feeling of muscular tension and gastro-intestinal disturbances. With respect to irritability and sleep disturbances both drugs were found to be equally effective. In patients' self-ratings chlorazepate was considered superior to diazepam in giving more alertness and less drowsiness during day time. The results are discussed with reference to EEG-studies and pharmaco-kinetic properties of chlorazepate and diazepam. Performance tests in simulated car-driving by healthy volunteers did not demonstrate any significant difference as compared with placebo. The psycho-physiological effects, however, are more pronounced after diazepam than after chlorazepate medication.     

天葵降压片联合西药降压药治疗高血压病的随机、双盲、安慰剂对照、多中心临床试验

摘 要 目的： 考察天葵降压片联合西药降压药治疗“已经过西药降压药系统治疗但血压仍未达标者”的高血压病（肝阳上亢证)的疗效及安全性。方法: 采用随机、双盲、安慰剂平行对照、多中心临床试验,经6家临床试验中心对240 例受试者（试验组160 例,对照组80 例）进行临床试验,试验组口服天葵降压片 4 片,tid,疗程8 周。对照组口服天葵降压片模拟剂4 片,tid。观察药物的疗效和安全性。结果:试验组和对照组的降血压疗效显效率分别为63.23%和31.65%,中医证候疗效显效率分别为48.39%和20.25%;两组差异均有统计学意义（P<0.05）。两组均无严重不良事件发生;实验室检查各项指标变化,研究者均判定与试验药物无关。结论: 天葵降压片联合西药降压药治疗“已经过西药降压药物系统治疗但血压仍未达标者”的高血压病（肝阳上亢证),具有较好的疗效和安全性。     

Peak B endorphin concentration in cerebrospinal fluid: reduced in chronic pain patients and increased during the placebo response

The level of an endogenous opioid (peak B endorphin) was measured in chromatographically fractionated cerebrospinal fluid (CSF) sampled from two groups of chronic pain patients before and after intrathecal saline (placebo) injection. As assessed by a verbal rating scale, one group reported no change in their level of pain (non-responders, NR;n=6) while the other group reported complete or >50% pain relief (placebo responders, PR;n=14). We find, as has been reported previously, that initial peak B levels were lower (by 50%) in these chronic pain patients' CSF than in CSF from pain-free (PF) normal controls (P<0.001,t-test). Peak B levels measured from CSF of the NR group undergoing this procedure did not change (P>0.4, pairedt-test). In contrast, a significant 2.3-fold increase was measured in the CSF peak B level of the PR group (P<0.05, pairedt-test). This is the first direct evidence that a CSF opioid is correlated with placebo pain relief in chronic pain patients. Peak B is a potent analgesic substance when administered by the intracerebroventricular route in mice and its level is related to the patients' pain status in a presumably causal manner.     

Treatment of depressive outpatients with lorazepam,alprazolam, amytriptyline and placebo

This randomized double-blind study in 342 mildly to moderately depressive outpatients investigated the antidepressant effectiveness and speed of action of lorazepam, alprazolam and amitriptyline versus placebo. Six weeks of drug treatment were followed by a drug taper period, a control period with placebo and a control period without placebo, of 2 weeks duration each. Clinical improvement was assessed by rating scales (Clinical Global Impressions, Hamilton Rating Scales for Depression and Anxiety) and patient's self-ratings (Patient's Global Impressions, Self-rating Depression Scale and Visual Analogue Scale). At the end of week 6 all active drugs showed similar efficacy which was significantly superior to placebo. Compared to placebo, onset of efficacy was earlier on benzodiazepines than on amitriptyline. While tapering by decreasing the dosage, replacing drug with placebo and finally discontinuing placebo, clear withdrawal phenomena were not seen, but 20% of patients, equally distributed to all treatment groups, did not want to stop taking tablets after replacing drug with placebo. Drop-out rate during the treatment period was very low (9%). Significantly interfering adverse effects were seen in 27 patients, without predominance in one of the active drug groups.     

Placebo response mitigation with a participant-focused psychoeducational procedure: a randomized,single-blind,all placebo study in major depressive and psychotic disorders

The remarkably high and growing placebo response rates in clinical trials for CNS indications, such as depression and schizophrenia, constitute a major challenge for the drug development enterprise. Despite extensive literature on participant expectancies and other potent psychosocial factors that perpetuate placebo response, no empirically validated participant-focused strategies to mitigate this phenomenon have been available. This study evaluated the efficacy of the Placebo-Control Reminder Script (PCRS), a brief interactive procedure that educates participants about factors known to cause placebo response, which was administered prior to the primary outcome assessments to subjects with major depressive or psychotic disorders who had at least moderate depression. Participants were informed they would participate in a 2-week randomized clinical trial with a 50% chance of receiving either an experimental antidepressant medication or placebo. In actuality, all participants received placebo. Participants randomly assigned to receive the PCRS (n = 70) reported significantly smaller reductions (i.e., less placebo response) in depression than those who did not receive the PCRS (n = 67). The magnitude of this effect was medium (Cohen’s d = 0.40) and was not significantly impacted by diagnostic status. The number of adverse events (i.e., nocebo effect) was also lower in the PCRS group, particularly in the first week of the study. These findings suggest that briefly educating participants about placebo response factors can help mitigate the large placebo response rates that are increasingly seen in failed CNS drug development programs.Subject terms: Human behaviour, Drug discovery