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PubMed1991

Implications of placebo theory for clinical research and practice in pain management.

We review three possible theoretical mechanisms for the placebo effect: conditioning, expectancy and endogenous opiates and consider the implications of the first two for clinical research and practice in the area of pain management. Methodological issues in the use of placebos as controls are discussed and include subtractive versus additive expectancy effects, no treatment controls, active placebo controls, the balanced placebo design, between- versus within-group designs, triple blind methodology and the double expectancy design. Therapeutically, the possibility of shaping negative placebo responses through placebo sag, overservicing and the use of placebos on their own are explored. Suggestions for using conditioned placebos strategically in conjunction with nonplacebos are made and ways of maximizing the placebo component of nonplacebo treatments are examined. Finally, the importance of investigating the placebo effect in its own right is advocated in order to better understand the long-neglected psychological aspects of the therapeutic transaction.

Chronic Disease↗
PubMed2002

The influence of placebo awareness on stimulant drug response in a double-blind trial.

RATIONALE: Critics have called into question findings from double-blind placebo-controlled studies because subjects are given drug administration instructions informing them of a placebo condition. The assertion that these drug administration instructions bias estimates of effectiveness has undergone surprisingly little empirical investigation. OBJECTIVES: The primary objective of this study was to determine whether drug administration instructions informing subjects of a placebo condition affect the drug response and affect the saliva concentration of the stimulant. METHODS: We assessed caffeine responses and levels of saliva concentration of caffeine in 52 subjects who were randomly assigned to receive one of two drug administration instructions: (a) placebo-informed instructions (i.e., individuals informed of the placebo) analogous to those used in double-blind studies and (b) placebo-uninformed instructions (i.e., individuals informed they are taking an active stimulant). RESULTS: On most measures (systolic blood pressure, heart rate, hand steadiness, reaction time, fatigue, and tension), drug administration instructions did not significantly influence caffeine response. Instructions also had no significant effect on saliva concentration of caffeine. However, only individuals who were uninformed of the placebo condition showed significant diastolic blood pressure and vigor increases with 125 mg caffeine, and significant hand steadiness impairment and vigor increases with 325 mg caffeine compared to placebo. CONCLUSIONS: These overall findings suggest that a limited bias is introduced by drug administration instructions. The results do not support any suggestion that information about the existence of a placebo condition dramatically influences conclusions drawn about drug responses in placebo-controlled trials.

Affect↗
PubMed2003

Benefits and burdens of placebos in psychiatric research.

RATIONALE: The debate over the use of placebos in clinical trials when proven treatments exist continues to be lively, especially in psychiatric research. Current practice permits placebos in such settings, as long as the benefits outweigh the risks and burdens. OBJECTIVES: To examine in depth the risk-benefit framework typically used to justify placebo controls in psychiatric drug development, by making explicit the implicit ethical tradeoffs. METHODS: Analysis informed by a review of currently available data on the benefits and burdens of exposing psychiatric research subjects to placebos. RESULTS: Various risk/burden thresholds for limiting placebo controls have been proposed, ranging from the currently used standards of no increased mortality or permanent morbidity to more recent proposals of 'serious but reversible harm' and 'severe discomfort.' Placebo exposure in antidepressant and antipsychotic trials appears not to increase mortality by suicide. Direct data on long-term effects are lacking. Symptom-related burdens of placebos need to be better quantified and more integrated into the ethical analysis of placebos. While the perspective of those who benefit from the practice of using placebo controls is well represented, virtually no data from the perspective of potential subjects exist. CONCLUSIONS: The ethical analysis of placebos in psychiatric research has an important but limited evidence base. Suggestions for areas of further inquiry to increase that evidence base are given.

Antipsychotic Agents↗
PubMed2004

Stimulant and relaxant drugs combined with stimulant and relaxant information: a study of active placebo.

RATIONALE: The active placebo hypothesis states that placebo effects are potentiated when an active drug is administered. OBJECTIVE: This hypothesis was tested in an experiment where information about the effect of a drug was combined with administration of an active drug or placebo. METHODS: Information that a drug acted as a relaxant, a stimulant, or as a placebo was crossed with oral administration of a relaxant drug (700 mg carisoprodol), a stimulant drug (400 mg caffeine) or placebo (lactose) in healthy volunteers ( n=94). Dependent variables were subjective and physiological measures of arousal, as well as serum carisoprodol and caffeine levels. Data were collected from 15 to 280 min after administration of drug or placebo. RESULTS: Caffeine increased alertness, systolic and diastolic blood pressure, startle blink reflexes, and skin conductance responses. Subjects were calmer after carisoprodol, and heart rate was increased. There was a positive correlation between increased arousal and carisoprodol levels when stimulant information had been provided. However, this was only seen when carisoprodol levels were very low. There was no evidence that caffeine modulated the placebo response. CONCLUSIONS: Active placebo responses were seen only transiently when carisoprodol levels were low, and only in the subjective arousal data. Caffeine did not support active placebo responses. The overall findings did not favour the active placebo hypothesis.

Adult↗
PubMed2005

Expectations and placebo response: a laboratory investigation into the role of somatic focus.

It has been theorized that expectations are an important causal determinant of the placebo effect. Placebo expectations, however, do not always yield placebo effects. In a laboratory study, we tested the hypothesis that one's level of somatic focus moderates the effect of placebo expectations on placebo responding. We also varied whether participants were told the placebo was a drug, could either be a drug or placebo, or was a placebo. The results revealed that individuals who thought they were taking a drug (i.e., unconditional expectations) reported more placebo symptoms when they closely focused on their symptoms. Individuals told they may or may not be receiving a drug (i.e., conditional expectations) did not differ from control participants regardless of how closely they attended to their symptoms. The findings have theoretical implications for expectancy models of the placebo effect as well as for practical research comparing the type of expectations held by individuals in clinical trials and clinical practice.

Adult↗
PubMed1979

The current status of placebo in hospital practice.

Despite a voluminous literature on the topic of placebo, there has been little documentation of either actual clinical practice of prescribing placebo or the attitudes that surround it. Through a questionnaire survey of all head nurses of clinical units in one health services area of Connecticut, data were obtained on current practices regarding placebo use in the natural hospital setting. Multiple reasons for placebo use in the natural hospital setting. Multiple reasons for placebo use were given, and it was noted that patients receiving placebo tended to be viewed in certain ways. The effectiveness of placebo in symptom relief was reported as nearly double that reported in the experimental literature. Methodologic issues of the study and of placebo investigation, in general, are discussed. Because common clinical problems appear to generate most instances of placebo use, several issues pertinent to medical education are raised. Some future directions for placebo research are proposed.

Adolescent↗
PubMed2006

Placebo effects in laser-evoked pain potentials.

Placebo treatment may affect multiple components of pain, including inhibition of nociceptive input, automatic or deliberative appraisal of pain, or cognitive judgments involved in pain reporting. If placebo analgesia is due in part to an attenuation of early nociceptive processing, then pain-evoked event-related potentials (ERPs) should be reduced with placebo. In this study, we tested for placebo effects in P2 laser-evoked potentials at midline scalp electrodes. We found that placebo treatment produced significant decreases in P2 amplitude, and that P2 placebo responses were large enough to reflect a meaningful difference in nociceptive processing. However, we also found evidence that the very robust placebo-induced decreases in reported pain are not solely explained by early reductions in P2. N2 amplitude was affected by neither placebo nor reduction of laser intensity. These results suggest that placebo treatment affects early nociceptive processing, but that another component of placebo effects in reported pain occurs later, either in evaluation of pain or cognitive judgments about pain reports.

Adult↗
PubMed2005

Increased placebo analgesia over time in irritable bowel syndrome (IBS) patients is associated with desire and expectation but not endogenous opioid mechanisms.

A study was conducted to determine whether changes in expected pain levels, desire for pain relief, or anxiety contribute to an increase in placebo analgesia over time as well as to determine whether placebo analgesic effects of IBS patients are related to endogenous opioid mechanisms. Twenty-six women with IBS were exposed to rectal stimulation (35 or 55 mmHg for 30 s) and tested under natural history (NH), rectal placebo (RP) and rectal lidocaine (RL) conditions. During all conditions, 16 patients were given saline intravenously (to test for a placebo effect) and 10 patients were given naloxone intravenously (to test naloxone antagonism of the placebo effect) on a double blind basis. Patients rated expected pain level, desire for pain relief and anxiety at 2 and 22 min after the onset of NH, RP, and RL conditions and they rated actual pain intensity at 5-min intervals for 40 min. There was a large and significant placebo effect (P<0.001) that increased over time. Ratings of expected pain levels, desire for pain relief and anxiety decreased over time and contributed to more variance in placebo and lidocaine responses during the last half of the session. These changes suggest that a reduction in negative emotions may be central to placebo effects. There was no significant difference between psychological mediators (desire, expectation, anxiety) or the placebo effect in the saline and naloxone groups, indicating that neither the psychological mediators nor the placebo analgesic effect were associated with endogenous opioids in this clinically related paradigm.

Adult↗
PubMed2006

Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies.

To assess the efficacy and tolerability of lamotrigine in pain associated with diabetic neuropathy, two replicate randomized, double-blind, placebo-controlled studies were conducted. Patients (n=360 per study) with painful diabetic neuropathy were randomized to receive lamotrigine 200, 300, or 400 mg daily or placebo during the 19-week treatment phase, including a 7-week dose-escalation phase and a 12-week, fixed-dose maintenance phase. The mean reduction in pain-intensity score from baseline to week 19 (primary endpoint) was greater (p < or = 0.05) in patients receiving lamotrigine 400 mg than placebo in Study 2 (observed scores, -2.7 versus -1.6 on a 0- to 10-point scale). This finding was not replicated in Study 1. Lamotrigine 200 and 300 mg did not significantly differ from placebo at week 19 in either study. Lamotrigine 300 and 400 mg were only occasionally more effective than placebo for secondary efficacy endpoints. The 200-mg dose did not separate from placebo. In a post hoc analysis of pooled data including only patients who reached their target dose, lamotrigine 400 mg conferred greater (p0.05) mean reduction in pain-intensity score from baseline to week 19 than placebo (-2.5 for 300 mg and -2.7 for 400mg versus -2.0 for placebo). Adverse events were reported in 71-82% of lamotrigine-treated patients compared with 63-70% of placebo-treated patients. The most common adverse events with lamotrigine were headache and rash. Compared with placebo, lamotrigine (300 and 400 mg daily) was inconsistently effective for pain associated with diabetic neuropathy but was generally safe and well tolerated.

Diabetic Neuropathies↗
PubMed2006

Selecting an appropriate placebo for a trial of spinal manipulative therapy.

Selecting an appropriate control group or placebo for randomised controlled trials of spinal manipulative therapy is essential to the final interpretation and usefulness of these studies. Prior to starting a randomised controlled trial of spinal manipulative therapy for acute low back pain we wanted to ensure that the placebo selected would be considered appropriate by experts in the field thereby making the results more likely to be accepted and more likely to influence clinical practice. We developed ten placebo techniques that aimed to mimic spinal manipulative therapy as closely as possible which, while not including the active component of spinal manipulative therapy, were still credible. This list of placebo techniques with detailed descriptions was sent to 25 experts in the field from Australia and New Zealand including both clinicians and academics. We asked the experts to rate whether they believed each technique was appropriate for use as a placebo in a trial of spinal manipulative therapy. Sixteen (64%) of the experts responded. There were extremely low levels of agreement between the experts on which placebos were appropriate (kappa = 0.05, 95% CI 0.01 to 0.10). For nine of the ten placebos at least one expert considered the placebo to include the active component of spinal manipulative therapy while at least one other expert believed the same placebo was not only not active but also not credible. The results of this study demonstrate the different views of experts on what constitutes an appropriate placebo for trials of spinal manipulative therapy. Different beliefs about what is the active component of spinal manipulative therapy appear to be responsible for much of the disagreement.

Clinical Trials as Topic↗
PubMed2003

Placebo analgesia and the heart.

Placebo-activated endogenous opioids act on pain mechanisms inducing analgesia, as well as on the respiratory centers inducing respiratory depression. Here, we show that placebo analgesia is accompanied by a reduced beta-adrenergic activity of the heart. We measured heart rate during placebo-induced expectation of analgesia, both in the clinical and the laboratory setting. In the clinical setting, we found that the placebo analgesic response to an electrical noxious stimulus was accompanied by a reduced heart rate response. In order to investigate this effect from a pharmacological viewpoint, we reproduced the same effect in the laboratory setting by using experimental ischemic arm pain. We found that the opioid antagonist naloxone completely antagonized both placebo analgesia and the concomitant reduced heart rate response, whereas the beta-blocker propranolol antagonized the placebo heart rate reduction, but not placebo analgesia. By contrast, both placebo responses were present during muscarinic blockade with atropine, indicating no involvement of the parasympathetic system. In order to better understand the effects of naloxone and propranolol, we performed a spectral analysis of the heart rate variability for the identification of the sympathetic and parasympathetic components, and found that the beta-adrenergic low frequency (0.15 Hz) spectral component was reduced during placebo analgesia, an effect that was reversed by naloxone. These findings indicate that placebo analgesia is accompanied by a complex cascade of events which affect the cardiovascular system.

Adult↗
PubMed1999

An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm.

Placebo analgesia was produced by conditioning trials wherein heat induced experimental pain was surreptitiously reduced in order to test psychological factors of expectancy and desire for pain reduction as possible mediators of placebo analgesia. The magnitudes of placebo effects were assessed after these conditioning trials and during trials wherein stimulus intensities were reestablished to original baseline levels. In addition, analyses were made of the influence of these psychological factors on concurrently assessed pain and remembered pain intensities. Statistically reliable placebo effects on sensory and affective measures of pain were graded according to the extent of surreptitious lowering of stimulus strength during the manipulation trials, consistent with conditioning. However, all of these effects were strongly associated with expectancy but not desire for relief. These results show that although conditioning may be sufficient for placebo analgesia, it is likely to be mediated by expectancy. The results further demonstrated that placebo effects based on remembered pain were 3 to 4 times greater than those based on concurrently assessed placebo effects, primarily because baseline pain was remembered as being much more intense than it actually was. However, similar to concurrent placebo effects, remembered placebo effects were strongly associated with expected pain levels that occurred just after conditioning. Taken together, these results suggest that magnitudes of placebo effect are dependent on multiple factors, including conditioning, expectancy, and whether analgesia is assessed concurrently or retrospectively.

Administration, Topical↗
PubMed1999

Alternatives to placebo-controlled trials in psychiatry. ECNP Consensus Meeting, September 26, 1996, Amsterdam. European College of Neuropsychopharmacology.

Patients receiving placebo do not merely receive an inert substance but also receive support, concern, and reassurance that assists the therapeutic alliance and encourages the positive attitude that forms the basis of cognitive treatment. Response to non-specific factors is seen in all fields of medicine but is particularly potent in psychiatry. The placebo response is variable across settings and across time and is unpredictable. Historical data cannot therefore provide an adequate control for treatment effects in studies of new drugs. The scientific position is clear that a comparison against placebo is required for the unequivocal demonstration of the efficacy of a treatment. Evidence from at least two positive well designed and conducted placebo-controlled studies is generally accepted as appropriate to establish the efficacy of a drug. Attention to diagnosis, severity of illness, and to possible comorbid conditions is needed in the design and conduct of placebo-controlled studies in order to optimise the chance of obtaining valid data. The use of all data obtained, including dropouts due to lack of efficacy, should be maximised. The use of placebo may not be possible in some conditions that represent medical emergencies or may be difficult to justify in serious disorders where an effective treatment has already been established. Alternative designs to placebo-controlled studies can be considered. Consistent superior efficacy compared with a well accepted, effective treatment, given in an easily defended dose, is considered to be good evidence of efficacy provided that the studies are well designed and well conducted. Evidence of superior efficacy to an established effective comparator treatment may be regarded as evidence of efficacy. The demonstration of a dose-response relationship where one dose is found to be significantly better than another, can be taken as evidence for efficacy, particularly where there is already placebo-controlled evidence of the efficacy of the identified dose. Where a new treatment is found, under controlled conditions, to be equivalent to an existing well accepted comparator treatment, given at a clearly effective dose, this may be taken as evidence of efficacy, but only if the comparator is consistently superior to placebo and if equivalence has been defined beforehand. The claims for efficacy based on results from equivalence studies are less easily sustained than the evidence from placebo-controlled studies or studies demonstrating superior efficacy, due to the fact that those studies have no internal validation.

Controlled Clinical Trials as Topic↗
PubMed1999

The failure of placebo-controlled studies. ECNP Consensus Meeting, September 13, 1997, Vienna. European College of Neuropsychopharmacology.

In recent years an increasing number of clinical trials to test the efficacy of new potential treatments have failed to demonstrate a difference from placebo for either the new treatment or for an established reference drug. A rise in the response rate to placebo observed in a range of psychiatric disorders has not been paralleled by a rise in the response to drug and small effect sizes make it difficult to establish significant differences. A number of factors are thought to contribute to the rising placebo response or the smaller effect sizes. These include differences over time in the populations studied, changes in investigator behaviour, and failures of trial design. The inclusion of a greater number of patients with mild disorder or whose disorder has a fluctuating course is thought likely to increase the placebo response rates. Close attention needs to be paid to patient selection in terms of diagnosis, severity and absence of confounding comorbidity such as alcoholism, personality disorders or brief depression. The rising placebo response is associated with an increasing variability of placebo response seen in some centres. The ability of some centres to select appropriate patients for studies to demonstrate a separation of reference treatment and placebo and the inability of other centres suggests that a more careful selection of investigators is important. Selection should be based on their experience, their record from previous studies, and their aptitude for being trained. The inclusion of a reference treatment arm provides a useful means to judge the performance of individual centres. The exclusion of eccentric centres that fail to reach predetermined performance criteria, such as a failure to separate reference treatment from placebo, may be considered. Trial designs need to qualify adequately the study population and pay sufficient attention to diagnosis, minimum severity and comorbidity at entry. Greater care is needed in excluding concomitant overt or covert psychotherapy and in reducing the unnecessary therapeutic contact that has been increased unwittingly by some protocols. Identifying patients with prior stability of illness, with clear disability, and with a minimum severity at entry is likely to lower the placebo response substantially and increase the effect size and power of the study. The possible influence of comedication should also be considered. The inclusion of a placebo run in period is considered unhelpful and the use of better statistical techniques should be adopted to maximise the sensitivity of the study and increase the chances of testing efficacy.

Controlled Clinical Trials as Topic↗
PubMed2001

Interindividual variations in beliefs about the placebo effect: a study in 300 rheumatology inpatients and 100 nurses.

PATIENTS AND METHODS: Three hundred patients admitted to a rheumatology department (mean age, 49.2+/-15.5 years) and 100 nurses working in the same teaching hospital (mean age, 36+/-8.6 years) completed a questionnaire on the placebo effect in the treatment of pain. RESULTS: The patients believed that the percentages of subjects who responded occasionally or consistently to a placebo were 32% (+/- 22%) and 21% (+/- 17%), respectively. The figures given by the nurses were only slightly higher: 42% (+/- 23%) and 23% (+/- 17%), respectively. Only 27% of the patients and 58% of the nurses knew that pain could resolve completely under placebo therapy. The mean percentage improvement induced by placebo therapy as compared to the study analgesic was estimated at 21% (+/- 17%) by the patients and 30% (+/- 18%) by the nurses. Only 23% of patients and 24% of nurses knew about nocebo effects. CONCLUSION: These data suggest that during double-blind placebo-controlled trials three-quarters of the placebo arm patients who experience a marked improvement or a nocebo effect may believe they received the active drug. This is likely to reduce the difference between the placebo and active drug groups. Furthermore, most patients and nurses have a negative perception of placebo therapy. It may be useful to include a brief description of placebo and nocebo effects into the patient's information and informed consent documents used in double-blind placebo-controlled trials.

Adult↗
PubMed1999

Clinical and microbiological effects of initial periodontal therapy in conjunction with amoxicillin and clavulanic acid in patients with adult periodontitis. A randomised double-blind, placebo-controlled study.

The aim of the present study was to investigate the clinical and microbiological effects of initial periodontal therapy in conjunction with systemic amoxicillin plus clavulanic acid in adult periodontitis patients using a double-blind, parallel-group, and placebo-controlled protocol. 21 patients with a clinical diagnosis of generalised adult periodontitis were recruited. Clinical measurements and microbiological assessments were carried out at baseline, 3, and 12 months post-treatment. Approximately 6 weeks after initial periodontal treatment (3-6 h), patients were randomly assigned to receive coded study medication of 500 mg amoxicillin plus 125 mg clavulanic acid (Augmentin) or placebo, every 8 h for 10 days. Patients returned for follow-up visits 3, 6, 9, and 12 months after completion of the medication. The mean plaque index (PI) at baseline was 1.1 for placebo group and 0.9 for the test group. At 3 months, the PI had dropped to 0.3 in both groups, and was maintained during the rest of the study. The changes in bleeding on probing (BOP) and gingival index (GI) in the course of the study were similar in both groups. The mean whole mouth probing pocket depth (PPD) in the placebo group was 3.8 mm at baseline and 3.9 mm in the test group. A mean reduction of 1.0 mm in the placebo group and 0.9 mm in the test group was observed during the first 3 months. No further reduction in PPD was noticed during the study period in either group. There was no statistically significant difference in the PPD reduction between the 2 groups. The change in clinical attachment level (CAL) from baseline to 3 months amounted to 0.5 mm in both groups. Between 3 and 12 months, the CAL changed in neither group. In both groups, treatment resulted in a decrease in the number of spirochetes and motile rods in positive patients, but no significant differences between either group were noted in any of the dark field microscopy observations. At baseline, 1 patient in the placebo group and 2 patients in the test group were culture positive for Actinobacillus actinomycetemcomitans (Aa). After therapy, Aa was not detectable in the placebo group and 1 patient remained positive in the test group. In the placebo group, the number of patients positive for Porphyromonas gingivalis (Pg) decreased from 7 to 2 after therapy. In the test group, the 4 patients positive for Pg at baseline remained positive after therapy. In both groups, all subjects were positive for Prevotella intermedia (Pi) and Fusobacterium nucleatum (Fn) at baseline. At 12 months, all subjects had detectable subgingival Fn. 9 out of the 11 placebo and 8 of the 10 test patients remained positive for Pi. There were no differences in detection frequency of Peptostreptococcus micros (Pm) and Bacteroides forsythus (Bf) in both groups between baseline, 3, and 12 months post-treatment. The findings demonstrated that, in comparison to placebo, systemic amoxicillin plus clavulanic acid provided no additional clinical and microbiological effects in the treatment of adult periodontitis patients.

Adult↗
PubMed2002

Bupropion SR enhances weight loss: a 48-week double-blind, placebo- controlled trial.

OBJECTIVE: To critically examine the efficacy of bupropion SR for weight loss. RESEARCH METHODS AND PROCEDURES: This 24-week multicenter, double-blind, placebo-controlled study randomized obese adults to placebo, bupropion SR 300, or 400 mg/d. Subjects were counseled on energy-restricted diets, meal replacements, and exercise. During a 24-week extension, placebo subjects were randomized to bupropion SR 300 or 400 mg/d in a double-blinded manner. RESULTS: Of 327 subjects enrolled, 227 completed 24 weeks; 192 completed 48 weeks. Percentage losses of initial body weight for subjects completing 24 weeks were 5.0%, 7.2%, and 10.1% for placebo, bupropion SR 300, and 400 mg/d, respectively. Compared with placebo, net weight losses were 2.2% (p = 0.0468) and 5.1% (p < 0.0001) for bupropion SR 300 and 400 mg/d, respectively. The percentages of subjects who lost >or=5% of initial body weight were 46%, 59%, and 83% (p vs. placebo < 0.0001) for placebo, bupropion SR 300, and 400 mg/d, respectively; weight losses of >or=10% were 20%, 33%, and 46% (p vs. placebo = 0.0008) for placebo, bupropion SR 300, and 400 mg/d, respectively. Withdrawals, changes in pulse and blood pressure did not differ significantly from placebo at 24 weeks. Subjects who completed 48 weeks maintained mean losses of initial body weight of 7.5% and 8.6% for bupropion SR 300 and 400 mg/d, respectively. DISCUSSION: Bupropion SR 300 and 400 mg/d were well-tolerated by obese adults and were associated with a 24-week weight loss of 7.2% and 10.1% and sustained weight losses at 48 weeks.

Adolescent↗
PubMed2004

A meta-analysis of the placebo rates of remission and response in clinical trials of active Crohn's disease.

BACKGROUND & AIMS: Placebo-controlled, randomized clinical trials (PC-RCTs) are commonly used to assess therapies for Crohn's disease (CD). Knowledge of the placebo rates of remission and response and understanding of design factors that influence these rates is important for designing future clinical trials evaluating pharmacotherapy of CD. The aims of this study were to estimate rates of remission and response in patients with active CD receiving placebo and to identify factors influencing these rates. METHODS: We performed a systematic review and meta-analysis of PC-RCTs evaluating therapies for active CD identified from MEDLINE from 1966 to 2001. RESULTS: The pooled estimates of the placebo rates of remission and response were 18% (95% confidence interval, 14%-24%; range, 0%-50%) and 19% (95% confidence interval, 13%-28%; range, 0%-46%), respectively, both with significant heterogeneity among studies (P < 0.01 for remission, P < 0.03 for response). In multivariate models, study duration, number of study visits, and entry Crohn's Disease Activity Index score were important predictors of the placebo remission rate, with study duration the most important. However, no single factor could account for all of the heterogeneity. Factors that influence the placebo response rates were similar to those affecting the placebo remission rates. The absolute benefit of active treatment beyond placebo was generally larger when outcome was measured by response than remission. CONCLUSIONS: Placebo remission and response rates in PC-RCTs for active CD are variable. Study duration, number of study visits, and disease severity at entry have a large influence on placebo remission rates.

Controlled Clinical Trials as Topic↗