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Differential Effectiveness of Placebo Treatments A Systematic Review of Migraine Prophylaxis
Abstract
Importance
When analyzing results of randomized clinical trials, the treatment with the greatest specific effect compared with its placebo control is considered to be the most effective one. Although systematic variations of improvements in placebo control groups would have important implications for the interpretation of placebo-controlled trials, the knowledge base on the subject is weak.Objective
To investigate whether different types of placebo treatments are associated with different responses using the studies of migraine prophylaxis for this analysis.Design, Setting, and Participants
We searched relevant sources through February 2012 and contacted the authors to identify randomized clinical trials on the prophylaxis of migraine with an observation period of at least 8 weeks after randomization that compared an experimental treatment with a placebo control group. We calculated pooled random-effects estimates according to the type of placebo for the proportions of treatment response. We performed meta-regression analyses to identify sources of heterogeneity. In a network meta-analysis, direct and indirect comparisons within and across trials were combined. Additional analyses were performed for continuous outcomes.Exposure
Active migraine treatment and the placebo control conditions.Main Outcomes and Measures
Proportion of treatment responders, defined as having an attack frequency reduction of at least 50%. Other available outcomes in order of preference included a reduction of 50% or greater in migraine days, the number of headache days, or headache score or a significant improvement as assessed by the patients or their physicians. Results
Of the 102 eligible trials, 23 could not be included in the meta-analyses owing to insufficient data. Sham acupuncture (proportion of responders, 0.38 [95% CI, 0.30-0.47]) and sham surgery (0.58 [0.37-0.77]) were associated with a more pronounced reduction of migraine frequency than oral pharmacological placebos (0.22 [0.17-0.28]) and were the only significant predictors of response in placebo groups in multivariable analyses (P = .005 and P = .001, respectively). Network meta-analysis confirmed that more patients reported response in sham acupuncture groups than in oral pharmacological placebo groups (odds ratio, 1.88 [95% CI, 1.30-2.72]). Corresponding analyses for continuous outcomes showed similar findings.Conclusions and Relevance
Sham acupuncture and sham surgery are associated with higher responder ratios than oral pharmacological placebos. Clinicians who treat patients with migraine should be aware that a relevant part of the overall effect they observe in practice might be due to nonspecific effects and that the size of such effects might differ between treatment modalities.
... Other techniques that are available include transcranial alternating current stimulation, transcranial near-infrared stimulation, functional electrical stimulation, transcutaneous electrical nerve stimulation, pulsed radio-frequency, peripheral nerve stimulation, and electroacupuncture [29]. Meanwhile, numerous placebo treatments for migraine offer safe and alternative outcomes [30,31]. However, similar to the use of medication treatments, everyone will not respond the same way to nonpharmacological modalities. ...
... Studies have shown that endogenous opiate and dopamine circuits are affected in placebo pain research [138,139] and that individual differences in these systems may be directly related to hypoalgesia [140]. Sham acupuncture and surgery demonstrated a greater decrease in migraine attacks than oral placebos [30]. One sham acupuncture pain study showed that psychological factors could decrease migraine frequency and that baseline GM medial prefrontal cortex volume could be used to predict future placebo responses in migraine patients [60]. ...
... The potential side effects of tDCS are not yet known [123]. As for placebo, the observed effects might be due to nonspecific causes, and the extent of these effects will be different, depending on the techniques used [30]. ...
Migraine is a difficult disorder to identify with regard to its pathophysiological mechanisms, and its treatment has been primarily difficult owing to interindividual differences. Substantial rates of nonresponsiveness to medications are common, making migraine treatment complicated. In this review, we systematically analyzed recent studies concerning neuroimaging findings regarding the neurophysiology of migraine. We linked the current imaging research with anecdotal evidence from interindividual factors such as duration and pain intensity of migraine, age, gender, hormonal interplay, and genetics. These factors suggested the use of nonpharmacological therapies such as transcranial magnetic stimulation, transcranial direct current stimulation, and placebo therapy for the treatment of migraine. Finally, we discussed how interindividual differences are related to such nondrug treatments.
... The therapeutic context can be subdivided into external and internal context (Wager & Atlas, 2015). External context may include characteristics of the person administering the placebo (Howe, Goyer, & Crum, 2017), patient-practitioner/participant-experimenter relationship (Kaptchuk et al., 2008), type of placebo object (Meissner et al., 2013), and the environment in which the placebo is administered (Wager & Atlas, 2015). Internal context refers to participant factors such as outcome expectations, desires, memories, personality traits, mood, and precognitive associations (See Table 1.1 for definitions of key terms; Kelley et al., 2009;Linde et al., 2007;Morton, Watson, El-Deredy, & Jones, 2009;Wager & Atlas, 2015). ...
... By manipulating expectations and/or using learned associations, researchers have detected placebo effects in a variety of clinical and nonclinical domains. Robust placebo effects have been documented in both subjective and objective measures for a variety of clinical domains, including irritable bowel syndrome (Kaptchuk et al., 2008;Lee et al., 2012;Price, Craggs, Verne, Perlstein, & Robinson, 2007;Vase, Robinson, Verne, & Price, 2005;Vase, Robinson, Verne, & Price, 2003), migraines (Meissner et al., 2013), neuropathic pain (Tuttle et al., 2015), various types of chronic pain (Jonas et al., 2015;Madsen, Gøtzsche, & Hróbjartsson, 2009), osteoarthritis (Bannuru et al., 2015;Moseley et al., 2002), urological conditions (Sorokin, Schatz, & Welliver, 2015), Parkinson's Disease (Benedetti et al., 2004;Benedetti et al., 2003;de la Fuente-Fernández et al., 2001;Goetz et al., 2008;Lidstone et al., 2010;Schmidt, Braun, Wager, & Shohamy, 2014), Schizophrenia (Rutherford et al., 2014), depression (Cuijpers et al., 2012;Fournier et al., 2010;Khan, Faucett, Lichtenberg, Kirsch, & Brown, 2012;Kirsch, 2011;Kirsch et al., 2008;Kirsch & Sapirstein, 1998;Leuchter, Hunter, Tartter, & Cook, 2014), and anxiety disorders (Bandelow et al., 2015). Moreover, placebo effects have been effective in reducing various types of experimental pain (Atlas et al., 2012;Montgomery & Kirsch, 1997;Voudouris et al., 1985Voudouris et al., , 1989Voudouris et al., , 1990 and emotional distress (B. ...
Placebos offer an effective way to manage a host of clinical disorders and nonclinical conditions. However, the commonly held belief that people need to be deceived in order for placebos to work prevents their widespread use. Research on placebos administered without deception (non-deceptive placebos) has challenged this assumption and opens the possibility of harnessing the beneficial effects of placebos. However, as this research accumulates, old placebo issues proliferate, such as controversy about whether the beneficial effects from non-deceptive placebos reflect true effects or are the byproduct of response bias. In four studies, I attempted to address some of these new issues and advance the basic understanding of non-deceptive placebo effects. Chapter I provides an overview of placebos, placebo effects, and non-deceptive placebos. Chapter II tests a novel non-deceptive placebo manipulation and finds beneficial effects on self-reported emotional distress; however, it was not effective for skin conductance response or an implicit cognitive-based measure of emotional reactivity. Chapter II also shows that the non-deceptive placebo manipulation may work for female participants but not male participants, dictating the methodology of subsequent studies. Chapter III replicates this finding with an all-female sample and finds a similar pattern of modulation for self-reported emotional distress but none for skin conductance response. Chapter IV uses a different objective measure but finds null effects on pain tolerance duration. Chapter V uses an objective neural measure and finds that non-deceptive placebos reduced neural measures of emotional reactivity, suggesting that effects are more than response bias and are true psychobiological effects. Chapter V provides important insights into the neural mechanisms and time course of the non-deceptive placebo effect. Non-deceptive placebos appear to increase attentional allocation to emotional stimuli before exerting their regulatory effect at a later time. Taken together, this work presents a nuanced understanding of non-deceptive placebo effects, suggesting that they are indeed true psychobiological effects in specific circumstances: the objective measure must be carefully selected, with the type of manipulation and the time course of beneficial effects in mind. This delayed regulatory finding provides an important insight regarding the beneficial effects of non-deceptive placebos and when these effects should be assessed. Moreover, this work has important translational implications for medical practice, psychopathology, and emotion regulation in daily life.
... Beyond the numerous studies in animals, classic conditioning has also been proven as an analgesic in humans in different pathologies associated with pain [145][146][147][148][149]. Multiple meta-analyses from clinical studies report a weak therapeutic effect on central neuropathic pain [148] and the complex regional pain syndrome, and a moderate effect in postherpetic neuralgia [150], peripheral diabetic neuropathy [150], VIH associated pain [150], fibromyalgia [151], and migraines [146,147,152]. ...
... Beyond the numerous studies in animals, classic conditioning has also been proven as an analgesic in humans in different pathologies associated with pain [145][146][147][148][149]. Multiple meta-analyses from clinical studies report a weak therapeutic effect on central neuropathic pain [148] and the complex regional pain syndrome, and a moderate effect in postherpetic neuralgia [150], peripheral diabetic neuropathy [150], VIH associated pain [150], fibromyalgia [151], and migraines [146,147,152]. On the other hand, only three open-label place studies related to pain have been performed to this day [130,133,153]. ...
The placebo effect can be defined as the improvement of symptoms in a patient after the administration of an innocuous substance in a context that induces expectations regarding its effects. During recent years, it has been discovered that the placebo response not only has neurobiological functions on analgesia, but that it is also capable of generating effects on the immune and endocrine systems. The possible integration of changes in different systems of the organism could favor the well-being of the individuals and go hand in hand with conventional treatment for multiple diseases. In this sense, classic conditioning and setting expectations stand out as psychological mechanisms implicated in the placebo effect. Recent advances in neuroimaging studies suggest a relationship between the placebo response and the opioid, cannabinoid, and monoaminergic systems. Likewise, a possible immune response conditioned by the placebo effect has been reported. There is evidence of immune suppression conditioned through the insular cortex and the amygdala, with noradrenalin as the responsible neurotransmitter. Finally, a conditioned response in the secretion of different hormones has been determined in different studies; however, the molecular mechanisms involved are not entirely known. Beyond studies about its mechanism of action, the placebo effect has proved to be useful in the clinical setting with promising results in the management of neurological, psychiatric, and immunologic disorders. However, more research is needed to better characterize its potential use. This review integrates current knowledge about the psycho-neuro-endocrine-immune basis of the placebo effect and its possible clinical applications.
... 6 In migraine, subcutaneous placebo was superior to the oral route, 9,26 another meta-analysis showed greater effect with intranasal route, 30 and finally sham acupuncture surgery and sham surgery had more pronounced reduction of migraine frequency than oral placebos. 27 Such studies corroborate the hypothesis that a good part of the clinical treatment of migraine might be due to nonspecific effects and that the size of such effects might differ between different routes of administration. Therefore, we aim to answer the question: Do different routes of administration have different placebo effects in migraine? ...
... 34 Placebo response in BoNTA could be affected by the result in forehead wrinkle improvement in the treatment group. The metaanalysis, 27 which showed the superiority of sham acupuncture surgery and sham surgery over oral placebo, questions whether the placebo effect of head injection vs botulin toxin would not be inferior because the side effect of muscle relaxation would lead to the unblinding of the patients and physicians, decreasing the placebo effect. Despite this fact having an impact on the placebo response, in our study we saw the superiority of the placebo response through head injection in relation to other routes of administration, going contrary to this thought. ...
Placebo response is a powerful determinant of health outcomes in several disorders. Meta-analysis of clinical trials in pain conditions shows that it can contribute up to 75% of the overall treatment effect. Placebo response deriving from different routes of administration is poorly understood in primary headaches' pharmacological prevention. Thus, this meta-analysis aims to analyze how different routes of administration affect the placebo response in chronic migraine (CM). We conducted a meta-analysis with 7 randomized, double-blind, placebo-controlled clinical trials, with 5672 patients older than 18 years who suffer from CM without associated comorbidities. We compared those who received a placebo-administered agent for the preventive treatment of CM subcutaneous, endovenous, or oral against those who received multiple head injections. The primary outcome was reduction in the number of days with migraine in the month assessed at 12, 16, and 24 weeks of treatment compared with baseline. Our study shows that placebo responses were greater when botulinum toxin was applied to the head, followed by intravenous injection of the anti-calcitonin gene-related peptide monoclonal antibody eptinezumab. Oral topiramate and subcutaneous monoclonal showed no difference, being inferior to head injection. Administration route affects placebo responses in CM preventive treatment. Elucidating the underlying mechanisms that mediate a placebo response in migraine treatment is beneficial to clinical practice and drug development, especially when comparing drugs with different routes of administration, with the effect of application to the head being superior to the other routes in this study. In our study the placebo response accounted for approximately 75% of the therapeutic gain in the treatment of CM.
... In clinical trials (CT), a placebo is commonly used as a control therapy to evaluate the clinical effectiveness of the treatments tested. 1 Placebo has been defined as 'an inert substance or sham procedure that is provided to research participants with the aim of making it impossible for them, and usually the researchers themselves, to know who is receiving an active or inactive intervention.' 2 Placebo interventions are methodological tools used to treat participants in the study arm and the control arm in exactly the same way, except that the study group receives an active substance and the control group does not. ...
... Studies suggested that physical placebo treatments might have a greater effect on these types of outcome compared with pharmacological placebo and that this effect might be a consequence of physical contact. 1 16 17 Moreover, especially when subjective PROs outcomes are used, the absence of clinician blinding could also increase the possibility of performance bias. 14 Therefore, a better understanding of sham procedures in manual treatment would be fundamental to define the real difference in efficacy between manual and ST, with a better knowledge of the effect of manual contact on PROs such as pain relief and drop-outs. ...
Objective
To assess the effects and reliability of sham procedures in manual therapy (MT) trials in the treatment of back pain (BP) in order to provide methodological guidance for clinical trial development.
Design
Systematic review and meta-analysis.
Methods and analysis
Different databases were screened up to 20 August 2020. Randomised controlled trials involving adults affected by BP (cervical and lumbar), acute or chronic, were included.
Hand contact sham treatment (ST) was compared with different MT (physiotherapy, chiropractic, osteopathy, massage, kinesiology and reflexology) and to no treatment. Primary outcomes were BP improvement, success of blinding and adverse effect (AE). Secondary outcomes were number of drop-outs. Dichotomous outcomes were analysed using risk ratio (RR), continuous using mean difference (MD), 95% CIs. The minimal clinically important difference was 30 mm changes in pain score.
Results
24 trials were included involving 2019 participants. Very low evidence quality suggests clinically insignificant pain improvement in favour of MT compared with ST (MD 3.86, 95% CI 3.29 to 4.43) and no differences between ST and no treatment (MD -5.84, 95% CI −20.46 to 8.78).
ST reliability shows a high percentage of correct detection by participants (ranged from 46.7% to 83.5%), spinal manipulation being the most recognised technique.
Low quality of evidence suggests that AE and drop-out rates were similar between ST and MT (RR AE=0.84, 95% CI 0.55 to 1.28, RR drop-outs=0.98, 95% CI 0.77 to 1.25). A similar drop-out rate was reported for no treatment (RR=0.82, 95% 0.43 to 1.55).
Conclusions
MT does not seem to have clinically relevant effect compared with ST. Similar effects were found with no treatment. The heterogeneousness of sham MT studies and the very low quality of evidence render uncertain these review findings.
Future trials should develop reliable kinds of ST, similar to active treatment, to ensure participant blinding and to guarantee a proper sample size for the reliable detection of clinically meaningful treatment effects.
PROSPERO registration number
CRD42020198301.
... We considered a patient a "responder to acute treatment" when they achieved pain freedom within 2 h in ≥ 4 of 5 attacks while insufficient responders achieved pain freedom in ≤ 3 of 5 attacks [14]. As for a response to preventative treatment, we considered a patient a responder to "preventative treatment" when there was a ≥ 50% reduction in the monthly headache days frequency compared to the baseline frequency [15]. ...
Introduction
White matter hyperintensities (WMHs) are frequently found in migraineurs. However, their clinical significance and correlation to different migraine phenotypes and treatment responses are not well defined. The study aimed to examine the association of WMHs with migraine clinical patterns and treatment response.
Aim of work
We aimed to evaluate the association between WMHs and migraine phenotypes and explore the relationship of WMHs to treatment response.
Methods
Our cross-sectional study formed of 500 migraineurs who sought treatment in Kafr el-sheik university hospital and underwent (3 T) MRI to evaluate WMHs. Different migraine phenotypes were compared between patients with and without WMHs. According to reduced headache pain intensity and frequency, these patients were divided into treatment responder and non-responder groups.
Results
A total of 145 patients (29%) had WMHs. Patients with WMHs were significantly older, had a longer disease duration, and higher attack frequency. Patients who did not respond to acute and maintenance medications had a higher frequency of WMHs and high WMHs Scheltens score. Migraine with Aura and the presence of vomiting and dizziness were predictors for the development of WMHs.
Conclusion
WMHs are more common in migraine with aura. It is more frequent in migraine associated with vomiting and dizziness. WMHs increased with advancing age and more severe disease burden. Poorer response to acute and prophylactic medications was found in patients with WMHs.
... Apart from this, we found that acupuncture has no effect on reducing the degree of PSD compared with antidepressants; these results are contrary to those reported in a previous study [43]. When exploring the reasons for this discrepancy, we found that the placebo effect [44] is an important factor that cannot be ignored. Placebo interventions aim to intentionally utilize the placebo effect by increasing patients' expectations [45]. ...
Background
Acupuncture for post-stroke depression (PSD) has been evolving, but uncertainty remains. To assess the existing evidence from randomized clinical trials (RCTs) of acupuncture for PSD, we sought to draw conclusions by synthesizing RCTs.
Methods
An exhaustive literature search was conducted in seven electronic databases from their inception dates to April 19, 2020, to identify systematic reviews (SRs) and meta-analyses (MAs) on this topic. The primary RCTs included in the SRs/MAs were identified. We also conducted a supplementary search for RCTs published from January 1, 2015, to May 12, 2020. Two reviewers extracted data separately and pooled data using RevMan 5.3 software. The quality of evidence was critically appraised with the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) system.
Results
A total of 17 RCTs involving 1402 patients were included. Meta-analysis showed that participants who received a combination of acupuncture and conventional treatments exhibited significantly lower scores on the HAM-D 17 , HAM-D 24 and HAM-D (MD, − 5.08 [95% CI, − 6.48 to − 3.67], I ² = 0%), (MD, − 9.72 [95% CI, − 14.54 to − 4.91], I ² = 65%) and (MD, − 2.72 [95% CI, − 3.61 to − 1.82], respectively) than those who received conventional treatment. However, there was no significant difference in acupuncture versus antidepressants in terms of the 17-item, 24-item and HAM-D scales (MD, − 0.43 [95% CI, − 1.61 to 0.75], I ² = 51%), (MD, − 3.09 [95% CI, − 10.81 to 4.63], I ² = 90%) and (MD, − 1.55 [95% CI, − 4.36 to 1.26], I ² = 95%, respectively). For adverse events, acupuncture was associated with fewer adverse events than antidepressants (RR, 0.16 [95% CI, 0.07 to 0.39], I ² = 35%), but there was no significant difference in the occurrence of adverse events between the combination of acupuncture and conventional treatments versus conventional treatments (RR, 0.63 [95% CI, 0.21 to 1.83], I ² = 38%). The quality of evidence was low to very low due to the substantial heterogeneity among the included studies.
Conclusions
The current review indicates that acupuncture has greater effect on PSD and better safety profile than antidepressants, but high-quality evidence evaluating acupuncture for PSD is still needed.
... Furthermore, additional trials were identified from an existing systematic review of migraine treatments. 20 For search terms, see Supplemental Information 1. In total, the search led to 9012 articles (Supplemental Fig 3). ...
Context:
Migraine is a common neurologic disorder in children and adolescents. However, a comparison of multiple nonpharmacological treatments is lacking.
Objective:
To examine whether nonpharmacological treatments are more effective than waiting list and whether there are differences between interventions regarding efficacy.
Data sources:
Systematic review and network meta-analysis of studies in Medline, Cochrane, Embase, and PsycINFO published through August 5, 2019.
Study selection:
Randomized controlled trials of nonpharmacological treatments in children and adolescents diagnosed with episodic migraine.
Data extraction:
Effect sizes, calculated as standardized mean differences (SMDs) for the primary outcome efficacy, were assessed in a random-effects model.
Results:
Twelve studies (N = 576) were included. When interventions were classified into groups on the basis of similarity of treatment components, self-administered treatments, biofeedback, relaxation, psychological treatments, and psychological placebos were significantly more effective than waiting list with effect sizes ranging between SMD = 1.14 (95% confidence interval, 0.09 to 2.19) for long-term psychological placebos to SMD = 1.44 (95% confidence interval, 0.26 to 2.62) for short-term self-administered treatments. However, when all interventions were examined individually (ie, 1 node per intervention), none were significantly more effective compared with waiting list, mainly because of lack of statistical power.
Limitations:
Because of our focus on pediatric migraine, only a small number of studies could be included.
Conclusions:
Our findings reveal that components of nonpharmacological interventions are effective in treating pediatric migraine. Some effects have to be interpreted carefully because they are based on small studies. Future researchers should identify factors associated with individual responses in large, multicentered studies.
... For complex intervention studies, inert pills are not considered adequate controls, mainly because less elaborate placebos produce less pronounced placebo effects [46,89,54]. Efficacy trials of complex interventions require complex control interventions, matching some or most features of the intervention. ...
... Placebo research has shown that effect sizes increase with the "invasiveness" of the procedure (pills < acupuncture < sham surgery). 25 In line with previous findings from our group, 9 most patients who experienced a seizure during suggestive induction did so through hyperventilation or photic stimulation, but 44% only did so after an intravenous injection (accounting for 25% of all placebo inductions performed across the study). Although some have argued for the abolishment of intravenous placebo for suggestive induction in favor of exclusively non-invasive, placebo procedures (hyperventilation or photic stimulation), 10,11 our findings suggest that this will come at a significant cost to the diagnostic yield. ...
Objective
To determine the utility of suggestive seizure induction for inpatient work‐up of suspected psychogenic nonepileptic seizures (PNES).
Methods
Prospective study of epilepsy center inpatient admissions with suspected PNES. Patients were randomized to undergo suggestive induction first (group A) and then, if necessary, long‐term video–electroencephalography (EEG) monitoring, or vice versa (group B). Diagnostic pathways were compared. Potential clinical predictors for diagnostic success were evaluated.
Results
Length of in‐hospital stay did not significantly differ between groups. Suspicion of PNES was confirmed in 43 of 77 (56%) patients, evenly distributed between group A (22 of 39) and group B (21 of 38). In nine patients, recorded habitual seizures were epileptic and in 25 cases, no diagnostic event could be recorded. Diagnosis of PNES was ascertained primarily by recording a typical seizure through suggestive induction in 24 patients and through long‐term monitoring in 19 patients. In group A (induction first), monitoring was not deemed necessary in 21% of cases. In group B (monitoring first), 13% would have remained inconclusive without suggestive induction. Patients who reported triggers to their habitual seizures were not more likely to have spontaneous or provoked PNES during monitoring or suggestive inducion, respectively. Patients with subjective seizure prodromes (auras) were significantly more likely to have a PNES during suggestive induction than those without (odds ratio [OR] 3.4, 95% confidence interval [CI] 1.1‐10.4). There was no significant difference in seizure frequency between patients with spontaneous PNES during long‐term monitoring and those with nondiagnostic monitoring sessions.
Significance
Our results support the notion that suggestive seizure induction can reduce the number of inconclusive inpatient workups, and can obviate resource‐intensive long‐term monitoring in one fifth of cases. Patients who are aware of prodromes might have a higher chance of having seizures induced through suggestion.
... Finally, contextual factors such as the features of the medical setting, the clinical environment, the invasiveness of the intervention, as well as the appearance of the health care provider are also able to shape patients' expectation and treatment outcome [39,40]. For example, more invasive interventions such as acupuncture, surgery, injections, or infusions seemed to induce a more pronounced treatment expectation and subsequently a larger health benefit than less invasive oral treatments such as ingestion of a pill [41,42]. cal levels. ...
Patients’ expectations towards the benefit of a treatment are key determinants of placebo responses and can affect the development and course of medical conditions and the efficacy and tolerability of active medical treatment. The mechanisms mediating these placebo and nocebo effects have been best described in the field of experimental pain and placebo analgesia. However, also in dermatology experimental and clinical studies demonstrate that various skin diseases such as inflammatory dermatoses and allergic reactions can be modulated by patients’ expectations. Dermatologists should consider the important modulatory role of patients’ expectations on the efficacy and tolerability of specific treatments and the key role of verbal information, patients’ prior treatment experiences (associative learning), and the quality and quantity of doctor-patient communication in shaping treatment expectation. As a consequence, techniques aiming at maximizing patients’ expectation effects should be implemented into daily clinical routine. By contrast, in clinical studies expectation effects should be maximally controlled and harmonized to improve the “assay sensitivity” to detect new compounds. Further translational studies, also in dermatoses that have not been investigated yet, are needed to better characterize the mechanisms underlying patients’ expectation and to gain further insights into potential clinical implications of these effects in dermatologic conditions. Therefore, in this review, we provide a brief overview on the concept of expectation effects on treatment outcome in general, summarize what is already known about this topic for dermatologic diseases, and finally present the relevance of this topic in clinical dermatology.
... In a systematic review of migraine prophylaxis, Meissner et al. discussed that more invasive placebo treatments had a stronger effect than less invasive ones. A stronger reduction of migraine frequency was found in sham acupuncture (proportion of responders, 0. 38 [75]. ...
Objective:
Current recommendations controversially discuss local infiltration techniques as specific treatment for refractory pain syndromes. Evidence of effectiveness remains inconclusive and local infiltration series are discussed as a therapeutic option in patients not responding to standard therapy. The aim of this study was to investigate the effectiveness of infiltration series with techniques such as sphenopalatine ganglion (SPG) block and ganglionic local opioid analgesia (GLOA) for the treatment of neuropathic pain in the head and neck area in a selected patient group.
Methods:
In a retrospective clinical study, 4960 cases presenting to our university hospital outpatient pain clinic between 2009 and 2016 were screened. Altogether, 83 patients with neuropathic pain syndromes receiving local infiltration series were included. Numeric rating scale (NRS) scores before, during, and after infiltration series, comorbidity, and psychological assessment were evaluated.
Results:
Maximum NRS before infiltration series was median 9 (IQR 8-10). During infiltration series, maximum NRS was reduced by mean 3.2 points (SD 3.3, p < 0.001) equaling a pain reduction of 41.0% (SD 40.4%). With infiltration series, mean pain reduction of at least 30% or 50% NRS was achieved in 54.2% or 44.6% of cases, respectively. In six percent of patients, increased pain intensity was noted. Initial improvement after the first infiltration was strongly associated with overall improvement throughout the series.
Conclusion:
This study suggests a beneficial effect of local infiltration series as a treatment option for refractory neuropathic pain syndromes in the context of a multimodal approach. This effect is both significant and clinically relevant and therefore highlights the need for further randomized controlled trials.
... Several studies have suggested that sham acupuncture may have a stronger effect than placebo pills, which may be associated with the special ritual of acupuncture and a better patient-doctor relationship during treatment [43][44][45]. Many randomized controlled trials comparing acupuncture with sham acupuncture found a slight difference between them [12,25,46]; although an individual patient data meta-analysis found a statistically significant difference between them in the treatment of chronic pain, the difference was clinically irrelevant [47]. ...
Background
Acupuncture is commonly used for migraine prophylaxis; however, evidence of its efficacy was equivocal.AimWe aimed to evaluated the efficacy of acupuncture in migraine prophylaxis and calculated the required information size (RIS) to determine whether further clinical studies are required.Methods
We searched Cochrane library, EMBASE and PubMed from inception to April 23th, 2020. Randomized trials that compared acupuncture with conventional drug therapy or sham acupuncture were included. The primary outcome was migraine episodes. Secondary outcomes were responder rate and adverse event.ResultsTwenty studies (n = 3380) met the inclusion criteria. When it comes to migraine episodes, Acupuncture was superior over sham acupuncture [SMD = − 0.29, 95% CI (− 0.47 to − 0.11), P = 0.002] after treatment, while the difference between acupuncture and prophylactic drugs was not significant [SMD = − 0.21, 95% CI (− 0.42 to 0.00), P = 0.06].Both TSA graphs indicated that more RCTs are needed. As for responder rate, the results after treatment showed that acupuncture was statistically significantly better than sham acupuncture [RR 1.30, 95% CI (1.09–1.55), P = 0.003] as well as conventional drugs [RR 1.24, 95% CI (1.04–1.48), P = 0.01]. Both of their cumulative Z-curves intersected with the trial sequential monitoring boundaries favoring acupuncture. Compared to prophylactic medication, acupuncture can cause less adverse events [RR 0.34, 95% CI (0.14–0.81), P = 0.01].Conclusion
Acupuncture can reduce migraine episodes compared to sham one and can be an alternative and safe prophylactic treatment for conventional drugs therapy, but it should be further verified through more RCTs. Available studies suggested acupuncture was superior to sham acupuncture and conventional drugs in terms of responder rate as verified by TSA.
... Whether the clinical effect of acupuncture is equivalent to placebo acupuncture has always been the focus of debate. However, it is undeniable that the nonspecific effect of acupuncture is an important part of the clinical effects [51]. In fact, clinical practice desires to explicitly understand the maximum potential of an intervention. ...
Background
Acupuncture, as one of the promising non-pharmacological interventions, has been proved to be beneficial for patients. However, the magnitude of acupuncture’s specific and nonspecific effects, as well as their neurological and psychological determinants, remains unclear. Therefore, this study is designed to examine the acupuncture efficacy, investigate whether the brain mechanisms between the specific and nonspecific effects of acupuncture are different, and to evaluate how psychological factors affect the acupuncture effects.
Methods
This is a randomized, controlled, crossover clinical trial. A total of 60 patients with knee osteoarthritis will receive 4 weeks of acupuncture treatment and 4 weeks of sham acupuncture treatment in a random order separated by a washout period of 2 weeks. The changes in clinical characteristics based on pain-related scales will be assessed to investigate the clinical efficacy of acupuncture. Resting state functional magnetic resonance imaging (fMRI) scans will be used to identify the brain activity changes related to the specific and nonspecific effects of acupuncture. The questionnaires of psychological factors will be used to evaluate patients’ psychological properties. Correlation and mediation analyses will be conducted among psychological factors, brain activity changes, and symptoms improvement to explore the neurological and psychological correlates of the acupuncture effects.
Discussion
This study will concentrate on distinguishing and clarifying the specific and nonspecific effects of acupuncture. The results of this study may contribute to rationally optimize the acupuncture therapies by flexible application of the specific and nonspecific effects of acupuncture.
Trial registration
Chinese Clinical Trial Registry ChiCTR1900025807. Registered on 9 September 2019
... It is often regarded as a sham control group, because its acupuncture depth is only broken and does not reach the anatomical layer of the acupuncture point. Studies [42][43][44] have shown that the placebo effect of sham acupuncture is more pronounced than drug-based placebo, especially for subjective outcomes and pain management. Therefore, our study has set a sham acupuncture group to eliminate the effects of placebo effects and patients' expectations. ...
Introduction:
Whether there is the long-term effect of acupuncture on patients with knee osteoarthritis (KOA) or not is controversial. According to the basic theory of traditional acupuncture, deqi is the key to the efficacy of acupuncture. This randomized controlled trial aims to evaluate the existence of long-term effects caused by deqi in patients with KOA.
Methods and analysis:
A three-armed, parallel-design, randomized controlled trial is underway in China.108 KOA patients recruited by the rehabilitation center of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine will be randomly assigned to the acupuncture with deqi group (A group), the acupuncture without deqi group (B group) and the waiting-list group (C group). Each patient will receive 5 30-minute sessions per week for 4 consecutive weeks and rest for 2 days between treatments, and undergo a 20-week follow-up. The primary outcome is the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC score). The secondary outcomes include Western Ontario and McMaster Universities Osteoarthritis index (WOMAC score), Knee Injury and Osteoarthritis Outcome Score (KOOS), arthritis quality of life measurement scale simplified scale (AIMS2-SF), emotional monitoring and expectation scale. The pain visual analogue scale (VAS) and the Chinese version of modified Massachusetts General Hospital Acupuncture Sensation Scale (C-MMASS) will be used to evaluate the deqi sensation after each acupuncture treatment. At the same time, adverse events (AEs) occurred in the whole process will be recorded and analyzed. We will perform an intention-to-treat analysis and protocol (PP) analysis to statistically analyze the results of the trial.
Discussion:
This trial will be useful to study the long-term effect of acupuncture and the influence of the deqi sensation on the long-term in the treatment of KOA, and to provide a clinical basis for treatment of patients with mild to moderate knee osteoarthritis in clinic.
Trial registration:
Chinese Clinical Trial Registry, IDF: ChiCTR2000029291. Registered on January 21, 2020.
... From an average baseline of 16 monthly migraine days, eptinezumab-treated patients had approximately 8 fewer migraine days each month on average relative to baseline and approximately 2 days fewer relative to placebo. The placebo effect observed in PROMISE-2 may be due to the route of administration, frequency of on-site visits, patient expectations and beliefs, or other contextual factors [17][18][19][20]. Despite the placebo response, eptinezumab demonstrated statistically and nominally different improvements in migraine frequency across 24 weeks of treatment. ...
Background:
PROMISE-2 was a phase 3, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of repeat intravenous (IV) doses of the calcitonin gene-related peptide-targeted monoclonal antibody eptinezumab (ALD403) for migraine prevention in adults with chronic migraine. This report describes the results of PROMISE-2 through 24 weeks of treatment.
Methods:
Patients received up to two 30-min IV administrations of eptinezumab 100 mg, 300 mg, or placebo separated by 12 weeks. Patients recorded migraine and headache endpoints in a daily eDiary. Additional assessments, including patient-reported outcomes, were performed at regularly scheduled clinic visits throughout the 32-week study period (screening, day 0, and weeks 2, 4, 8, 12, 16, 20, 24, and 32).
Results:
A total of 1072 adults received treatment: eptinezumab 100 mg, n = 356; eptinezumab 300 mg, n = 350; placebo, n = 366. The reduction in mean monthly migraine days observed during the first dosing interval (100 mg, - 7.7 days; 300 mg, - 8.2 days; placebo, - 5.6 days) was further decreased after an additional dose (100 mg, - 8.2 days; 300 mg, - 8.8 days; placebo, - 6.2 days), with both doses of eptinezumab demonstrating consistently greater reductions from baseline compared to placebo. The ≥50% and ≥ 75% migraine responder rates (MRRs) increased after a second dose, with more eptinezumab-treated patients experiencing migraine response than placebo patients (≥50% MRRs weeks 13-24: 100 mg, 61.0%; 300 mg, 64.0%; placebo, 44.0%; and ≥ 75% MRRs weeks 13-24: 100 mg, 39.3%; 300 mg, 43.1%; placebo, 23.8%). The percentages of patients who improved on patient-reported outcomes, including the Headache Impact Test and Patient Global Impression of Change, increased following the second dose administration at week 12, and were greater with eptinezumab than with placebo at all time points. No new safety concerns were identified with the second dose regarding the incidence, nature, and severity of treatment-emergent adverse events.
Conclusion:
Eptinezumab 100 mg or 300 mg administered IV at day 0 and repeated at week 12 provided sustained migraine preventive benefit over a full 24 weeks and demonstrated an acceptable safety profile in patients with chronic migraine.
Trial registration:
ClinicalTrials.gov (Identifier: NCT02974153 ). Registered November 23, 2016.
... 48 The placebo influence includes patient enthusiasm and optimism to have a new treatment, increased doctor-patient interactions, increased expectations of treatment effects, and decreased negative emotions such as anxiety and invasiveness of the procedure. [49][50][51] The placebo effect in interventional procedures with medical device insertion can be significant, particularly in measuring subjective outcomes like pain. [52][53][54][55] There is a controversy surrounding placebo (sometimes called sham intervention) methodology as it may be challenging to reproduce the entire experience of the treatment arm without breaking patient and physician blinding. ...
Background:
Healthcare clinical and even policy decisions are progressively made based on research-based evidence. The process by which the appropriate trials are developed and well-written manuscripts by means of evidence-based medicine recommendations has resulted in unprecedented necessity in evidence-based medicine in neuromodulation.
Methods:
The essential considerations in the planning of neuromodulation research are discussed in the light of available scientific literature as well as the authors' scientific expertise regarding research study design and scientific manuscript preparation.
Conclusion:
This article should enable the reader to understand how to appropriately design a clinical research study and prepare scientific manuscripts. The high-quality and well-designed studies, when performed and reported effectively, support evidence-based medicine and foster improved patient outcomes.
... Second, we performed a traditional contrastbased meta-analysis, in which the effect size of an intervention may vary as the effect size of its control changes. Linde's study showed the placebo effect of different treatments varied significantly (Meissner et al., 2013), and a recent systematic review showed that the response rate to CGRPmAbs placebo was 23.6 vs. 36.4% in BoNT-A placebo-showing a difference as large as 13% (Kokoti et al., 2020). These findings indicated that a head-to-head comparison between CGRPmAbs and BoNT-A may still be warranted. ...
Purpose: Calcitonin gene-related peptide monoclonal antibodies (CGRPmAbs) are new agents approved by the US Food and Drug Administration for preventive treatment of chronic migraine. Comparison between CGRPmAbs and previously approved Botulinum neurotoxin A (BoNT-A) will inform optimal preventive treatment of chronic migraine, but head-to-head trials are lacking. We therefore aimed to perform adjusted indirect comparison between CGRPmAbs and BoNT-A through a meta-analysis.
Methods: OVID MEDLINE, EMBASE and the Cochrane central register of controlled trials, clinical registries, and government websites were searched from inception to September 2019. Randomized controlled trials comparing CGRPmAbs or BoNT-A with placebo in the preventive treatment of chronic migraine were included. The primary outcomes were headache days and migraine days measured at week 12. Data were synthesized by using a frequentist approach; and the treatments were ranked by P-score.
Results: We included 10 trials ( n = 4,678) after screening 1049 candidates. Six trials were with low risk of bias. Fremanezumab had an effect similar to BoNT-A in the reduction of headache days at week 12 (standard mean difference [SMD] 0.08, 95%CI -0.55 to -0.7). Galcanezumab reduced more migraine days than BoNT-A at week 12 (SMD, -0.94, 95%CI −1.24 to −0.63); fremanezumab showed similar findings (SMD, −0.55, 95%CI −0.85 to −0.24). Galcanezumab and fremanezumab had better effect in mitigating headache impact at week 12. CGRPmAbs and BoNT-A had similar adverse event rate.
Conclusion: CGRPmAbs and BoNT-A had similar effect in the preventive treatment of chronic migraine. BoNT-A might be preferentially selected owing to its cost-effectiveness profiles. Further studies with direct comparison of the two treatments are warranted.
... It is clear that different types of placebo produce different response rates and that the more invasive or dramatic a placebo is, the more likely it is to have an effect. For instance, it has been shown that placebo injections, acupuncture, sham surgery, and medical devices cause greater placebo effects than do oral placebos [8][9][10][11][12]. Additionally, it has been shown that "expensive" placebos appear to be more effective than "cheaper" ones [13]. ...
PurposeTo investigate the presence of a placebo dose–response effect in four randomized, double-blind, placebo-controlled, multi-dose hot flash clinical trials conducted at Mayo Clinic.Methods
Hot flash score, frequency, and hot flash-related distress for each placebo dose level were summarized at each time point by mean and standard deviation and changes from baseline were plotted to visualize a possible placebo dose–effect response. Furthermore, a meta-analysis was conducted for each endpoint in the highest and lowest dosage arms across the four trials.ResultsLongitudinal plots of mean hot flash scores, frequencies, and hot flash-related distress scores in patients taking placebo in each study showed a decline in hot flash scores over time without any clinically meaningful differences between the lowest and highest dosage arms in each study. The meta-analysis for each endpoint in the highest and lowest dosage arms across the four trials revealed no clinically important differences either.Conclusion
While the current study cannot rule out the existence of a placebo dose–response effect in multi-dose placebo-controlled trials in patients with hot flashes or other conditions, it suggests, along with the available data in the placebo literature, that, at least in well-conducted multi-dose clinical trials in which the placebo was used as control, such an effect, if it exists at all, should be very small. Therefore, pooling data from different placebo subgroups is unlikely to compromise the validity of comparisons between the combined placebo arms and each treatment arm.
... 14 Moreover, a systematic review comparing the effectiveness of different placebo treatments on migraines showed that elaborately designed placebo methods (e.g., sham acupuncture and sham surgery) had stronger treatment responses, compared with orally administered pharmacologic placebos. 41 However, in contrast to the initial hypothesis, the authors found no prominent effects of OLP acupuncture in this study. As mentioned above, placebo acupuncture is conducted using an intricately designed sham device that induces substantial tactile sensations, thus increasing the probability that participants will perceive the placebo as a real treatment. ...
Objective: An open-label placebo (OLP) is a placebo treatment in which the patient is aware that the treatment is a placebo. OLPs are considered effective for reducing pain, and previous studies have shown a stronger placebo effect for placebo acupuncture than for placebo pills. In this study, the authors compared the analgesic effects of OLP pills, OLP acupuncture, and a no treatment condition in healthy participants, and then examined the factors contributing to the OLP effect. Design: Randomized controlled crossover trial. Settings/Location: College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea. Subjects: 34 healthy participants. Intervention: Participants received three different treatments ("OLP-pill," "OLP-acupuncture," and "no treatment") on three separate days in random order. Outcome Measurements: Before and after the treatment, heat pain stimuli were applied to the participants' hands, and pain tolerance, intensity, and unpleasantness were measured using a visual analog scale (range, 0-10). Results: Data of 31 participants were included in the analysis. The authors found significant analgesic effects of the placebo pill and placebo acupuncture in the OLP condition. Regression analyses revealed that expectations regarding treatment and practitioner identity influenced the analgesic effects of OLP acupuncture. There was no adverse event. Conclusions: Expectations regarding treatment and practitioner identity influenced the analgesic effect of placebo acupuncture without deception. These findings provide new information regarding the cognitive factors underlying pharmacologic and nonpharmacologic treatments. Clinical Trial Registration Number: KCT0004928.
... A key question left unanswered from experimental studies is the longevity of expectation effects in clinical populations. Cumulative evidence from placebocontrolled RCTs has shown significant and clinically-relevant placebo effects in the preventive treatment for migraine [38], with especially strong placebo effects for those treatments that induce strong expectations such as the novel CGRP-ligand antibodies [4; 36] or botulinumtoxin A [22; 53]. Meta-analyses further confirm that a relevant proportion of adverse effects is driven by nocebo effects, as they are also observed in the placebo groups of the RCTs in migraine patients [3; 39]. ...
Migraine is one of the leading causes of years lived with disability and considered to be a major global health concern. Pharmacological preventive treatment often causes side effects that limit the adherence to longer-term treatment regiments. Both experimental and clinical evidence suggests that positive expectations can modulate pain and analgesic treatment effects. However, the role of expectations in migraine prophylactic treatment has not systematically been investigated. Here, we examined the influence of treatment expectation prior to commencing pharmacological preventive treatment on its efficacy and tolerability in N=134 episodic (30%) and chronic migraine (70%) patients in a prospective, longitudinal observational study over the course of six months. The migraine prophylaxis reduced the number of headache and migraine days with acceptable tolerability. Positive treatment expectation was associated with a generally lower number of headache and migraine days and a stronger reduction in headache days over the course of the treatment in chronic but not in episodic migraine patients. Moreover, patients with prior treatment showed a stronger reduction in headache days with higher expectation as compared to patients without prior experience. Our results underscore the relevance of further exploring the role of treatment expectation and its systematic modulation in migraine patients and other pain conditions.
... 14 Several studies have shown higher placebo effects with placebo injection compared with oral placebo, 15 and findings from a meta-analysis of migraine prevention trials have also shown greater placebo effects in trials with sham acupuncture or surgery arms compared with oral administration of placebo. 16 Despite the current study being a placebocontrolled study of an injectable drug, a very low placebo effect was observed. One potential explanation may be that the study investigators were a highly selected group of clinicians who were specialized in the treatment of migraine and who had considerable clinical trial experience in migraine. ...
Objective
This study was designed to assess the efficacy and safety of galcanezumab in comparison with placebo for the prevention of migraine in Japanese patients with episodic migraine.
Methods
In this double-blind, placebo-controlled study, which was conducted over 6 months, randomized adult patients received subcutaneous injections of galcanezumab (120 mg n = 115, 240 mg n = 114) or placebo ( n = 230) once monthly. The primary endpoint was the overall mean change from baseline in the number of monthly migraine headache days. The key secondary outcome measures were response rates (≥50%, ≥75%, and 100%); the Migraine-Specific Quality-of-Life Questionnaire Role Function-Restrictive score; monthly migraine headache days requiring acute treatment; and Patient Global Impression of Severity (PGI-S).
Results
The mean change from baseline in monthly migraine headache days over months 1–6 was significantly ( p < 0.001) greater for the 120-mg galcanezumab dose (−3.60 days) and the 240-mg galcanezumab dose (−3.36 days) compared with placebo (−0.59 days). Both the 120-mg and 240-mg doses of galcanezumab were superior compared with placebo for each of the key secondary endpoints except for PGI-S (only the 240-mg dose was superior). The most commonly reported treatment-emergent adverse events were local injection-site reactions; erythema, swelling, pruritus, and pain were more commonly reported by patients who were treated with galcanezumab than those treated with placebo.
Conclusion
The number of monthly migraine headache days was reduced with both doses of galcanezumab, and both doses were safe and well tolerated in Japanese patients with episodic migraine.
... The stimulating effect of red-colored "inert" pills and the tranquilizing effect of blue ones are a direct consequence of the meaning they generate. Meaning responses explain why placebo effects are more pronounced with more invasive procedures (Meissner et al., 2013), the influence of awareness of a treatment (e.g., Colloca et al., 2004), and the need for active placebos (Boot et al., 2013) to control for meaning responses to bodily sensations following "real" interventions. A meaning response does not refer only to conscious semantic meaning (Kirmayer, 2003;Thompson et al., 2009). ...
Due to their complexity and variability, placebo effects remain controversial. We suggest this is also due to a set of problematic assumptions (dualism, reductionism, individualism, passivity). We critically assess current explanations and empirical evidence, and propose an alternative theoretical framework-the enactive approach to life and mind-based on recent developments in embodied cognitive science. We review core enactive concepts such as embodiment, agency, and sense-making. Following these ideas we suggest moving from binary distinctions (e.g., conscious vs. nonconscious) to the more workable categories of reflective and pre-reflective activity. We introduce an ontology of individuation, following the work of Gilbert Simondon, that allows us to see placebo interventions not as originating causal chains, but as modulators and triggers in the regulation of tensions between ongoing embodied and interpersonal processes. We describe these interrelated processes involving looping effects through three intertwined dimensions of embodiment: organic, sensorimotor, and intersubjective. Finally, we defend the need to investigate therapeutic interactions in terms of participatory sense-making, going beyond the identification of individual social traits (e.g., empathy, trust) that contribute to placebo effects. We discuss resonances and differences between the enactive proposal, popular explanations such as expectations and conditioning, and other approaches based on meaning responses and phenomenological/ecological ideas.
... However, with the application of acupuncture in the worldwide, more and more high-level research teams and magazines pay attention to the effect of acupuncture in clinical research [42][43][44][45]. Although some studies raised doubts and challenges on the specific effect of acupuncture, it cannot be denied that the nonspecific effect of acupuncture is a key part of clinical effect [46]. Besides, few studies compared the proportion of specific and nonspecific effects of acupuncture in the holistic effect [13,14]. ...
Background:
Research on the effect of acupuncture has been limited. Whether the effect of acupuncture is equivalent to placebo has been the focus of debate in this field. This study will explore the specific and non-specific effects of acupuncture for knee osteoarthritis (KOA) by functional magnetic resonance imaging (fMRI).
Methods and design:
Ninety participants diagnosed with KOA will be randomly divided into the acupuncture group, sham acupuncture group, and waiting list group in a ratio of 1:1:1. Except for the waiting list group, the other participants will receive acupuncture or sham acupuncture three sessions per week for 4 weeks respectively. The primary outcome will be the response rate which is defined on an individual basis as at least a 2-point decrease in the numerical rating scale (NRS) of pain at the end of intervention period compared with the baseline. fMRI scans will be performed at baseline and the end of the intervention period to examine the response of various brain regions. The secondary outcomes will include the Western Ontario and McMaster Osteoarthritis Index (WOMAC), State-Trait Anxiety Scale-State Anxiety Subscale (STAI-S), and Stanford Expectations of Treatment Scale (SETS). Pearson's correlation coefficient will be performed to investigate the changes in brain activity and clinical variables.
Discussion:
The results of our study will help to evaluate the specific and nonspecific effects of acupuncture combined with clinical and brain function changes based on KOA.
Trial registration:
Chinese Clinical Trial Registry ChiCTR1900025799. Registered on 9 September 2019.
... Therefore, sham therapies are used to verify the effectiveness of the applied technique [52]. However, in these clinical trials, sham treatment may have a greater effect on outcomes that depend on the patient's report, such as pain [53][54][55], as in our study. We observed a reduction at headache intensity in both groups; both groups were satisfied regardless of the treatment performed. ...
Background
Migraine patients have musculoskeletal disorders and pain in the cervical. And, despite the pathophysiology demonstrating the relationship between migraine and the cervical spine, the effectiveness of craniocervical exercises in these patients has not been verified. So, the aimed of this study was verify the effectiveness of craniocervical muscle-strengthening exercise (CMSE) in reducing the frequency and intensity of headache in migraine patients.
Methods
A two-armed, parallel-group randomized controlled trial with a 3-month follow-up was performed. For eight weeks, the volunteers in the intervention group ( n = 21) performed a protocol of CMSE, while those in the sham ultrasound group ( n = 21) received the application of disconnected therapeutic ultrasound in the upper trapezius and guideline for home-stretching. The primary outcomes were the frequency and intensity of the headache. The secondary outcomes were questionnaires about migraine and neck disability, and satisfaction with the treatment, cervical range of motion, the pressure pain threshold, craniocervical flexion test (CCFT), cervical muscle strength and endurance test, and the cervical muscle activity during the physical tests.
Results
No differences were observed for the changes observed in primary outcomes after eight weeks and at the 3-months follow up ( p > 0.05). For the secondary outcomes, craniocervical exercises improved the sensitivity of the frontal muscle ( p = 0.040) and promoted a reduced amplitude of muscle activity of the anterior scalene and upper trapezius in the last stages of CCFT ( p ≤ 0.010). There was also reduced muscle activity of the anterior scalene and splenius capitis in the endurance test ( p ≤ 0.045), as evaluated by surface electromyography.
Conclusion
CMSE were insufficient in reducing the frequency and intensity of headache, improving the performance of the cervical muscles, or reducing migraine and neck pain-related disabilities. This was found despite a decreased electromyographic activity of the cervical muscles during the last stages of CCFT and increased median frequency during the endurance test.
Trial registration
Accession code RBR-8gfv5j , registered 28/11/2016 in the Registro Brasileiro de Ensaios Clínicos (ReBEC).
... 9 In migraine, sham acupuncture has been shown to have a higher response rate than oral pharmacological placebo. 11 Different placebo response rates can lead to an "efficacy paradox" where a more powerful intervention with less contextual effect is less likely to reduce symptoms in real life than a less powerful drug with greater contextual effect. 12 The "efficacy paradox" is also observed when a drug with modest effect in a randomized clinical trial seems to be highly effective in clinical practice. ...
Background:
CGRP Antibodies are high-cost newly licensed migraine preventatives.
Objective:
To calculate the overall reduction in monthly migraine days and the proportion contextual effect (PCE) using meta-analysis. The PCE is the ratio between the reduction in Monthly Migraine Days in the placebo group and the reduction in Monthly Migraine Days in the CGRP-Ab group after 3 months of treatment.
Methods:
Meta-analysis of randomized double-blind placebo-controlled trials of anti-CGRP antibodies in people with episodic migraine (EM) or chronic migraine (CM) in persons aged 18 or over. Non-randomized trials and trials in persons under 18 years excluded. Search of National Clinical Trials Register 2000-2019, MEDLINE to September 2019, Hand search of major headache conference abstract books 2012-2019. Two investigators used standard proforma to reach consensus. Trial quality assessed using Cochrane Collaboration risk of bias tool. PRISMA guidelines followed.
Results:
21 completed trials with 13367 participants (8075 EM, 5292 CM). Compared to placebo, pooled reduction in MMD was 1.50 days in 15 EM trials (95%CI 1.16, 1.84; I2 = 69%, Phetereogeneity < .001) and 2.24 days in 7 CM trials (95%CI 1.82, 2.65, I2 = 15%, Phetereogeneity = .320). In EM trials, pooled PCE was 0.66 (95%CI 0.59,0.75; I2 = 64%, Phetereogeneity = .001). In CM trials the PCE was .68 (95%CI 0.61, 0.75; I2 = 20%, Phetereogeneity = .280). Industry funded every study, but risk of bias was low.
Conclusions:
CGRPAbs are effective but sixty-six percent of the benefit is from contextual effects, including placebo effect. Contextual effects merit further scrutiny as a means of improving migraine headache.
... Riboflavin catalyzes the activity of flavoenzymes in mitochondrial respiratory chain and thereby, alleviates clinical and biochemical anomalies in patients with mitochondrial metabolic errors. Given the abnormality of energy metabolism in the brain during migraine headaches, riboflavin is supposed to alleviate migraine headaches through this mechanism (29,30). A metaanalysis also reported the effectiveness of riboflavin in significantly reducing the frequency and the duration of migraine attacks (31), though the first clinical study into the effects of riboflavin on migraine headaches among children reported no significant difference between the intervention and the placebo groups probably due to the small sample size of the study (32). ...
Background and aims: Migraine is a neurologic disorder with wide global spread. Quality of life (QOL) and dietary factors are important parameters in migraine management. The aim of this study was to evaluate the relationship of mood status, QOL, and dietary intake with migraine symptoms among women with migraine. Methods: This cross-sectional study was conducted on 143 women with migraine aged 20–40 years who were randomly selected from two clinics in Isfahan, Iran. Data were collected using the Food Frequency Questionnaire for Assessing Dietary Patterns, a visual analogue scale for migraine headaches, the Migraine-Specific Quality of Life Questionnaire, and the Depression Anxiety Stress Scale. The serum level of calcitonin gene-related peptide (CGRP) was also measured. Results: Participants’ age and number of sleeping hours per 24 hours had significant relationship with migraine severity, depression and anxiety had significant relationship with migraine severity and the duration of migraine attacks, and QOL had significant relationship with migraine severity and the duration and frequency of migraine attacks. Daily intake of riboflavin also had significant relationship with frequency of migraine attacks, while daily intake of water had significant relationship with migraine severity (P < 0.05). However, serum level of CGRP had no significant relationship with migraine (P > 0.05). The relationships of vitamin D and magnesium intake with depression were also significant (P < 0.05). Conclusion: Serum level of CGRP has no significant relationship with migraine attacks, while depression, anxiety, QOL, and magnesium and vitamin D intake have significant relationship with migraine attacks.
... While this meta-analysis showed that placebo responses are similar across treatment modalities in TRD (placebo, pharmacotherapy, brain stimulation, or psychotherapy), this is not the case for other disorders; for example, a meta-analysis in migraine prophylaxis pointed out that sham acupuncture and sham surgery resulted in higher placebo responses than oral placebos. 6 The fact that placebo response ratios vary across disorders and treatments outlines the need for more mechanistic research to be translated into clinical trial methodology and development. ...
... Однако наши данные совпадают с данными из клинической практики в других странах [14,16]. Безусловно, мы не можем исключить эффект плацебо, который достаточно высок у пациентов с головной болью [22,23], но большое количество рандомизированных клинических исследований показывает эффективность эренумаба по сравнению с плацебо [24,25]. ...
Introduction . Migraine is one of the most common disabling neurological disorders. Recently developed monoclonal antibodies to calcitonin gene-related peptide (CGRP) or its receptor are the first targeted medication for preventive therapy of both episodic and chronic migraine. They have been thoroughly investigated in clinical trials; however, there is little data from real-world clinical practice available to date. The aim of this study is to assess the efficacy and safety of 6 months of treatment with erenumab in real-world clinical practice and investigate the effect of the drug on the patients’ sensitivity to medicines for migraine headaches relief and patient satisfaction after treatment.
Materials and methods . Our observational cohort prospective study included patients in our Headache Clinic prescribed monoclonal antibodies blocking the CGRP-receptor – erenumab. During the investigation, we evaluated the previous preventive therapy and its efficacy, the number of days with migraine per month, adverse events occurring during the erenumab treatment, depression and anxiety (HADS), migraine disability (MIDAS), the presence of allodynia (ACS-12) and improved response to acute therapy after treatment. A total of 42 patients participated in the study: 6 men, 36 women, the average age was 43.9 ± 12.2. Of them, 38 patients (90%) had chronic migraine. Thirty-two patients (76%) had previously been prescribed preventive therapy, which proved ineffective, and 10 patients (24%) had not once received any type of migraine prevention.
Results . Among our patients, we identified 11 patients with resistant migraine and one patient with refractory migraine. During the study, two patients dropped out due to adverse events (constipation). Thirty patients continued the administration of erenumab 70 mg for at least six months. The average number of migraine days per month before treatment was 22.8, and after six months of treatment, it dropped to 7.3. Twenty-nine patients (72.5%) also noted that the response to acute headache treatment improved after the therapy.
Conclusion . The results of our study are consistent with the international experience of using erenumab and confirm its effectiveness for migraine preventive therapy, including difficult-to-treat migraine cases. However, further studies with more participants and evaluation of predictors of successful monoclonal antibody therapy are still needed.
In the past few decades, research on pain and placebo analgesia has gained importance both scientifically and clinically. In this article, the current findings and focus of research as well as the significance of placebo research for assessing the effectiveness of pain medication are illustrated. The underlying mechanisms of placebo analgesia not only have implications for theoretical models but also offer clinically relevant guidelines for everyday interventions in pain treatment. However, many placebo phenomena are not fully understood and have to be investigated further in order to exploit the full potential of placebo effects. Interindividual differences and their inclusion in treatment will play a major role in this aspect.
Much has been written about the placebo effects in functional gastrointestinal disorders (FGD), especially in irritable bowel syndrome (IBS), driven by the early hypothesis that in randomized controlled trials (RCTs) of IBS, the placebo effect might be specifically high and thus, corrupts the efficacy of novel drugs developed for this condition. This narrative review is based on a specific search method, a database (www.jips.online) developed since 2004 containing more than 4,500 papers (data papers, meta-analyses, systematic reviews, reviews) pertinent to the topic placebo effects/placebo response. Three central questions—deducted from the body of current literature—are addressed to explore the evidence behind this hypothesis: What is the size placebo effect in FGD, especially in IBS, and is it different from the placebo effect seen in other gastrointestinal disorders? Is the placebo effect in FGD different from other functional, non-intestinal disorders, e.g. in other pain syndromes? Is the placebo effect in FGD related to placebo effects seen in psychiatry, e.g. in depression, anxiety disorders, and alike? Following this discussion, a fourth question is raised as the result of the three: What are the consequences of this for future drug trials in FGD? In summary it is concluded that, contrary to common belief and discussion, the placebo effect seen in RCT in FGD is not specifically high and extraordinary as compared to other comparable (i.e. functional) disorders. It shares less than expected commonalities with the placebo effect in psychiatry, and very few predictors have yet been identified that determine its effect size, especially some that are driven by design features of the studies. Current practice of RCT in IBS seems to limit and control the placebo effect quite well, and future trial practice, e.g. head-to-head trial, still offers options to maintain this control, even in the absence of placebos used.
Objective:
To evaluate the association between the degree of response to placebo in migraine studies and the observed difference between drug and placebo across studies of preventative treatments for migraine.
Methods:
A systematic review was performed using MEDLINE and the Cochrane Central Register of Controlled Clinical Trials from January 1988 to June 2019. Randomized, double-blind, parallel-group, placebo-controlled trials on oral or injection preventative treatments for migraine were included. Single- and multi-variable linear regression analyses were performed on the placebo-subtracted response rate (i.e. placebo responders subtracted from active responders), and the proportion of placebo responders. Fisher's exact tests were performed on the level of placebo response and the success in meeting the study's primary endpoint.
Results:
After adjusting for route of administration and number of randomized subjects, there was a statistically significant association between the proportion of patients who were placebo responders and the placebo-subtracted response rate (b = -0.27, p = 0.02). There was a statistically significant difference in trial success rate (60%) between studies with ≤20% placebo responders and studies with > 30% placebo responders (p = 0.03).
Conclusion:
Considering the detrimental impact that high placebo response can have on clinical trials, it is imperative to find effective solutions to decrease the placebo response and increase assay sensitivity.
Despite their ubiquitous presence, placebos and placebo effects retain an ambiguous and unsettling presence in biomedicine. Specifically focused on chronic pain, this review examines the effect of placebo treatment under three distinct frameworks: double blind, deception, and open label honestly prescribed. These specific conditions do not necessarily differentially modify placebo outcomes. Psychological, clinical, and neurological theories of placebo effects are scrutinized. In chronic pain, conscious expectation does not reliably predict placebo effects. A supportive patient-physician relationship may enhance placebo effects. This review highlights “predictive coding” and “bayesian brain” as emerging models derived from computational neurobiology that offer a unified framework to explain the heterogeneous evidence on placebos. These models invert the dogma of the brain as a stimulus driven organ to one in which perception relies heavily on learnt, top down, cortical predictions to infer the source of incoming sensory data. In predictive coding/bayesian brain, both chronic pain (significantly modulated by central sensitization) and its alleviation with placebo treatment are explicated as centrally encoded, mostly non-conscious, bayesian biases. The review then evaluates seven ways in which placebos are used in clinical practice and research and their bioethical implications. In this way, it shows that placebo effects are evidence based, clinically relevant, and potentially ethical tools for relieving chronic pain.
Aims:
The difference in the benefit of invasive cardiovascular interventions compared with placebo controls has not been analysed systematically.
Methods and results:
MEDLINE and Web of Science were searched through 29 March 2020. Randomized, placebo-controlled trials of invasive cardiovascular interventions (including catheter-based interventions and pacemaker-like devices) investigating predefined primary outcomes were included. Standardized mean differences (SMD) and odds ratios were calculated for continuous and dichotomous outcomes, respectively. Meta-regression analyses were performed to assess whether estimates of treatment effects were associated with methodological characteristics of trials. Thirty trials, including 4102 patients, were analysed. The overall risk of bias was judged to be low in only 43% of the trials. Ten trials (33%) demonstrated statistically significant superiority of invasive interventions over placebo controls for the respective predefined primary outcomes. In almost half of the 16 trials investigating continuous predefined primary outcomes, the SMD between the active and placebo procedure indicated a small (n = 4) to moderate (n = 3) treatment effect of active treatment over placebo. In contrast, one trial indicated a small treatment effect in favour of the placebo procedure. In the remaining trials, there was no relevant treatment effect of active treatment over placebo. In trials with a protocol-mandated stable and symmetrical use of co-interventions, the superiority of active procedures vs. invasive placebo procedures was significantly larger as compared with trials with frequent or unbalanced changes in co-interventions (P for interaction 0.027).
Conclusions:
The additional treatment effect of invasive cardiovascular interventions compared with placebo controls was small in most trials.
This thesis examines the phenomenon of healing efficacy among the Akha of highland Laos, in light of the science of ‘placebo effects.’ Swidden farmers of Tibeto-Burman language origin, the Akha have a rich ancestral system of oral customs, centred on animism and a robust shamanic tradition. Based on 18 months of ethnographic fieldwork in a remote village, the first part of the dissertation is a detailed investigation of the whole gamut of Akha therapeutic practices. Among its key findings is that rituals for spirit affliction challenge a number of assumptions about healing performances that are widespread in medical anthropology. Specifically, the analysis shows that only few of these rituals engage the sick person’s senses in a way that harness ‘placebo effects’, as prevailing theories would predict. It is argued, however, that the most compelling aspect of efficacy lies at the level of Akha aetiology. The ways of explaining illness and healing – through a distinction between naturalistic and personalistic causes – reveal intriguing parallels with the aetiological picture of symptom perception that is borne out of placebo science. Overall, Akha thought is shown to capture something fundamental about the nature of illness and healing. The final part of the dissertation dwells on the implications of this finding. The material analysed invites a shift in focus from the narrow domain of the patient-healer interaction to the wider social and conceptual framework that underpins the phenomenon of health. It also has direct bearings on the understanding of the ‘placebo effect’, a notion that captures a nexus of contradictions central to modern naturalism. Espousing a kind of anthropology that looks at the ‘other’ for insights into one’s own culture and the human condition, the thesis examines how Akha resolve these contradictions, and what we can learn from them.
Background and aim:
Despite recent publications, practitioners remain unfamiliar with the current terminology related to the placebo and nocebo phenomena observed in clinical trials and practice, nor with the factors that modulate them. To cover the gap, the European Headache Federation appointed a panel of experts to clarify the terms associated with the use of placebo in clinical trials.
Methods:
The working group identified relevant questions and agreed upon recommendations. Because no data were required to answer the questions, the GRADE approach was not applicable, and thus only expert opinion was provided according to an amended Delphi method. The initial 12 topics for discussion were revised in the opinion of the majority of the panelists, and after a total of 6 rounds of negotiations, the final agreement is presented.
Results/recommendations:
Two primary and mechanism-based recommendations are provided for the results of clinical trials: [1] to distinguish the placebo or nocebo response from the placebo or nocebo effect; and [2] for any favorable outcome observed after placebo administration, the term "placebo response" should be used, and for any unfavorable outcome recorded after placebo administration, the term "nocebo response" should be used (12 out of 17 panelists agreed, 70.6% agreement). The placebo or nocebo responses are attributed to a set of factors including those that are related to the medical condition (e.g. natural history, random comorbidities, etc.), along with idiosyncratic ones, in which the placebo or nocebo effects are attributed to idiosyncratic, or nonspecific mechanisms, exclusively (e.g. expectation, conditioning, observational learning etc.). To help investigators and practitioners, the panel summarized a list of environmental factors and idiosyncratic dynamics modulating placebo and nocebo effects. Some of them are modifiable, and investigators or physicians need to know about them in order to modify these factors appropriately to improve treatment. One secondary recommendation addresses the use of the terms "placebo" and "nocebo" ("placebos" and "nocebos" in plural), which refer to the triggers of the placebo/nocebo effects or responses, respectively, and which are inert agents or interventions that should not be confused with the placebo/nocebo responses or effects themselves (all panelists agreed, 100% agreement).
Conclusion:
The working group recommends distinguishing the term response from effect to describe health changes from before to after placebo application and to distinguish the terms placebo(s) or nocebo(s) from the health consequences that they cause (placebo/nocebo responses or effects).
Ein Physiotherapeut kann seine Behandlung erfolgreicher gestalten, wenn er beim Patienten gezielt Placeboreaktionen auslöst. Wichtig für dieses Add-On zur Standardbehandlung ist das Zusammenspiel von Soft Skills, berufliche Qualifikationen des Therapeuten und dem Therapiesetting, welches die Erwartungen der Patienten beeinflusst. Die klinische Forschung zeigt, dass das empathische und kompetente Auftreten, die wertschätzende Kommunikation und das Berücksichtigen individueller Bedürfnisse, Vorerfahrungen und Erwartungen eines Patienten dessen Behandlung positiv beeinflussen können.
Gastrointestinal dysmotility represents a severe constellation of symptoms resulting from malfunction of the stomach, small intestine, or large intestine. By definition excluding organic origins of obstruction, the etiologies of the condition range from diabetes to Parkinson’s to more exotic myopathies, although idiopathy remains the most commonly cited cause. Patient presentation typically includes epigastric pain, nausea, vomiting, early satiety, and poor oral intake; constipation characterizes lower GI dysmotility. Severity of the symptoms can range from mildly aggravating to requiring a feeding jejunostomy or even total parental nutrition for survival. CT scan, EGD, and barium swallow are helpful to rule out organic causes, but nuclear medicine emptying studies are required to make diagnosis. Treatment options remain poor. Symptomatic relief with various anti-nausea medications can alleviate minor cases. Metoclopromide remains the only FDA-approved medication for gastroparesis but comes with well-described, severe side effects. Other, more exotic interventions like intrapyloric botulinum injections and implanted gastric pacemakers lack convincing evidence of efficacy. More dramatic, surgical cures like pyloroplasty, jejunostomy feeding tubes, and even small bowel transplant are indicated in particularly severe cases.
Purpose
The Prevention of Migraine via Intravenous ALD403 Safety and Efficacy 1 (PROMISE-1) study was a phase III, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy, tolerability, and pharmacokinetic properties of repeat intravenous (IV) doses of the calcitonin gene–related peptide‒targeted monoclonal antibody eptinezumab (ALD403) for migraine prevention in adults with episodic migraine. Here we present the results of PROMISE-1 through 1 year of treatment (up to 4 doses).
Methods
Patients received up to 4 IV administrations of eptinezumab 30 mg, 100 mg, 300 mg, or placebo every 12 weeks. Patients recorded migraine and headache in an electronic diary daily. Additional assessments, including the patient-reported outcomes, were performed at regularly scheduled clinic visits throughout the 56-week study period.
Findings
A total of 888 adults (mean age, 39.8 years; 84.3% female; 83.8% white) received treatment: eptinezumab 30 mg, n = 219; eptinezumab 100 mg, n = 223; eptinezumab 300 mg, n = 224; and placebo, n = 222. During the primary 12-week study evaluation period, single doses of eptinezumab 100 mg and 300 mg led to significant reductions in mean monthly migraine-days versus placebo, beginning as early as the first day after the initial dose. The reduction in mean monthly migraine-days was maintained throughout the study (100 mg, −3.9, −4.5, −4.7, and −4.5 days; 300 mg, −4.3, −4.8, −5.1, and −5.3 days; and placebo, −3.2, −3.8, −4.0, and −4.0 days during weeks 1–12, 13–24, 25–36, and 37–48, respectively). Overall, the number of patients with a ≥50% or ≥75% reduction in migraine for each 12-week interval during the entire study was consistently numerically higher in the eptinezumab groups than in the placebo group. The proportions of patients with ≥50% reduction in migraine were similar across the eptinezumab groups. Eptinezumab was well tolerated throughout the study. Adverse events were similar across dosing periods, and there were no serious tolerability signals identified with continued dosing.
Implications
IV eptinezumab administered every 12 weeks for up to 4 doses was associated with early and sustained migraine-preventive effects and a favorable safety profile in adults with episodic migraine. ClinicalTrials.gov identifier: NCT02559895.
This article is a summary of a talk presented in February 2019 at a conference on acupuncture sponsored by the National Institutes of Cancer (NCI) and the National Center for Complementary and Integrative Health (NCCIH) at the National of Institutes of Health (NIH). The article touches on the history of placebos in biomedicine and its absence in traditional East Asian Medicine. It then examines some of the predicaments of evaluating acupuncture's efficacy in relationship to placebo controls. Although acupuncture in randomized controlled trials (RCTs) generally demonstrate equivalence or even superiority to medical interventions or other nonpharmacologic therapies, acupuncture's ability to show superiority to placebo controls has been inconclusive, contradictory and, at best, modest. This article highlights the efforts of the German health insurance funds to evaluate acupuncture. Using a large meta-analysis, the article summaries acupuncture's effectiveness and efficacy. Subsequently, RCTs and meta-analyses testing the hypothesis that sham acupuncture, and other device placebos, have augmented placebo responses are described. It seems that acupuncture, and devices in general, have enhanced placebo responses. These findings may be relevant to designing and evaluating placebo-control acupuncture RCTs. Research into placebo acupuncture may also be helpful for other conditions where detection of intervention-placebo differences can be problematic. Further research is warranted.
Spinal cord stimulation (SCS) is an interventional non-pharmacologic treatment used for chronic pain and other indications. Methods for evaluating the safety and efficacy of SCS have evolved from uncontrolled and retrospective studies to prospective randomized controlled trials (RCTs). While randomization overcomes certain types of bias, additional challenges to the validity of RCTs of SCS include blinding, choice of control groups, non-specific effects of treatment variables (e.g., paresthesia, device programming and recharging, psychological support, and rehabilitative techniques), and safety considerations. In order to address these challenges, three professional societies (IMMPACT, ION, INS) convened a meeting to develop consensus recommendations on the design, conduct, analysis, and interpretation of RCTs of SCS for chronic pain. This paper summarizes the results of this meeting. Highlights of our recommendations include disclosing all funding source and potential conflicts; incorporating mechanistic objectives when possible; avoiding non-inferiority designs without internal demonstration of assay sensitivity; achieving and documenting double-blinding whenever possible; documenting investigator and site experience; keeping all information provided to patients balanced with respect to expectation of benefit; disclosing all information provided to patients, including verbal scripts; using placebo/sham controls when possible; capturing a complete set of outcome assessments; accounting for ancillary pharmacologic and non-pharmacologic treatments in a clear manner; providing a complete description of intended and actual programming interactions; making a prospective ascertainment of SCS-specific safety outcomes; training patients and researchers on appropriate expectations, outcome assessments, and other key aspects of study performance; and providing transparent and complete reporting of results according to applicable reporting guidelines.
Background: Ample evidence demonstrates that placebo effects are modulated by contextual factors. Few interventions, however, attempt to combine a broad range of these factors. Here, we explore the therapeutic power of placebos by leveraging factors including social proof, positive suggestion, and social learning. This study aimed to test the feasibility of an elaborate “super placebo” intervention to reduce symptoms of various disorders in a pediatric population.
Methods: In a single-arm qualitative study, participants entered an inactive MRI scanner which they were told could help their brain heal itself through the power of suggestion. The sample included 11 children (6–13 years old) diagnosed with disorders known to be receptive to placebos and suggestion (Attention Deficit Hyperactivity Disorder, Tourette Syndrome, chronic skin picking, and migraines). The children were given positive suggestions during 2–4 placebo machine sessions over the span of approximately 1 month. We assessed open-ended treatment outcomes via recorded interviews and home visits.
Results: The procedure was feasible and no adverse events occurred. Ten of the 11 parents reported improvements in their children after the intervention, ranging from minor transient changes to long-term reductions in subjective and objective symptoms (e.g., migraines and skin lesions).
Discussion: These preliminary findings demonstrate the feasibility and promise of combining a broad range of contextual factors in placebo studies. Future research is needed to assess the causal effects of such interventions.
Study Design
This is a narrative review focused on specific challenges related to adequate controls that arise in neuromodulation clinical trials involving perceptible stimulation and physiological effects of stimulation activation.
Objectives
1) To present the strengths and limitations of available clinical trial research designs for the testing of epidural stimulation to improve recovery after spinal cord injury. 2) To describe how studies can control for the placebo effects that arise due to surgical implantation, the physical presence of the battery, generator, control interfaces, and rehabilitative activity aimed to promote use‐dependent plasticity. 3) To mitigate Hawthorne effects that may occur in clinical trials with intensive supervised participation, including rehabilitation.
Materials and Methods
Focused literature review of neuromodulation clinical trials with integration to the specific context of epidural stimulation for persons with chronic spinal cord injury.
Conclusions
Standard of care control groups fail to control for the multiple effects of knowledge of having undergone surgical procedures, having implanted stimulation systems, and being observed in a clinical trial. The irreducible effects that have been identified as “placebo” require sham controls or comparison groups in which both are implanted with potentially active devices and undergo similar rehabilitative training.
Placebo effects have increasingly aroused scientific and public interest for their clinical and research values. However, underlying mechanisms of this mind–body phenomenon are not yet fully understood. In this article, I propose a new model according to which context-based placebo effects source from positive treatment beliefs but are directly caused by benefit expectations. By virtue of mediating belief-expectation transformation, placebo administration triggers, and thus has a pivotal role in, subsequent therapeutic responses.
Objective
There is an unmet need for new efficacious, well-tolerated, acute treatments for migraine in adolescents. Remote electrical neuromodulation (REN) is a novel, non-pharmacological treatment, that provides significant symptom relief with good tolerability. The current post-hoc analysis compared the efficacy of REN to that of standard-care medications, for the acute treatment of migraine in adolescents.
Design
Within-participant post-hoc analysis of data from a clinical trial.
Setting
Data from a clinical trial.
Subjects
Data from 35 adolescent participants was analyzed.
Methods
Efficacy was compared between a run-in phase in which attacks were treated with standard-care medications (triptans or over-the-counter medications), and an intervention phase in which attacks were treated with REN. Efficacy was compared within-participant using McNemar’s test, at four endpoints (two hours post-treatment): single-treatment pain freedom and pain relief, and consistency of pain freedom and pain relief (defined as response in at least 50% of the available first four treatments).
Results
At two hours post-treatment, pain freedom was achieved by 37.1% of the participants with REN, vs. 8.6% of the participants with medications (p = 0.004). Pain relief was achieved by 71.4% with REN, vs. 57.1% with medications (p = 0.225). Consistency of pain freedom was achieved by 40% with REN, vs. 8.6% with medications (p < 0.001). Consistency of pain relief was achieved by 80.0% with REN, vs. 57.2% with medications (p = 0.033)
Conclusions
Our results suggest that REN may have higher efficacy than certain standard-care medications for the acute treatment of migraine in adolescents. A larger scale, blinded, comparative effectiveness and tolerability study is needed.
Motor cortex stimulation via surgically implanted electrodes has been used as an off-label treatment for chronic neuropathic pain, but its efficacy has not been fully established. We aimed to objectively study the efficacy of motor cortex stimulation and characterize potential predictors of response.
In this randomized, double-blind, sham-controlled, single centre trial, we recruited 18 patients with chronic neuropathic pain who did not adequately respond to conventional treatment and had a numerical pain rating scale (NRS) score ≥6. Patients were initially assigned to receive 3 months of active (‘on’) or sham (‘off’) stimulation in a double-blind cross-over phase. This was followed by a 3-month single-blind phase, and 6 months of open-label follow-up. A meaningful response in our trial was defined as a ≥30% or 2-point reduction in NRS scores during active stimulation.
Using Bayesian statistics, we found a 41.4% probability of response towards on versus off motor cortex stimulation. The probability of improvement during active stimulation (double-blind, single-blind and open-label phases) compared to baseline was 47.2–68.5%. Thirty nine per cent of the patients were considered long-term responders, 71.4% of whom had facial pain, phantom limb pain or complex regional pain syndrome. In contrast, 72.7% of non-responders had either post-stroke pain or pain associated with brachial plexus avulsion. Thirty-nine per cent of patients had a substantial postoperative analgesic effect after electrode insertion in the absence of stimulation. Individuals with diagnoses associated with a good postoperative outcome or those who developed an insertional effect had a near 100% probability of response to motor cortex stimulation.
In summary, we found that ∼40% of patients responded to motor cortex stimulation, particularly those who developed an insertional effect or had specific clinical conditions that seemed to predict an appropriate postoperative response.
Aims:
The aim of this study is to determine whether there is difference in the change in each symptom of depression and in symptomatic improvement pattern between placebo and antidepressant responses.
Methods:
Using data from a randomized, double-blind (DB), placebo-controlled trial of esketamine (ESK) in patients with treatment-resistant depression (TRD), we conducted exploratory analyses. To determine differences in the change in each depressive symptom on the MADRS subscale between placebo and antidepressant responses, a two-way factorial analysis was conducted using the amount of change on Day 2 and 28 of treatment. In addition, exploratory and confirmatory factor analyses were conducted on the MADRS subtotal variables on Day 2 and 28 of treatment to determine symptomatic improvement pattern between placebo response and antidepressant responses.
Results:
We found that as well as MADRS total score, each subscale of MADRS score did not significantly differ between esketamine and placebo at Day 2 and 28. On the other hand, factor analysis revealed that the factor structure of the response was different between esketamine and placebo at 2nd day. There was no difference in the factor structure between esketamine and placebo in response on Day 28 of treatment.
Conclusion:
Factor analysis revealed different patterns of symptom improvement in the early phase of the intervention between esketamine and placebo. It suggests that data driven approach may provide detailed efficacy information in clinical trials for antidepressants. This article is protected by copyright. All rights reserved.
Genomic studies on the placebo hypoalgesic effects highlight a promising link between single nucleotide polymorphisms (SNPs) in the dopamine, opioid, and endocannabinoid genes and placebo hypoalgesia. Yet, epistasis, replication, GWAS, and omics studies are missing. In this chapter, we elaborate upon the state-of-the-science of the genomics of the placebo and nocebo effect across pain conditions and populations with a focus on current challenges and areas of future discovery. We indicate directions for future research that will help fully understand the complexity of placebo effects and molecular mechanisms that predict individuals who may display a placebo effect.
This paper describes version 0.8-2 of R package meta which has been published in February 2007.
Most R commands presented in the paper are still working today with the current version of meta.
The command
summary(m1, byvar = Fleiss93$year < 1980, bylab = "year<1980")
has been replaced by
summary(update(m1, byvar = year < 1980, bylab = "year<1980")).
Furthermore, the R function plot.meta() has been replaced by forest.meta().
The use of meta-analysis has become increasingly useful for clinical and policy decision making. A recent development in meta-analysis, multiple treatment comparison (MTC) meta-analysis, provides inferences on the comparative effectiveness of interventions that may have never been directly evaluated in clinical trials. This new approach may be confusing for clinicians and methodologists and raises specific challenges relevant to certain areas of medicine. This article addresses the methodological concepts of MTC meta-analysis, including issues of heterogeneity, choice of model, and adequacy of sample sizes. We address domain-specific challenges relevant to disciplines of medicine, including baseline risks of patient populations. We conclude that MTC meta-analysis is a useful tool in the context of comparative effectiveness and requires further study, as its utility and transparency will likely predict its uptake by the research and clinical community.
Network meta-analysis, in the context of a systematic review, is a meta-analysis in which multiple treatments (that is, three or more) are being compared using both direct comparisons of interventions within randomized controlled trials and indirect comparisons across trials based on a common comparator. To ensure validity of findings from network meta-analyses, the systematic review must be designed rigorously and conducted carefully. Aspects of designing and conducting a systematic review for network meta-analysis include defining the review question, specifying eligibility criteria, searching for and selecting studies, assessing risk of bias and quality of evidence, conducting a network meta-analysis, interpreting and reporting findings. This commentary summarizes the methodologic challenges and research opportunities for network meta-analysis relevant to each aspect of the systematic review process based on discussions at a network meta-analysis methodology meeting we hosted in May 2010 at the Johns Hopkins Bloomberg School of Public Health. Since this commentary reflects the discussion at that meeting, it is not intended to provide an overview of the field.
This study investigated the efficacy and tolerability of the highly selective iNOS inhibitor GW274150 in prophylaxis of migraine headache.
The study was conducted in two parts, each comprising a 4-week baseline period, a 12-week, double-blind, parallel-group treatment period, and a 4-week follow-up period. The study had an adaptive design in that findings of Part 1 of the study were used to inform the conduct of Part 2. Following an interim analysis at the end of Part 1, the trial could be stopped for futility or continued in Part 2 to study the full-dose response or to increase sample size in case initial assumptions had been violated. The primary end-point in both parts of the study was the probability of the occurrence of a migraine headache day during the baseline period and the treatment period.
In Part 1, adult male and female patients with migraine received GW274150 60 mg (n = 37), 120 mg (n = 37), or placebo (n = 38) once daily for 12 weeks. In Part 2, female patients with migraine received GW274150 60 mg (n= 160) or placebo (n = 154) once daily for 12 weeks. GW274150 was no more effective than placebo for the primary efficacy end-point or any secondary efficacy end-point in Part 1 or Part 2. GW274150 was generally well tolerated.
GW274150 at doses predicted to inhibit iNOS >80% did not differ from placebo in the prophylaxis of migraine. The results do not support a role of iNOS inhibition in migraine prevention.
The metafor package provides functions for conducting meta-analyses in R. The package includes functions for fitting the meta-analytic fixed- and random-effects models and allows for the inclusion of moderators variables (study-level covariates) in these models. Meta-regression analyses with continuous and categorical moderators can be conducted in this way. Functions for the Mantel-Haenszel and Peto's one-step method for meta-analyses of 2 x 2 table data are also available. Finally, the package provides various plot functions (for example, for forest, funnel, and radial plots) and functions for assessing the model fit, for obtaining case diagnostics, and for tests of publication bias.
To determine if the addition of preventive drug treatment (β blocker), brief behavioural migraine management, or their combination improves the outcome of optimised acute treatment in the management of frequent migraine.
Randomised placebo controlled trial over 16 months from July 2001 to November 2005.
Two outpatient sites in Ohio, USA.
232 adults (mean age 38 years; 79% female) with diagnosis of migraine with or without aura according to International Headache Society classification of headache disorders criteria, who recorded at least three migraines with disability per 30 days (mean 5.5 migraines/30 days), during an optimised run-in of acute treatment.
Addition of one of four preventive treatments to optimised acute treatment: β blocker (n=53), matched placebo (n=55), behavioural migraine management plus placebo (n=55), or behavioural migraine management plus β blocker (n=69).
The primary outcome was change in migraines/30 days; secondary outcomes included change in migraine days/30 days and change in migraine specific quality of life scores.
Mixed model analysis showed statistically significant (P≤0.05) differences in outcomes among the four added treatments for both the primary outcome (migraines/30 days) and the two secondary outcomes (change in migraine days/30 days and change in migraine specific quality of life scores). The addition of combined β blocker and behavioural migraine management (-3.3 migraines/30 days, 95% confidence interval -3.2 to -3.5), but not the addition of β blocker alone (-2.1 migraines/30 days, -1.9 to -2.2) or behavioural migraine management alone (-2.2 migraines migraines/30 days, -2.0 to -2.4), improved outcomes compared with optimised acute treatment alone (-2.1 migraines/30 days, -1.9 to -2.2). For a clinically significant (≥50% reduction) in migraines/30 days, the number needed to treat for optimised acute treatment plus combined β blocker and behavioural migraine management was 3.1 compared with optimised acute treatment alone, 2.6 compared with optimised acute treatment plus β blocker, and 3.1 compared with optimised acute treatment plus behavioural migraine management. Results were consistent for the two secondary outcomes, and at both month 10 (the primary endpoint) and month 16.
The addition of combined β blocker plus behavioural migraine management, but not the addition of β blocker alone or behavioural migraine management alone, improved outcomes of optimised acute treatment. Combined β blocker treatment and behavioural migraine management may improve outcomes in the treatment of frequent migraine.
Clinical trials NCT00910689.
Although meta-analyses have shown that placebo responses are large in Major Depressive Disorder (MDD) trials; the placebo response of devices such as repetitive transcranial magnetic stimulation (rTMS) has not been systematically assessed. We proposed to assess placebo responses in two categories of MDD trials: pharmacological (antidepressant drugs) and non-pharmacological (device- rTMS) trials.
We performed a systematic review and meta-analysis of the literature from April 2002 to April 2008, searching MEDLINE, Cochrane, Scielo and CRISP electronic databases and reference lists from retrieved studies and conference abstracts. We used the keywords placebo and depression and escitalopram for pharmacological studies; and transcranial magnetic stimulation and depression and sham for non-pharmacological studies. All randomized, double-blinded, placebo-controlled, parallel articles on major depressive disorder were included. Forty-one studies met our inclusion criteria - 29 in the rTMS arm and 12 in the escitalopram arm. We extracted the mean and standard values of depression scores in the placebo group of each study. Then, we calculated the pooled effect size for escitalopram and rTMS arm separately, using Cohen's d as the measure of effect size. We found that placebo response are large for both escitalopram (Cohen's d - random-effects model - 1.48; 95%C.I. 1.26 to 1.6) and rTMS studies (0.82; 95%C.I. 0.63 to 1). Exploratory analyses show that sham response is associated with refractoriness and with the use of rTMS as an add-on therapy, but not with age, gender and sham method utilized.
We confirmed that placebo response in MDD is large regardless of the intervention and is associated with depression refractoriness and treatment combination (add-on rTMS studies). The magnitude of the placebo response seems to be related with study population and study design rather than the intervention itself.
Most patients with chronic obstructive pulmonary disease (COPD) receive inhaled long-acting bronchodilators and inhaled corticosteroids. Conventional meta-analyses established that these drugs reduce COPD exacerbations when separately compared with placebo. However, there are relatively few head-to-head comparisons and conventional meta-analyses focus on single comparisons rather than on a simultaneous analysis of competing drug regimens that would allow rank ordering of their effectiveness. Therefore we assessed, using a network meta-analytic technique, the relative effectiveness of the common inhaled drug regimes used to reduce exacerbations in patients with COPD.
We conducted a systematic review and searched existing systematic reviews and electronic databases for randomized trials of >/= 4 weeks' duration that assessed the effectiveness of inhaled drug regimes on exacerbations in patients with stable COPD. We extracted participants and intervention characteristics from included trials and assessed their methodological quality. For each treatment group we registered the proportion of patients with >/= 1 exacerbation during follow-up. We used treatment-arm based logistic regression analysis to estimate the absolute and relative effects of inhaled drug treatments while preserving randomization within trials.
We identified 35 trials enrolling 26,786 patients with COPD of whom 27% had >/= 1 exacerbation. All regimes reduced exacerbations statistically significantly compared with placebo (odds ratios ranging from 0.71 (95% confidence interval [CI] 0.64 to 0.80) for long-acting anticholinergics to 0.78 (95% CI 0.70 to 0.86) for inhaled corticosteroids). Compared with long-acting bronchodilators alone, combined treatment was not more effective (comparison with long-acting beta-agonists: odds ratio 0.93 [95% CI 0.84 to 1.04] and comparison with long-acting anticholinergics: odds ratio 1.02 [95% CI 0.90 to 1.16], respectively). If FEV1 was </= 40% predicted, long-acting anticholinergics, inhaled corticosteroids, and combination treatment reduced exacerbations significantly compared with long-acting beta-agonists alone, but not if FEV1 was > 40% predicted. This effect modification was significant for inhaled corticosteroids (P = 0.02 for interaction) and combination treatment (P = 0.01) but not for long-acting anticholinergics (P = 0.46). A limitation of this analysis is its exclusive focus on exacerbations and lack of FEV1 data for individual patients.
We found no evidence that one single inhaled drug regimen is more effective than another in reducing exacerbations. Inhaled corticosteroids when added to long-acting beta-agonists reduce exacerbations only in patients with COPD with FEV1 </= 40%.
Behavioral medicine interventions that directly reduce arousal and negative emotions, such as relaxation training (RT), are conceptually different from interventions that temporarily increase negative emotions, such as written emotional disclosure (WED), but no studies have directly compared their efficacy. We compared the effects of RT and WED on people with tension or migraine headaches.
College students with either tension (n = 51) or migraine (n = 90) headaches were randomized to one of three groups: RT, WED, or a neutral writing control condition; four sessions were held over 2 weeks. Mood was measured before and after each session, and outcomes (headache frequency, severity, disability, and general physical symptoms) were assessed at baseline and at 1-month and 3-month follow-ups.
As expected, RT led to an immediate increase in calmness, whereas WED led to an immediate increase in negative mood, for both headache samples. Intent-to-treat analyses showed that, for the tension headache sample, RT led to improved headache frequency and disability compared to both WED and the control group, but WED had no effect. For migraine headaches, RT improved pain severity relative to the control group, but WED again had no effect.
A brief RT protocol was effective for tension headaches, but WED had no effect on health status for either tension or migraine headaches. Modifications to WED, such as targeting people with unresolved stress, providing guidance to enhance the potency of the writing, or including additional at-home writing and exposure exercises, may improve its efficacy for people with headaches and other health problems.
Background: High-frequency rTMS increases and low rTMS frequency decreases neural excitability. Clinically, rTMS shows beneficial effects in the treatment of neurological and psychiatric disorders. Furthermore, chronic and neuropathic pain have been shown to respond to rTMS treatment. A small sized pilot study revealed prophylactic effects of rTMS in migraine. As there is evidence for neuronal hyperexcitability in migraine we conducted this placebo-controlled and blinded study to evaluate the therapeutic effects of a low-frequency rTMS in migraine. The primary endpoint was defined as a significant reduction of migraine attacks, secondary outcomes were response (reduction of migraine attacks by at least 50% from baseline), a reduction in the total number of days with headache, hours with headache, pain intensity and a decrease of analgesic intake for migraine.
Methods: 27 migraineurs completed the study and were treated with rTMS on 5 consecutive days. For the verum group, two trains of 500 pulses with a frequency of 1Hz were applied over vertex with a round coil. For the treatment of the placebo group a figure-of-eight sham coil was used.
Results: A significant decrease of migraine attacks could be observed in the verum group. However, when comparing these effects with placebo, no significance was evident. The same was true concerning secondary outcome measures with regard to days with migraine and total hours with migraine. No response with a reduction of migraine attacks for at least 50% was seen and no effects were evident for pain intensity and use of analgesics. The rTMS treatment was well tolerated.
Conclusions: rTMS stimulation over vertex with 1Hz was not effective in migraine prophylaxis when compared with placebo.
Treatment with medication, be it symptomatic or with an etiopathogenic aim in mind, doesn’t always solve the problem of headaches, be they migraine or tension headaches.
One-hundred-sixteen patients suffering from vascular headache (migraine or combined migraine and tension) were, after 4 weeks of pretreatment baseline headache monitoring, randomly assigned to one of four conditions: (a) thermal biofeedback with adjunctive relaxation training (TBF); (b) TBF plus cognitive therapy; (c) pseudomeditation as an ostensible attention-placebo control; or (d) headache monitoring. The first three groups received 16 individual sessions over 8 weeks, while the fourth group continued to monitor headaches. All groups then monitored headaches for a 4-week posttreatment baseline. Analysis revealed that all treated groups improved significantly more than the headache monitoring group with no significant differences among the three treated groups. On a measure of clinically significant improvement, the two TBF groups had slightly higher (51%) degree of improvement than the meditation group (37.5%). It is argued that the attention-placebo control became an active relaxation condition.
Acupuncture is more and more used for the treatment of chronic headache patients. The question concerning the clinical effect of acupuncture is closely linked with the question concerning a possible explanation of the mechanism of action. A problem in the understanding of the effect of acupuncture is, that acupuncture as far as its effect is concerned, points rather to secondary reactions, which are subject to the autonomous laws of the organism, than to pharmacological direct effects. Acupuncture appeals according to its self-understanding as a therapeutical principle to the ability of the organism or the individual to keep itself in order or to heal itself and therefore is a regulatory therapy. In the present work the examinations of the mechanism of action of acupuncture are presented and the problem of the regulation is seen from the point of view of the traditional Chinese medicine (TCM) and the point of view of the modern Western medicine (MWM). In the clinical-experimental part of the work the results of an acupuncture treatment of patients with headache are presented by the example of the interval therapy of migraine with the help of two prospective therapeutical studies. In addition, as an external validation, the lead of the 'contingent negative variation' (CNV), of an event-correlated cortical potential at the lead positions C3, CZ and C4 according to the 10/20 system is carried out. In the studies, which have been carried out, the acupuncture shows a clinical-therapeutical effect and therefore is a useful interval therapeutical agent for migraine. The use of a verum acupuncture is much superior to the present design of a control treatment and points to a specific effect of acupuncture. The verum acupuncture is also able to modulate the amplitude of the CNV curve. From the point of view of the neurologist it is tried, by the inclusion of electrophysiological parameters, to build a bridge between the use of stimuli of the body surface and the central nervous processing of these stimuli from the point of view of regulation.
Acupuncture treatments were carried out under double-blind conditions in 44 patients with migraine refractory to treatment. The choice of the points was made according to the Academy of the Traditional Chinese Medicine, Peking. Placebo points were chosen outside the meridian, and the site of the puncture was retested for the sake of certainty about the freedom of the puncture point, using the electric point searching apparatus for the purpose. The criteria of the success of the treatment were evaluated according to the protocols of the patients about their attacks of migraine; the observation period after the acupuncture was 10 intervals. 21 patients revealed a very good result of treatment, 4 of them were entirely free of complaints. There were 4 patients with an accompanied migraine. In all, the focal symptoms had disappeared after the acupuncture treatment. One of the women patients was completely free from attacks. For the success of treatment it is a matter of indifference whether acupuncture points or placebo points are pricked.
Background: Acupuncture is an accepted treatment for migraine. Palpation of the radial pulses is one of the most important techniques in traditional Chinese medicine both for diagnosis and monitoring of treatment efficacy. The objective of the present study was to investigate the acute and chronic effects of acupuncture on the radial artery of patients suffering from severe migraine.
Methods: A double-blind parallel group study was conducted in 31 patients never exposed to acupuncture and randomized in two groups : real acupuncture versus sham acupuncture, applied 3 times at one month interval. At baseline and after 2 months, radial artery diameter was measured with a high resolution echotracking system before and during a 20 min’s acupuncture session. Migraine severity was assessed by self administrated questionnaires and visual analogic scale for pain at each visit. Patients and investigators (not acupuncture physician) were blinded as to the treatment allocation.
Results: During the first session, radial artery diameter significantly increased after real acupuncture, (+3.1% IQR [−3.2–8.5], P = 0.03 vs 0.9% IQR [−5.3–5.8], P = NS), and remained significantly higher after the two months treatment course 5.2% IQR [−3.9–14] vs. −4.4% IQR [−10.0–3.5], respectively; P < 0.01). Patients with the most severe pain at baseline were less prone to dilate their arteries during follow-up (P < 0.05). A larger arterial vasodilatation after real acupuncture was observed for any given level of pain intensity (P < 0.01).
Conclusion: an acupuncture-induced vasodilatation was observed at the site of the radial artery in patients suffering from severe migraine and naïve to acupuncture. The vasodilatation was maintained after chronic treatment.
Condensed abstract: This double-blind randomized, controlled trial aimed at showing the acute and chronic vasodilatory response to acupuncture in migrainers naïve to acupuncture. We show that real acupuncture is accompanied by acute and chronic vasodilation of the radial artery, the chronic vasodilation is inversely related to the level of pain at baseline.
Objective.—To assess the safety and efficacy of botulinum toxin type A (BOTOX; Allergan, Inc) in the prevention of migraine.
Background.—Current migraine preventive therapies are often unsatisfactory because of their limited efficacy, adverse effects, and drug interactions. Botulinum toxin type A injections often reduce the pain associated with conditions such as cervical dystonia, achalasia, rectal fissures, and myofascial pain syndrome. An open-label, noncontrolled study of botulinum toxin type A suggested benefits for patients with migraine.
Design and Methods.—This was a double-blind, vehicle-controlled study of 123 subjects with a history of two to eight moderate-to-severe migraine attacks per month, with or without aura. Participants were randomized to receive single administrations of vehicle or botulinum toxin type A, 25 U or 75 U, injected into multiple sites of pericranial muscles at the same visit. During a 1-month baseline period and for 3 months following injection, subjects kept daily diaries in which they recorded migraine frequency, migraine severity, and the occurrence of migraine-associated symptoms.
Results.—Compared with vehicle treatment, subjects in the 25-U botulinum toxin type A treatment group showed significantly fewer migraine attacks per month, a reduced maximum severity of migraines, a reduced number of days using acute migraine medications, and reduced incidence of migraine-associated vomiting. Both the 25-U and 75-U botulinum toxin type A groups were significantly better than the vehicle group on subject global assessment. Botulinum toxin A treatment was well tolerated, with only the 75-U treatment group exhibiting a significantly higher rate of treatment-related adverse events than vehicle.
Conclusions.—Pericranial injection of botulinum toxin type A, 25 U, was found to be a safe treatment that significantly reduced migraine frequency, migraine severity, acute medication usage, and associated vomiting.
In order to evaluate the specific effects of blood volume pulse (BVP) biofeedback in the treatment of migraine headaches, 21 female migraine patients were randomly assigned to one of three experimental conditions: temporal artery constriction feedback, temporal artery dilation feedback, or waiting list. Biofeedback training consisted of 15 sessions over an 8-week period. All patients completed 5 weeks of daily self-monitoring of headache activity and medication before and after treatment. Results showed that constriction and dilation biofeedback were equally effective in controlling migraines and produced greater benefits than the waiting-list condition. No significant relationships were found between therapeutic gains and BVP self-regulation skills. However, further analyses revealed that changes in headache activity and medication were associated with changes in vasomotor variability. The current rationale for the use of BVP biofeedback in the treatment of migraine is questioned and a new one is proposed.
Background and Objective: A recent Cochrane review on placebo interventions for all kinds of conditions found that ‘physical placebos’ (which included sham acupuncture) were associated with larger effects over no-treatment control groups than ‘pharmacological placebos’. We re-analyzed the data from this review to investigate whether effects associated with sham acupuncture differed from those of other ‘physical placebos’. Methods: All trials included in the Cochrane review as investigating ‘physical placebos’ were classified as investigating either (sham) acupuncture or other physical placebos. The latter group was further subclassified into groups of similar interventions. Data from the Cochrane review were re-entered into the RevMan 5 software for meta-analysis. The primary analysis was a random-effects analysis of trials reporting continuous outcomes of trials that used either sham acupuncture or other physical placebos. Results: Out of a total of 61 trials which
There is accumulating evidence from different methodological approaches that the placebo effect is a neurobiological phenomenon. Behavioral, psychophysiological, and neuroimaging results have largely contributed to accepting the placebo response as real. A major aspect of recent and future advances in placebo research is to demonstrate linkages between behavior, brain, and bodily responses. This article provides an overview of the processes involved in the formation of placebo responses by combining research findings from behavioral, psychophysiological, and neuroimaging methods. The integration of these different methodological approaches is a key objective, motivating our scientific pursuits toward a placebo research that can inform and guide important future scientific knowledge.
This study sought to compare the sensitivity and precision of Embase, Medline and PsycINFO bibliographic database searches for randomized controlled trials of cognitive therapy for depression. Searches in each database combined with a hand search in five selected journals formed the total pool against which each search was assessed. Sensitivities of standard searches (index terms only) were 68%, 84% and 38% in Embase, Medline and PsycINFO respectively. Sensitivities of expert searches (index and free text terms) were 76%, 97% and 65% for Embase, Medline and PsycINFO respectively. Medline appears to be the most efficient at identifying articles describing psychological treatment evaluation.
Using a comparative analysis of Navajo healing ceremonials, acupuncture and biomedical treatment, this essay examines placebo studies and ritual theory as mutually interpenetrating disciplines. Healing rituals create a receptive person susceptible to the influences of authoritative culturally sanctioned 'powers'. The healer provides the sufferer with imaginative, emotional, sensory, moral and aesthetic input derived from the palpable symbols and procedures of the ritual process-in the process fusing the sufferer's idiosyncratic narrative unto a universal cultural mythos. Healing rituals involve a drama of evocation, enactment, embodiment and evaluation in a charged atmosphere of hope and uncertainty. Experimental research into placebo effects demonstrates that routine biomedical pharmacological and procedural interventions contain significant ritual dimensions. This research also suggests that ritual healing not only represents changes in affect, self-awareness and self-appraisal of behavioural capacities, but involves modulations of symptoms through neurobiological mechanisms. Recent scientific investigations into placebo acupuncture suggest several ways that observations from ritual studies can be verified experimentally. Placebo effects are often described as 'non-specific'; the analysis presented here suggests that placebo effects are the 'specific' effects of healing rituals.
Investigations of the effect of placebo are often challenging to conduct and interpret. The history of placebo shows that assessment of its clinical significance has a real potential to be biased. We analyze and discuss typical types of bias in studies on placebo.
A methodological analysis and discussion.
The inherent nonblinded comparison between placebo and no-treatment is the best research design we have in estimating effects of placebo, both in a clinical and in an experimental setting, but the difference between placebo and no-treatment remains an approximate and fairly crude reflection of the true effect of placebo interventions. A main problem is response bias in trials with outcomes that are based on patients' reports. Other biases involve differential co-intervention and patient dropouts, publication bias, and outcome reporting bias. Furthermore, extrapolation of results to a clinical settings are challenging because of a lack of clear identification of the causal factors in many clinical trials, and the nonclinical setting and short duration of most laboratory experiments.
Creative experimental efforts are needed to assess rigorously the clinical significance of placebo interventions and investigate the component elements that may contribute to the therapeutic benefit.
Evidence that placebo acupuncture is an effective treatment for chronic pain presents a puzzle: how do placebo needles appearing to patients to penetrate the body, but instead sitting on the skin's surface in the manner of a tactile stimulus, evoke a healing response? Previous accounts of ritual touch healing in which patients often described enhanced touch sensations (including warmth, tingling or flowing sensations) suggest an embodied healing mechanism. In this qualitative study, we asked a subset of patients in a singleblind randomized trial in irritable bowel syndrome to describe their treatment experiences while undergoing placebo treament. Analysis focused on patients' unprompted descriptions of any enhanced touch sensations (e.g., warmth, tingling) and any significance patients assigned to the sensations. We found in 5/6 cases, patients associated sensations including "warmth" and "tingling" with treatment efficacy. The conclusion offers a "neurophenomenological" account of the placebo effect by considering dynamic effects of attentional filtering on early sensory cortices, possibly underlying the phenomenology of placebo acupuncture.
To evaluate the efficacy, safety, and optimum dose of a highly purified Clostridium botulinum type A toxin-hemagglutinin complex (Dysport) for migraine prophylaxis.
Botulinum toxin type-A has demonstrated good efficacy in several open-label studies of patients with migraine, involving either individualized or standardized protocols, although data from placebo-controlled trials have been conflicting.
A 12-week, double-blind, randomized trial of Dysport (120 or 240 units) vs placebo was conducted in 6 centers in Thailand to evaluate the efficacy, safety, and optimum dose of botulinum toxin type-A (Dysport) for migraine prophylaxis. A total of 128 patients with migraine without aura were enrolled. The primary end point was the change in the mean number of migraine attacks per 4-week period from the pre-treatment period to 8-12 weeks post injection. Secondary efficacy measures included the change in the mean total intensity score from the pre-treatment period to 8-12 weeks, the investigator and patient global assessments of change at each visit compared with pre-treatment, and Migraine Disability Assessment and Short Form-36 scores.
Change in number of migraine attacks from pre-treatment to weeks 8-12 was not significantly different. There was a greater improvement in total intensity score at weeks 8-12 with Dysport-240 (not significant), and interim visit data showed that this was significant at weeks 0-4 (P = .03 Dysport-240 vs placebo). The mean duration of headache during weeks 0-4 was lower with Dysport-240 (P = .04 vs placebo). Improvements in patient and investigator global assessments of change between weeks 0-4 and 8-12 were significant for the Dysport-240 group (both P < .05 vs placebo).
Limitations in study design and assessment tools employed may have contributed to the inconclusive nature of the primary end point data. Dysport-240 showed significant benefit over placebo at some end points and further trials with more appropriate outcome measures are required to evaluate effectively this treatment.
Several pharmacological treatments are used to manage post-herpetic neuralgia (PHN). The use of topical analgesics, such as 5% lidocaine-medicated plaster (5% LMP), may be preferable to systemic treatments in that they are formulated to produce a local pain relieving effect with minimal systemic absorption. However, direct head-to-head comparisons are relatively few, and a rigorous assessment of the relative efficacy and safety of the various treatment options is lacking. The objective of this study was to compare 5% LMP for the relief of PHN with other relevant interventions and placebo. Six databases were searched up to May 2010. Quantitative methods for data synthesis were used, and a network meta-analysis was conducted. Twenty unique studies (32 publications) were included. Placebo-controlled studies showed 5% LMP to be effective in providing pain relief and reducing allodynia while adverse event rates were generally low. A comparison between 5% LMP and pregabalin indicated the non-inferiority of 5% LMP for pain reduction and showed greater improvement of quality of life for 5% LMP. Adverse events (AE) were significantly fewer with 5% LMP. In the network meta-analysis, only 5% LMP and gabapentin were associated with a greater change in pain from baseline than placebo [-15.50 (95% CI -18.85 to -12.16) and -7.56 (95% CI -12.52 to -2.59) respectively]. 5% LMP was shown to be more effective than capsaicin [-16.45 (95% CI -20.04 to -12.86)], gabapentin [-7.95 (95% CI -13.29 to -2.61)] and pregabalin [-13.45 (95% CI -19.19 to -7.71)]. For pain relief, two comparators were more effective than placebo [mean pain relief, gabapentin: 32.77 (95% CI 15.57-49.97); 5% LMP: 26.77 (95% CI 9.11-44.43)]. 5% LMP was shown to be comparable to gabapentin [-6.00 (95% CI -25.32-13.32)]. The results suggest that 5% LMP and gabapentin have similar effects on pain relief and that 5% LMP is more effective than capsaicin and pregabalin (change in pain from baseline). Topical agents, such as 5% LMP, are associated with fewer and less clinically significant AE than is the case for systemic agents. However, small numbers, and limited size and quality of included studies should be taken into account. Further studies are needed.
A recent Cochrane review on placebo interventions for all kinds of conditions found that 'physical placebos' (which included sham acupuncture) were associated with larger effects over no-treatment control groups than 'pharmacological placebos'. We re-analyzed the data from this review to investigate whether effects associated with sham acupuncture differed from those of other 'physical placebos'.
All trials included in the Cochrane review as investigating 'physical placebos' were classified as investigating either (sham) acupuncture or other physical placebos. The latter group was further subclassified into groups of similar interventions. Data from the Cochrane review were re-entered into the RevMan 5 software for meta-analysis. The primary analysis was a random-effects analysis of trials reporting continuous outcomes of trials that used either sham acupuncture or other physical placebos.
Out of a total of 61 trials which reported a continuous outcome measure, 19 compared sham acupuncture and 42 compared other physical placebos with a no-treatment control group. The trials re-analyzed were highly heterogeneous regarding patients, interventions and outcomes measured. The pooled standardized mean difference was -0.41 (95% confidence interval -0.56, -0.24) between sham acupuncture and no treatment and -0.26 (95% CI -0.37, -0.15) between other physical placebos and no treatment (p value for subgroup differences = 0.007). Significant differences were also observed between subgroups of other physical placebos.
Due to the heterogeneity of the trials included and the indirect comparison our results must be interpreted with caution. Still, they suggest that sham acupuncture interventions might, on average, be associated with larger effects than pharmacological and other physical placebos.
Background:
Placebo interventions are often claimed to substantially improve patient-reported and observer-reported outcomes in many clinical conditions, but most reports on effects of placebos are based on studies that have not randomised patients to placebo or no treatment. Two previous versions of this review from 2001 and 2004 found that placebo interventions in general did not have clinically important effects, but that there were possible beneficial effects on patient-reported outcomes, especially pain. Since then several relevant trials have been published.
Objectives:
Our primary aims were to assess the effect of placebo interventions in general across all clinical conditions, and to investigate the effects of placebo interventions on specific clinical conditions. Our secondary aims were to assess whether the effect of placebo treatments differed for patient-reported and observer-reported outcomes, and to explore other reasons for variations in effect.
Search strategy:
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 4, 2007), MEDLINE (1966 to March 2008), EMBASE (1980 to March 2008), PsycINFO (1887 to March 2008) and Biological Abstracts (1986 to March 2008). We contacted experts on placebo research, and read references in the included trials.
Selection criteria:
We included randomised placebo trials with a no-treatment control group investigating any health problem.
Data collection and analysis:
Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. Trials with binary data were summarised using relative risk (a value of less than 1 indicates a beneficial effect of placebo), and trials with continuous outcomes were summarised using standardised mean difference (a negative value indicates a beneficial effect of placebo).
Main results:
Outcome data were available in 202 out of 234 included trials, investigating 60 clinical conditions. We regarded the risk of bias as low in only 16 trials (8%), five of which had binary outcomes.In 44 studies with binary outcomes (6041 patients), there was moderate heterogeneity (P < 0.001; I(2) 45%) but no clear difference in effects between small and large trials (symmetrical funnel plot). The overall pooled effect of placebo was a relative risk of 0.93 (95% confidence interval (CI) 0.88 to 0.99). The pooled relative risk for patient-reported outcomes was 0.93 (95% CI 0.86 to 1.00) and for observer-reported outcomes 0.93 (95% CI 0.85 to 1.02). We found no statistically significant effect of placebo interventions in four clinical conditions that had been investigated in three trials or more: pain, nausea, smoking, and depression, but confidence intervals were wide. The effect on pain varied considerably, even among trials with low risk of bias.In 158 trials with continuous outcomes (10,525 patients), there was moderate heterogeneity (P < 0.001; I(2) 42%), and considerable variation in effects between small and large trials (asymmetrical funnel plot). It is therefore a questionable procedure to pool all the trials, and we did so mainly as a basis for exploring causes for heterogeneity. We found an overall effect of placebo treatments, standardised mean difference (SMD) -0.23 (95% CI -0.28 to -0.17). The SMD for patient-reported outcomes was -0.26 (95% CI -0.32 to -0.19), and for observer-reported outcomes, SMD -0.13 (95% CI -0.24 to -0.02). We found an effect on pain, SMD -0.28 (95% CI -0.36 to -0.19)); nausea, SMD -0.25 (-0.46 to -0.04)), asthma (-0.35 (-0.70 to -0.01)), and phobia (SMD -0.63 (95% CI -1.17 to -0.08)). The effect on pain was very variable, also among trials with low risk of bias. Four similarly-designed acupuncture trials conducted by an overlapping group of authors reported large effects (SMD -0.68 (-0.85 to -0.50)) whereas three other pain trials reported low or no effect (SMD -0.13 (-0.28 to 0.03)). The pooled effect on nausea was small, but consistent. The effects on phobia and asthma were very uncertain due to high risk of bias. There was no statistically significant effect of placebo interventions in the seven other clinical conditions investigated in three trials or more: smoking, dementia, depression, obesity, hypertension, insomnia and anxiety, but confidence intervals were wide.Meta-regression analyses showed that larger effects of placebo interventions were associated with physical placebo interventions (e.g. sham acupuncture), patient-involved outcomes (patient-reported outcomes and observer-reported outcomes involving patient cooperation), small trials, and trials with the explicit purpose of studying placebo. Larger effects of placebo were also found in trials that did not inform patients about the possible placebo intervention.
Authors' conclusions:
We did not find that placebo interventions have important clinical effects in general. However, in certain settings placebo interventions can influence patient-reported outcomes, especially pain and nausea, though it is difficult to distinguish patient-reported effects of placebo from biased reporting. The effect on pain varied, even among trials with low risk of bias, from negligible to clinically important. Variations in the effect of placebo were partly explained by variations in how trials were conducted and how patients were informed.
To assess the relative contribution of specific and nonspecific effects of skin temperature biofeedback upon migraine headache, 11 migraine patients were taught to increase the temperature of their hand. Training to decrease the skin temperature of the hand served as a control for 12 other migraine patients. An additional 11 control subjects were not trained but kept records of migraine activity. Under carefully controlled double-blind procedures, migraine patients who learned to raise finger temperatures showed statistically significant and clinically therapeutic improvement during a 6-week follow-up period. However, they were not significantly better than those trained to lower finger temperatures, those who did not meet a learning criterion, or those receiving no training. While these groups did show some significant improvement when compared to subjects who learned to decrease finger temperature, the results are most parsimoniously explained through nonspecific rather than specific factors. The necessity of using double-blind procedures in evaluating therapeutic effectiveness is again stressed. Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/44087/1/10484_2005_Article_BF00999808.pdf
