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OBJECTIVES: Adequate relief (AR) of irritable bowel syndrome (IBS) symptoms (IBS-AR) has been used as a primary end point in many randomized controlled trials of IBS and is considered by the Rome III committee to be an acceptable primary end point. However, controversy exists on whether baseline severity confounds the effect of the treatment outcome. The aim (1) is to compare a subjective report of IBS-AR with global assessment of improvement (IBS-GAI), change in IBS symptom severity scale (IBS-SSS), and IBS quality of life (IBS-QOL); (2) to explore whether initial IBS symptom severity influences the ability of these outcome measures to detect differences post treatment; and (3) to determine whether psychological symptoms influence the sensitivity of these measures, in a randomized controlled treatment trial.
METHODS: A total of 289 adult IBS patients were recruited to a treatment trial. Baseline IBS-SSS scores were used to classify IBS severity as mild (<175), moderate (175–300), or severe (>300). Questionnaires were completed at baseline and after 3 weeks of treatment with sham acupuncture or wait-list control.
RESULTS: IBS baseline severity (IBS-SSS) significantly affected the proportion of patients who reported IBS-AR at 3 weeks (mild, 70%; moderate, 49.7%; severe, 38.8%) (P<0.05). However, once the patients who reported IBS-AR at baseline (28.0%) were excluded from the analysis, baseline severity no longer affected the proportion of patients reporting IBS-AR. Baseline severity did not have a significant effect on patients reporting moderate or significant improvement on the IBS-GAI (mild, 30%; moderate, 25.3%; severe, 18.8%) (P=NS). Psychological symptoms had no significant correlations with responders after adjusting for baseline severity.
CONCLUSIONS: These data suggest that IBS-AR as an end point is inversely related to baseline symptom severity. However, if patients who report AR at screening were excluded from study participation, baseline symptom severity was no longer confounded with a report of AR at the study end point.
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Objective To investigate whether placebo effects can experimentally be separated into the response to three components—assessment and observation, a therapeutic ritual (placebo treatment), and a supportive patient-practitioner relationship—and then progressively combined to produce incremental clinical improvement in patients with irritable bowel syndrome. To assess the relative magnitude of these components.
Design A six week single blind three arm randomised controlled trial.
Setting Academic medical centre.
Participants 262 adults (76% women), mean (SD) age 39 (14), diagnosed by Rome II criteria for and with a score of ≥150 on the symptom severity scale.
Interventions For three weeks either waiting list (observation), placebo acupuncture alone (“limited”), or placebo acupuncture with a patient-practitioner relationship augmented by warmth, attention, and confidence (“augmented”). At three weeks, half of the patients were randomly assigned to continue in their originally assigned group for an additional three weeks.
Main outcome measures Global improvement scale (range 1-7), adequate relief of symptoms, symptom severity score, and quality of life.
Results At three weeks, scores on the global improvement scale were 3.8 (SD 1.0) v 4.3 (SD 1.4) v 5.0 (SD 1.3) for waiting list versus “limited” versus “augmented,” respectively (P<0.001 for trend). The proportion of patients reporting adequate relief showed a similar pattern: 28% on waiting list, 44% in limited group, and 62% in augmented group (P<0.001 for trend). The same trend in response existed in symptom severity score (30 (63) v 42 (67) v 82 (89), P<0.001) and quality of life (3.6 (8.1) v 4.1 (9.4) v 9.3 (14.0), P<0.001). All pairwise comparisons between augmented and limited patient-practitioner relationship were significant: global improvement scale (P<0.001), adequate relief of symptoms (P<0.001), symptom severity score (P=0.007), quality of life (P=0.01).Results were similar at six week follow-up.
Conclusion Factors contributing to the placebo effect can be progressively combined in a manner resembling a graded dose escalation of component parts. Non-specific effects can produce statistically and clinically significant outcomes and the patient-practitioner relationship is the most robust component.
Trial registration Clinical Trials NCT00065403.
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Background: The diagnostic framework and clinical reasoning process in Chinese medicine emphasizes the contextual and qualitative nature of a patient's illness. Chinese medicine assessment data may help interpret clinical outcomes. Objectives: As part of a study aimed at assessing the validity and improving the inter-rater reliability of the Chinese diagnostic process, a structured assessment instrument was developed for use in clinical trials of acupuncture and other Chinese medical therapies. Study design: To foster collaboration and maximize resources and information, an interdisciplinary advisory team was assembled. Under the guidance of two group process facilitators, and in order to establish whether the assessment instrument was consistent with accepted Chinese medicine diagnostic categories (face validity) and included the full range of each concept's meaning (content validity), a panel of Traditional Chinese Medicine (TCM) expert clinicians was convened and their responses were organized using the Delphi process, an iterative, anonymous, idea-generating and consensus-building process. An aggregate rating measure was obtained by taking the mean of mean ratings for each question across all 10 experts. Results: Over three rounds, the overall rating increased from 7.4 (SD = 1.3) in Round 1 to 9.1 (SD = 0.5) in Round 3. The level of agreement among clinicians was measured by a decrease in SD. Conclusions: The final instrument TEAMSI-TCM (Traditional East Asian Medicine Structured Interview, TCM version) uses the pattern differentiation model characteristic of TCM. This modular, dynamic version was specifically designed to assess women, with a focus on gynecologic conditions; with modifications it can be adapted for use with other populations and conditions. TEAMSI-TCM is a prescriptive instrument that guides clinicians to use the proper indicators, combine them in a systematic manner, and generate conclusions. In conjunction with treatment manualization and training it may serve to increase inter-rater reliability and inter-trial reproducibility in Chinese medicine clinical trials. Testing of the validity and reliability of this instrument currently is underway.
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A successful clinical trial is dependent on recruitment. Between December 2003 and February 2006, our team successfully enrolled 289 participants in a large, single-center, randomized placebo-controlled trial (RCT) studying the impact of the patient-doctor relationship and acupuncture on irritable bowel syndrome (IBS) patients. This paper reports on the effectiveness of standard recruitment methods such as physician referral, newspaper advertisements, fliers, audio and video media (radio and television commercials) as well as relatively new methods not previously extensively reported on such as internet ads, ads in mass-transit vehicles and movie theater previews. We also report the fraction of cost each method consumed and fraction of recruitment each method generated. Our cost per call from potential participants varied from $3–$103 and cost per enrollment participant varied from $12–$584. Using a novel metric, the efficacy index, we found that physician referrals and flyers were the most effective recruitment method in our trial. Despite some methods being more efficient than others, all methods contributed to the successful recruitment. The iterative use of the efficacy index during a recruitment campaign may be helpful to calibrate and focus on the most effective recruitment methods.
A successful clinical trial is dependent on recruitment. Between December 2003 and February 2006, our team successfully enrolled 289 participants in a large, single-center, randomized placebo-controlled trial (RCT) studying the impact of the patient-doctor relationship and acupuncture on irritable bowel syndrome (IBS) patients. This paper reports on the effectiveness of standard recruitment methods such as physician referral, newspaper advertisements, fliers, audio and video media (radio and television commercials) as well as relatively new methods not previously extensively reported on such as internet ads, ads in mass-transit vehicles and movie theater previews. We also report the fraction of cost each method consumed and fraction of recruitment each method generated. Our cost per call from potential participants varied from $3–$103 and cost per enrollment participant varied from $12–$584. Using a novel metric, the efficacy index, we found that physician referrals and flyers were the most effective recruitment method in our trial. Despite some methods being more efficient than others, all methods contributed to the successful recruitment. The iterative use of the efficacy index during a recruitment campaign may be helpful to calibrate and focus on the most effective recruitment methods.
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During selective attention, ∼7–14 Hz alpha rhythms are modulated in early sensory cortices, suggesting a mechanistic role for these dynamics in perception. Here, we investigated whether alpha modulation can be enhanced by “mindfulness” meditation (MM), a program training practitioners in sustained attention to body and breath-related sensations. We hypothesized that participants in the MM group would exhibit enhanced alpha power modulation in a localized representation in the primary somatosensory neocortex in response to a cue, as compared to participants in the control group. Healthy subjects were randomized to 8-weeks of MM training or a control group. Using magnetoencephalographic (MEG) recording of the SI finger representation, we found meditators demonstrated enhanced alpha power modulation in response to a cue. This finding is the first to show enhanced local alpha modulation following sustained attentional training, and implicates this form of enhanced dynamic neural regulation in the behavioral effects of meditative practice.
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Background: This paper describes the experiences of 8 licensed acupuncturists in a placebo-controlled randomized clinical trial (RCT). This information is important to the design and conduct of high-quality trials. Methods: We conducted a RCT (N = 135) with a 2-week placebo run-in followed by 4 weeks of twice-weekly treatments comparing genuine to sham acupuncture (using the Streitberger placebo needle) in the treatment of arm pain caused by repetitive use. At the end of this study, we conducted written structured interviews with 8 participating acupuncturists. The acupuncturists were not aware of the study's results at the time of these interviews. The questions focused on their experiences in the study, adherence to study protocols, their thoughts about the technical and ethical issues involved in using a sham needling device, and their expectations of trial outcomes. The questions were motivated by expressions of concerns the acupuncturists raised in feedback groups during the course of the study, and our desire to improve further trials. Results: The acupuncturists differed widely in their comfort levels with the research methods used, their adherence to the study protocol, and their expectations of trial outcomes. Conclusions: We conclude that careful monitoring of acupuncturists, including observation of treatments and frequent meetings to support them throughout the trial, is necessary to maintain a high degree of quality control.
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Few complementary and alternative medicine (CAM) institutions require their students to undergo substantive training in research literacy and conduct, and well-developed programs to train CAM institution faculty in research are virtually non-existent. As part of a National Center for Complementary and Alternative Medicine (NCCAM) initiative to increase research capacity at CAM institutions, the New England School of Acupuncture (NESA), in collaboration with the Harvard Medical School (HMS) Osher Institute, was awarded a Developmental Center for Research on Complementary and Alternative Medicine (DCRC) grant. This article discusses a number of initiatives that we designed and implemented to train NESA students, faculty members, and alumni in the foundations of clinical research and to stimulate interest in both participating in research and receiving additional research training. Specific initiatives included a 30-hour faculty "Foundations of Research" course; a year-long course entitled, "How to Write a Publishable Case Report"; institution of a monthly research seminar series; revision of an already required student research course; and the addition of 2 new student-mentored independent research electives. We discuss successes and challenges encountered in developing and administering these initiatives and the overall impact they have had on research culture and productivity at NESA.
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Little is known about placebo effects with scientific precision. Poor methodology has confounded our understanding of the magnitude and even the existence of the placebo effect. Investigating placebo effects presents special research challenges including: the design of appropriate controls for studying placebo effects including separating such effects from natural history and regression to the mean, the need for large sample sizes to capture expected small effects, and the need to understand such potential effects from a patient's perspective. This article summarizes the methodology of an ongoing NIH-funded randomized controlled trial aimed at investigating whether the placebo effect in irritable bowel syndrome (IBS) exists and whether the magnitude of such an effect can be manipulated to vary in a manner analogous to “dose dependence.” The trial also uses an innovative combination of quantitative and qualitative methods.
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Patients in the placebo arms of randomized controlled trials (RCT) often experience positive changes from baseline. While multiple theories concerning such “placebo effects” exist, peculiarly, none has been informed by actual interviews of patients undergoing placebo treatment. Here, we report on a qualitative study (n = 27) embedded within a RCT (n = 262) in patients with irritable bowel syndrome. Besides identical placebo acupuncture treatment in the RCT, the qualitative study patients also received an additional set of interviews at the beginning, midpoint, and end of the trial. Interviews of the 12 qualitative subjects who underwent and completed placebo treatment were transcribed. We found that patients (1) were persistently concerned with whether they were receiving placebo or genuine treatment; (2) almost never endorsed “expectation” of improvement but spoke of “hope” instead and frequently reported despair; (3) almost all reported improvement ranging from dramatic psychosocial changes to unambiguous, progressive symptom improvement to tentative impressions of benefit; and (4) often worried whether their improvement was due to normal fluctuations or placebo effects. The placebo treatment was a problematic perturbation that provided an opportunity to reconstruct the experiences of the fluctuations of their illness and how it disrupted their everyday life. Immersion in this RCT was a co-mingling of enactment, embodiment and interpretation involving ritual performance and evocative symbols, shifts in bodily sensations, symptoms, mood, daily life behaviors, and social interactions, all accompanied by self-scrutiny and re-appraisal. The placebo effect involved a spectrum of factors and any single theory of placebo—e.g. expectancy, hope, conditioning, anxiety reduction, report bias, symbolic work, narrative and embodiment—provides an inadequate model to explain its salubrious benefits.
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Those with high baseline stress levels are more likely to develop mild cognitive impairment (MCI) and Alzheimer's Disease (AD). While meditation may reduce stress and alter the hippocampus and default mode network (DMN), little is known about its impact in these populations. Our objective was to conduct a "proof of concept" trial to determine whether Mindfulness Based Stress Reduction (MBSR) would improve DMN connectivity and reduce hippocampal atrophy among adults with MCI. 14 adults with MCI were randomized to MBSR vs. usual care and underwent resting state fMRI at baseline and follow-up. Seed based functional connectivity was applied using posterior cingulate cortex as seed. Brain morphometry analyses were performed using FreeSurfer. The results showed that after the intervention, MBSR participants had increased functional connectivity between the posterior cingulate cortex and bilateral medial prefrontal cortex and left hippocampus compared to controls. In addition, MBSR participants had trends of less bilateral hippocampal volume atrophy than control participants. These preliminary results indicate that in adults with MCI, MBSR may have a positive impact on the regions of the brain most related to MCI and AD. Further research with larger sample sizes and longer-follow-up are needed to further investigate the results from this pilot study.
Those with high baseline stress levels are more likely to develop mild cognitive impairment (MCI) and Alzheimer's Disease (AD). While meditation may reduce stress and alter the hippocampus and default mode network (DMN), little is known about its impact in these populations. Our objective was to conduct a “proof of concept” trial to determine whether Mindfulness Based Stress Reduction (MBSR) would improve DMN connectivity and reduce hippocampal atrophy among adults with MCI. 14 adults with MCI were randomized to MBSR vs. usual care and underwent resting state fMRI at baseline and follow-up. Seed based functional connectivity was applied using posterior cingulate cortex as seed. Brain morphometry analyses were performed using FreeSurfer. The results showed that after the intervention, MBSR participants had increased functional connectivity between the posterior cingulate cortex and bilateral medial prefrontal cortex and left hippocampus compared to controls. In addition, MBSR participants had trends of less bilateral hippocampal volume atrophy than control participants. These preliminary results indicate that in adults with MCI, MBSR may have a positive impact on the regions of the brain most related to MCI and AD. Further research with larger sample sizes and longer-follow-up are needed to further investigate the results from this pilot study.
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SummaryObjectives
To investigate neural representation evoked by acupuncture from human somatosensory cortices, especially from primary (SI) and secondary (SII) somatosensory areas.
Design and setting
Neuroimaging study – Blood-oxygenation-level-dependent (BOLD) functional MRI was performed during acupuncture on LI4 (n = 12 healthy participants). Sham acupuncture and innocuous tactile stimulation were also applied on the same acupuncture site as control comparisons.
Outcome measures
Responsive neural substrates were visualized and identified based on both individual and group-level surface activation maps.
Results
Discrete regions within the precentral gyrus (area 4) and the fundus of the central sulcus (area 3a) were selectively activated during the real acupuncture stimulation. In SII, the activation was extended in a postero-inferior direction to the fundus of the lateral sulcus.
Conclusion
This specific pattern of acupuncture-related activation indicates that deep tissue stimulation (as seen in area 3a activation) and concurrent processing of sensory stimulation (as seen in activation in SII) may mediate neural responses to manual acupuncture.
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Objective To explore participants’ experience in placebo-controlled randomized clinical trials (RCTs) specifically in relationship to their expectations. Background Aspects of being in RCTs, such as informed consent, perception of benefit and understanding of randomization, have been examined. In contrast, little is known concerning the formation of patient expectations before and during trials. Methods Qualitative methods using in-depth interviews with a semi-structured interview guide of nine patients from four different RCTs. Data analysis was conducted using a codebook format arranging participant responses under broad analytical headings. The interviewer used a semi-structured interview guide to direct the conversation from one broad topic to the next within the context of the ongoing conversation. A checklist of topics encouraged participants to describe their experiences in RCTs. Narratives concerning expectation, blinding and placebo were compared to identify common themes. Results Patient anticipatory processes were influenced and modified both before and during the trial from multiple inputs. Such factors as past experiences in RCTs, past experiences of ineffective treatment, stress of being off regular medications, fear of being a ‘placebo responder’, input of non-study doctors or other health professionals, the experience of other participants, measurements of health parameters made during the trial and the presence or absence of side-effects all affected patient expectation. Conclusion Expectations in RCTs are not fixed and instead may be viewed as continuously shaped by multiple inputs that include experience and information received both before and during the trial. Variability in placebo response observed in previous studies may be related to the fluid nature of expectations. Trying to control and equalize expectations in RCTs may be more difficult than previously assumed.
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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.
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Objective To investigate whether a sham device (a validated sham acupuncture needle) has a greater placebo effect than an inert pill in patients with persistent arm pain.
Design A single blind randomised controlled trial created from the two week placebo run-in periods for two nested trials that compared acupuncture and amitriptyline with their respective placebo controls. Comparison of participants who remained on placebo continued beyond the run-in period to the end of the study.
Setting Academic medical centre.
Participants 270 adults with arm pain due to repetitive use that had lasted at least three months despite treatment and who scored ≥3 on a 10 point pain scale.
Interventions Acupuncture with sham device twice a week for six weeks or placebo pill once a day for eight weeks.
Main outcomemeasures Arm pain measured on a 10 point pain scale. Secondary outcomes were symptoms measured by the Levine symptom severity scale, function measured by Pransky's upper extremity function scale, and grip strength.
Results Pain decreased during the two week placebo run-in period in both the sham device and placebo pill groups, but changes were not different between the groups (−0.14, 95% confidence interval −0.52 to 0.25, P = 0.49). Changes in severity scores for arm symptoms and grip strength were similar between groups, but arm function improved more in the placebo pill group (2.0, 0.06 to 3.92, P = 0.04). Longitudinal regression analyses that followed participants throughout the treatment period showed significantly greater downward slopes per week on the 10 point arm pain scale in the sham device group than in the placebo pill group (−0.33 (−0.40 to −0.26) v −0.15 (−0.21 to −0.09), P = 0.0001) and on the symptom severity scale (−0.07 (−0.09 to −0.05) v −0.05 (−0.06 to −0.03), P = 0.02). Differences were not significant, however, on the function scale or for grip strength. Reported adverse effects were different in the two groups.
Conclusions The sham device had greater effects than the placebo pill on self reported pain and severity of symptoms over the entire course of treatment but not during the two week placebo run in. Placebo effects seem to be malleable and depend on the behaviours embedded in medical rituals.
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OBJECTIVES: This study aimed to compare the effects of true and sham acupuncture in relieving symptoms of irritable bowel syndrome (IBS).
METHODS: A total of 230 adult IBS patients (75% females, average age: 38.4 years) were randomly assigned to 3 weeks of true or sham acupuncture (6 treatments) after a 3-week "run-in" with sham acupuncture in an "augmented" or "limited" patient–practitioner interaction. A third arm of the study included a waitlist control group. The primary outcome was the IBS Global Improvement Scale (IBS-GIS) (range: 1–7); secondary outcomes included the IBS Symptom Severity Scale (IBS-SSS), the IBS Adequate Relief (IBS-AR), and the IBS Quality of Life (IBS-QOL).
RESULTS: Although there was no statistically significant difference between acupuncture and sham acupuncture on the IBS-GIS (41 vs. 32%, P=0.25), both groups improved significantly compared with the waitlist control group (37 vs. 4%, P=0.001). Similarly, small differences that were not statistically significant favored acupuncture over the other three outcomes: IBS-AR (59 vs. 57%, P=0.83), IBS-SSS (31 vs. 21%, P=0.18), and IBS-QOL (17 vs. 13%, P=0.56). Eliminating responders during the run-in period did not substantively change the results. Side effects were generally mild and only slightly greater in the acupuncture group.
CONCLUSIONS: This study did not find evidence to support the superiority of acupuncture compared with sham acupuncture in the treatment of IBS.
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