Blinding, sham, and treatment effects in randomized controlled trials for back pain in 2000-2019: A review and meta-analytic approach.

BACKGROUND: Blinding aims to minimize biases from what participants and investigators know or believe. Randomized controlled trials, despite being the gold standard to evaluate treatment effect, do not generally assess the success of blinding. We investigated the extent of blinding in back pain trials and the associations between participant guesses and treatment effects. METHODS: We did a review with PubMed/OvidMedline, 2000-2019. Eligibility criteria were back pain trials with data available on treatment effect and participants' guess of treatment. For blinding, blinding index was used as chance-corrected measure of excessive correct guess (0 for random guess). For treatment effects, within- or between-arm effect sizes were used. Analyses of investigators' guess/blinding or by treatment modality were performed exploratorily. RESULTS: Forty trials (3899 participants) were included. Active and sham treatment groups had mean blinding index of 0.26 (95% confidence interval: 0.12, 0.41) and 0.01 (-0.11, 0.14), respectively, meaning 26% of participants in active treatment believed they received active treatment, whereas only 1% in sham believed they received sham treatment, beyond chance, that is, random guess. A greater belief of receiving active treatment was associated with a larger within-arm effect size in both arms, and ideal blinding (namely, "random guess," and "wishful thinking" that signifies both groups believing they received active treatment) showed smaller effect sizes, with correlation of effect size and summary blinding indexes of 0.35 (p = 0.028) for between-arm comparison. We observed uniformly large sham treatment effects for all modalities, and larger correlation for investigator's (un)blinding, 0.53 (p = 0.046). CONCLUSION: Participants in active treatments in back pain trials guessed treatment identity more correctly, while those in sham treatments tended to display successful blinding. Excessive correct guesses (that could reflect weaker blinding and/or noticeable effects) by participants and investigators demonstrated larger effect sizes. Blinding and sham treatment effects on back pain need due consideration in individual trials and meta-analyses.

Acupuncture for chronic pain: an update and critical overview.

PURPOSE OF REVIEW: Acupuncture is now recommended for several chronic pain conditions. Despite supportive evidence of its effectiveness, this ancient approach is often misunderstood, and may still be underused in mainstream practice. A critical review on its effectiveness and practice integration, and mechanisms of action is essential to the medical community that is continuing to seek nonopioid therapies for chronic pain. RECENT FINDINGS: Mounting evidence supports the effectiveness of acupuncture to treat chronic low back, neck, shoulder, and knee pain, as well as headaches. Additional data are emerging that support the use of acupuncture as an adjunct or alternative to opioids, and in perioperative settings. Findings related to its mechanisms of action include transient receptor potential cation channel vanilloid 1 activation in the periphery, microglial suppression in the cerebral cortex and spinal cord, and regulation of cytokines and other key inflammatory factors in the spinal cord. Incremental integration of acupuncture into pain medicine practices and training programmes continues to grow. SUMMARY: Acupuncture is effective, safe, and cost-effective for treating several chronic pain conditions when performed by well-trained healthcare professionals. Further studies on its use as an adjunct or alternative to opioids, and in perioperative settings are needed.

Bayesian analysis of multivariate mixed models for a prospective cohort study using skew-elliptical distributions.

Classical multivariate mixed models that acknowledge the correlation of patients through the incorporation of normal error terms are widely used in cohort studies. Violation of the normality assumption can make the statistical inference vague. In this paper, we propose a Bayesian parametric approach by relaxing this assumption and substituting some flexible distributions in fitting multivariate mixed models. This strategy allows for the skewness and the heavy tails of error-term distributions and thus makes inferences robust to the violation. This approach uses flexible skew-elliptical distributions, including skewed, fat, or thin-tailed distributions, and imposes the normal model as a special case. We use real data obtained from a prospective cohort study on the low back pain to illustrate the usefulness of our proposed approach.

Paradoxes in acupuncture research: strategies for moving forward.

In November 2007, the Society for Acupuncture Research (SAR) held an international symposium to mark the 10th anniversary of the 1997 NIH Consensus Development Conference on Acupuncture. The symposium presentations revealed the considerable maturation of the field of acupuncture research, yet two provocative paradoxes emerged. First, a number of well-designed clinical trials have reported that true acupuncture is superior to usual care, but does not significantly outperform sham acupuncture, findings apparently at odds with traditional theories regarding acupuncture point specificity. Second, although many studies using animal and human experimental models have reported physiological effects that vary as a function of needling parameters (e.g., mode of stimulation) the extent to which these parameters influence therapeutic outcomes in clinical trials is unclear. This White Paper, collaboratively written by the SAR Board of Directors, identifies gaps in knowledge underlying the paradoxes and proposes strategies for their resolution through translational research. We recommend that acupuncture treatments should be studied (1) "top down" as multi-component "whole-system" interventions and (2) "bottom up" as mechanistic studies that focus on understanding how individual treatment components interact and translate into clinical and physiological outcomes. Such a strategy, incorporating considerations of efficacy, effectiveness and qualitative measures, will strengthen the evidence base for such complex interventions as acupuncture.

Phenotypic profile clustering pragmatically identifies diagnostically and mechanistically informative subgroups of chronic pain patients.

ABSTRACT: Traditional classification and prognostic approaches for chronic pain conditions focus primarily on anatomically based clinical characteristics not based on underlying biopsychosocial factors contributing to perception of clinical pain and future pain trajectories. Using a supervised clustering approach in a cohort of temporomandibular disorder cases and controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment study, we recently developed and validated a rapid algorithm (ROPA) to pragmatically classify chronic pain patients into 3 groups that differed in clinical pain report, biopsychosocial profiles, functional limitations, and comorbid conditions. The present aim was to examine the generalizability of this clustering procedure in 2 additional cohorts: a cohort of patients with chronic overlapping pain conditions (Complex Persistent Pain Conditions study) and a real-world clinical population of patients seeking treatment at duke innovative pain therapies. In each cohort, we applied a ROPA for cluster prediction, which requires only 4 input variables: pressure pain threshold and anxiety, depression, and somatization scales. In both complex persistent pain condition and duke innovative pain therapies, we distinguished 3 clusters, including one with more severe clinical characteristics and psychological distress. We observed strong concordance with observed cluster solutions, indicating the ROPA method allows for reliable subtyping of clinical populations with minimal patient burden. The ROPA clustering algorithm represents a rapid and valid stratification tool independent of anatomic diagnosis. ROPA holds promise in classifying patients based on pathophysiological mechanisms rather than structural or anatomical diagnoses. As such, this method of classifying patients will facilitate personalized pain medicine for patients with chronic pain.

Bone mineral density, body mass index, postmenopausal period and outcomes of low back pain treatment in Korean postmenopausal women.

Women going through menopause experience bone loss and increased musculoskeletal pain, including low back pain. This study explored the relationships between bone mineral density (BMD) and body mass index (BMI), postmenopausal period and outcomes of treatment for low back pain in postmenopausal Korean women. On examining the medical records of 78 postmenopausal women hospitalized for low back pain, investigators found that women with low BMD were older and had been postmenopausal for longer periods than women with normal BMD. Postmenopausal length was positively correlated with pain scores at day 15 and 20 post-admission (P = 0.011 and 0.006) and negatively correlated with T-scores (P = 0.002). BMI was positively correlated with T-scores (r = 0.283, P = 0.022). In conclusion, age, postmenopausal length and BMI correlate with BMD in Korean women suffering from LBP. Larger studies investigating the associations between menopause, BMD, BMI and LBP seem desirable. Moreover, evidence-based therapeutic approaches should be explored for BMD and LBP management.

17-Allylamino-17-demethoxygeldanamycin down-regulates hyaluronic acid-induced glioma invasion by blocking matrix metalloproteinase-9 secretion.

Hyaluronic acid (HA) has been implicated in cell adhesion, motility, and tumor progression in gliomas. We previously reported that HA stimulates secretion of matrix metalloproteinase-9 (MMP-9) and induces glioma invasion. However, the molecular mechanism of HA action and therapeutic strategies for blocking HA-induced MMP-9 secretion remain unknown. Here, we report that the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) blocks MMP-9 secretion and that HA-induced nuclear factor-kappaB (NF-kappaB) activation is mediated by IkappaB kinase, which phosphorylates the NF-kappaB inhibitor IkappaBalpha and promotes its degradation. In addition, using an RNA interference approach, we show that the focal adhesion kinase plays a critical role in mediating HA-induced NF-kappaB activation, which resulted in increased MMP-9 expression and secretion, cell migration, and invasion. Importantly, we show that 17-AAG acts by blocking focal adhesion kinase activation, thereby inhibiting IkappaB kinase-dependent IkappaBalpha phosphorylation/degradation, NF-kappaB activation, and MMP-9 expression. This leads to suppression of HA-induced cell migration and invasion. Based on our data, we propose that 17-AAG is a candidate drug for treatment of highly invasive gliomas resulting from HA-induced, NF-kappaB-mediated MMP-9 secretion.

The role of mindfulness in positive reappraisal.

Mindfulness meditation is increasingly well known for therapeutic efficacy in a variety of illnesses and conditions, but its mechanism of action is still under debate in scientific circles. In this paper, we propose a hypothetical causal model that argues for the role of mindfulness in positive reappraisal coping. Positive reappraisal is a critical component of meaning-based coping that enables individuals to adapt successfully to stressful life events. Mindfulness, as a metacognitive form of awareness, involves the process of decentering, a shifting of cognitive sets that enables alternate appraisals of life events. We review the concept of positive reappraisal in transactional stress and coping theory, then describe research and traditional literature related to mindfulness and positive reappraisal, and detail the central role of mindfulness in the reappraisal process. With this understanding, we present a causal model explicating the proposed mechanism. The discussion has implications for clinical practice, suggesting how mindfulness-based integrative medicine interventions can be designed to support adaptive coping processes.

Case study projects by a Korean national research agency: Past 12 years and future.

OBJECTIVES: Scientific rigor is a known challenge to establish in heavily individualized practices of traditional medicine. A national research agency in Korea carried out a 12-year project to promote case reports among clinics of Korean Medicine (KM). This report aims at providing challenges, achievements, and thoughts for future endeavors. METHODS: We reviewed all the projects executed by the Korea Institute of Oriental Medicine between 2005 and 2017 promoting case reports in clinics of KM. The findings were categorized stage of project development, themes of project stage, achievement, and challenges. RESULTS: The implemented studies include eleven prospective- and five retrospective - case series, and one comparative trial. The project stages are divided into four, initial (surveying and building a database on Korean acupuncture), transitional (educating Korean Medicine doctors on writing case reports and building a case report system), stagnation (partially attributable to IRB's considering case report projects as clinical trial) and resurrection (building a rigorous evidence base from local clinics). The major challenges included practitioners' in clinics feeling burdened by the rigor of documentation requirement, the limited options of usable objective measurement tools available at general KM, and IRB's categorizing case report projects as clinical trials hence imposing unrealistic compliance burden. CONCLUSIONS: Promoting case reports in local clinics, while being warranted to remain as a crucial research method to build evidence based KM practice, requires supports from stakeholders including motivated clinicians of KM, extended use of diagnostic device available at KM practice, and insightful and flexible regulatory bodies' decision making.

Southampton needle sensation questionnaire: development and validation of a measure to gauge acupuncture needle sensation.

OBJECTIVE: The specific sensations (deqi) generated during acupuncture are thought to be important for a positive clinical outcome, particularly when treating pain. It is important to be able to measure these sensations and discriminate between deqi and pain. A greater understanding of this will greatly aid researchers who wish to conduct mechanistic studies of acupuncture. Previous questionnaire designs failed to consider patient experience and, hence, may have been flawed. The aim of this study was to generate and validate a new sensation questionnaire, that was able to discriminate between pain and deqi, taking into account patient experience and expert opinions. DESIGN: The questionnaire was designed following qualitative interviews with patients, literature review, and consultation with experts. The questionnaire was piloted and then validated. It was successfully completed by 227 patients and analyzed using factor analysis and partial correlation. SETTING: Patients were recruited via the physical therapy department at Southampton General Hospital and from private practice clinics in and around the Southampton area. SUBJECTS: The subjects were patients receiving acupuncture for any condition. RESULTS: Two (2) factors were clearly demonstrated: "Aching deqi" (7 items) which suggested deqi with pain and "Tingling deqi" (7 items) suggesting deqi only. One (1) item related solely to pain and 2 further items did not load into any factor. CONCLUSIONS: The final questionnaire is presented containing 17 items and is shown to be a valid, rigorous, soundly grounded, and patient-centered measure, capable of accurately recording deqi. We suggest that analysis should include a partial correlation of certain sensations against a pain visual analogue scale to ascertain how painful each sensation was, particularly if the questionnaire is to be used in a context in which pain and deqi need to be separated or their relationship clarified.

Acupuncture Resolves Persistent Pain and Neuroinflammation in a Mouse Model of Chronic Overlapping Pain Conditions.

Patients with chronic overlapping pain conditions have decreased levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. Consistent with clinical syndromes, we previously demonstrated that COMT inhibition in rodents produces persistent pain and heightened immune responses. Here, we sought to determine the efficacy of manual acupuncture in resolving persistent pain and neuroinflammation in the classic inbred C57BL/6 strain and the rapid-wound healing MRL/MpJ strain. Mice received subcutaneous osmotic minipumps to deliver the COMT inhibitor OR486 or vehicle for 13 days. On day 7 after pump implantation, acupuncture was performed at the Zusanli (ST36) point or a non-acupoint for 6 consecutive days. Behavioral responses to mechanical stimuli were measured throughout the experiment. Immunohistochemical analysis of spinal phosphorylated p38 mitogen-activated protein kinase, a marker of inflammation, and glial fibrillary acidic protein, a marker of astrogliosis, was performed on day 13. Results demonstrated that ST36, but not sham, acupuncture resolved mechanical hypersensitivity and reduced OR486-dependent increases in phosphorylated p38 and glial fibrillary acidic protein in both strains. The magnitude of the analgesic response was greater in MRL/MpJ mice. These findings indicate acupuncture as an effective treatment for persistent pain linked to abnormalities in catecholamine signaling and, furthermore, that analgesic efficacy may be influenced by genetic differences. PERSPECTIVE: Chronic overlapping pain conditions remain ineffectively managed by conventional pharmacotherapies. Here, we demonstrate that acupuncture alleviates persistent pain and neuroinflammation linked to heightened catecholaminergic tone. Mice with superior healing capacity exhibit greater analgesic efficacy. Findings indicate acupuncture as an effective treatment for chronic overlapping pain conditions and provide insight into treatment response variability.

Acupuncture application for neurological disorders.

BACKGROUND: Acupuncture has been widely used for a range of neurological disorders. Despite its popularity, the evidence to support the use of acupuncture is contradictory. METHODS: This review was designed to summarize and to evaluate the available evidence of acupuncture for neurological disorders. RESULTS: Most of the reviewed studies suffer from lack of methodological rigor. Owing to paucity and poor quality of the primary studies, no firm conclusion could be drawn on the use of acupuncture for epilepsy, Alzheimer's disease, Parkinson's disease, ataxic disorders, multiple sclerosis, amyotrophic lateral sclerosis and spinal cord injury. For stroke rehabilitation, the evidence from recent high-quality trials and previous systematic reviews is not convincing. CONCLUSION: More rigorous trials are warranted to establish acupuncture's role in neurological disorders.

Development and validation of Yin-Deficiency Questionnaire.

This study describes development and validation of a questionnaire as an adjunct to Traditional Chinese Medicine diagnosis of Yin-Deficiency Syndrome (Yin-DS). The Yin-Deficiency Questionnaire 1 (Yin-DQ1) consists of 10 items. Seventy-nine healthy volunteers and 44 patients diagnosed with Yin-DS were enrolled for the evaluation of discriminant validity and factorial validity. Another group of 83 healthy volunteers participated for test-retest reliability test. Internal consistency was high in both groups (Cronbach's alpha = 0.8615). Test-retest reliability (Spearman's rank correlation coefficient) ranged from 0.54 to 0.79 (p < 0.01). Factor analysis demonstrated that a two factor solution best explained the variance in responses (51.62%). The scores of all items in patients diagnosed with Yin-DS were significantly higher compared with those of healthy volunteers. The data show the internal consistency, test-retest reliability and strong discriminative properties of the Yin-DQ1. Further research determining the optimal cut-off score for Yin-DS and testing its usage as an outcome measure in a clinical trial is needed.

A close look at an integrative treatment package for Bell's palsy in Korea.

OBJECTIVE: To provide an overview of the integrative treatment package for Bell's palsy provided at Kyung Hee University Korean Medicine Hospital (KHU KMH). SUMMARY: The Facial Palsy Center at KHU KMH has been providing integrative treatment for Bell's palsy patients during the past three decades. Within 72 h of symptom onset, corticosteroids are recommended but complementary treatment including acupuncture and herbal medicine can be used to help suppress inflammation and nerve degeneration. If patients suffer from postauricular pain, pharmacopuncture and cupping is utilized. During the subacute or chronic periods, different acupuncture types are selected accordingly, and herbal medicine and moxibustion helps to improve immune functions and relieve accessory symptoms. Qigong programs are also provided to help relieve facial tension and paralysis. CONCLUSIONS: Although rigorous research is warranted, with limited treatment options, we highly suggest that it is worth applying integrative medicine to Bell's palsy patients.

Acupuncture for subacute stroke rehabilitation: a Sham-controlled, subject- and assessor-blind, randomized trial.

BACKGROUND: Any adjunctive therapy that may reduce persistent disability after stroke should be considered. Acupuncture is used for this purpose, but there is conflicting evidence on its effectiveness. METHODS: Patients with a recent (<4 weeks) episode of stroke were randomized to receive 12 sessions of either real or sham acupuncture during 2 weeks. The primary outcome was the change in Barthel activities of daily living score at the end of treatment. Secondary outcome measures included National Institutes of Health Stroke Scale score, motoricity index, and quality of life (EQ-5D [ EuroQoL-5 Dimensional form] and EQ-VAS [EuroQoL-Visual Analog Scale]). Assessments were carried out by blinded physicians. RESULTS: A total of 116 patients (56 in the real acupuncture group and 60 in the sham group) were randomized, and 98 (real, 48; sham, 50) completed treatment and the 2-week assessment. Patient blinding by means of the sham acupuncture device was successful. Acupuncture was well tolerated except for 1 seizure during a real acupuncture session. The improvements in the Barthel scores were 4 points (interquartile range [IQR], 0-8) vs 3 points (IQR, 0-7) in the real and sham acupuncture groups, respectively (P = .38). The secondary outcome measures also essentially showed no significant effect of acupuncture. Post hoc analysis by baseline severity showed a greater improvement in leg function in the subgroup with baseline Barthel score less than the median (median score, 6): 22 points (IQR, 0-37) vs 0 [corrected] points (IQR, 0-4) in the acupuncture and sham control groups, respectively (P = .02). CONCLUSIONS: Acupuncture is not superior to sham treatment for recovery in activities of daily living and health-related quality of life after stroke, although there may be a limited effect on leg function in more severely affected patients.

Ayurvedic medicine for rheumatoid arthritis: a systematic review.

OBJECTIVE: To systematically review all randomized controlled trials (RCTs) on the effectiveness of Ayurvedic medicine for rheumatoid arthritis (RA). METHODS: Computerized literature searches for all RCTs of Ayurvedic medicine for RA in the following databases: Medline (March 1969 to March 2003), Embase (February 1985 to February 2003), AMED (March 1980 to March 2003), Cochrane Controlled Trial Register (October 1997 to March 2003), and the abstract service of Central Council for Research in Ayurveda and Siddha (CCRAS; 1976 to March 2003). Hand searches were performed in 1 Sri Lankan and 3 Indian journals and the authors' personal files. Key data of included studies were extracted and reviewed. The methodological quality of all studies was evaluated with the Jadad scale. RESULTS: Seven studies met our inclusion criteria. Trials tested either Ayurvedic medicine against placebo or other Ayurvedic medicines. In general, patient and physician global assessments on the severity of pain, and morning stiffness were used as endpoints. Of 3 placebo-controlled RCTs, 1 high-quality trial did not show benefit of the active treatment against placebo, while another incompletely reported study indicated beneficial effects of an Ayurvedic medicine. A further incompletely reported study showed no significant difference. The remaining 4 trials were difficult to interpret because they tested an Ayurvedic medicine against other Ayurvedic medicines whose effects were not proven. CONCLUSION: There is a paucity of RCTs of Ayurvedic medicines for RA. The existing RCTs fail to show convincingly that such treatments are effective therapeutic options for RA.

Deqi sensation between the acupuncture-experienced and the naïve: a Korean study II.

Previous experience of acupuncture is believed to affect people's expectation of future treatments. Therefore, subjects who have had acupuncture are generally excluded from sham-controlled acupuncture clinical trials. However, this assumption has not been proven, but just accepted because of the lack of evidence to the contrary. To investigate the difference in frequency and intensity of acupuncture sensation between subjects who have had acupuncture and those who have not, 36 acupuncture-experienced subjects were invited to take part in the study. After informed consent was obtained, participants were asked to complete the acupuncture sensation scale (ASS) according to what they expected needling to feel like. The needling was done at the left Hegu (LI 4) point and consisted of insertion, stimulation for 30 seconds and removal. After needling, the subjects were asked to complete the same ASS according to what they actually experienced. Adverse events were monitored. The frequency of each sensation expected and experienced, as well as acupuncture sensation scores were compared. More than 60% of the subjects expected to feel sensations of penetrating (87.6% to 100%), aching (71.2% to 95.5%), tingling (87.6% to 100%), pricking (79.7% to 99.2%) and throbbing (64.2% to 91.4%). In fact, the subjects experienced sharp (60.9% to 89.1%), intense (60.9% to 89.1%), radiating (71.2% to 95.5%) and heavy (74.8% to 97.4%) sensations just as much. The subjects expected more hurting (p = 0.001), tingling (p < 0.001), pricking (p = 0.010), stinging (p = 0.012), burning (p = 0.001) and pulsing (p = 0.009) than they experienced, while more heaviness (p = 0.011) was experienced than expected. The same outcome measures were also compared between experienced and naive groups. Apart from the fact that the acupuncture-experienced participants expected to feel pricking (p = 0.030) and stinging (p = 0.002), and experienced hurting (p = 0.022) and stinging (p = 0.028) significantly less than those who had not had acupuncture before, there was no significant difference between first time and experienced subjects. The results indicate that previous experience does not affect the people's expectation and does not hinder people from experiencing Deqi. In addition, a constellation of Deqi-related acupuncture-specific sensations is more than just a general pain intensity dimension, which requires a biochemical and physiological exploration.