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.

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.

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.

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 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.

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.

Assessing blinding in trials of psychiatric disorders: a meta-analysis based on blinding index.

The assessment of blinding in RCTs is rarely performed. Currently most studies that do report data on evaluation of blinding merely report percentages of correct guessing, not taking into account correct guessing by chance. Blinding assessment using the blinding index (BI) has never been performed in a systematic review on studies of major psychiatric disorders. This study is a systematic review of psychiatric randomized control trials using the BI as a chance-corrected measurement of blinding, a tool to analyze and understand the patterns of blinding across studies of major psychiatric disorders with available data. Of 2467 psychiatric RCTs from 2000 to 2010, 66 reported on blinding and 40 studies were found to have enough information on evaluation of blinding to be analyzed using the BI. The experimental treatment groups had an average BI value of 0.14 and the control groups had an average BI value of 0.00. The most common BI scenario was random-random, indicating ideal blinding. A positive correlation between effect size and more correct guesses was also found. Overall, based on BI values and the most common blinding scenario, the published articles on major psychiatric disorders from 2000 to 2010, which reported on blinding assessment for patients, were effectively blinded.

From peripheral to central: the role of ERK signaling pathway in acupuncture analgesia.

UNLABELLED: Despite accumulating evidence of the clinical effectiveness of acupuncture, its mechanism remains largely unclear. We assume that molecular signaling around the acupuncture needled area is essential for initiating the effect of acupuncture. To determine possible bio-candidates involved in the mechanisms of acupuncture and investigate the role of such bio-candidates in the analgesic effects of acupuncture, we conducted 2 stepwise experiments. First, a genome-wide microarray of the isolated skin layer at the GB34-equivalent acupoint of C57BL/6 mice 1 hour after acupuncture found that a total of 236 genes had changed and that extracellular signal-regulated kinase (ERK) activation was the most prominent bio-candidate. Second, in mouse pain models using formalin and complete Freund adjuvant, we found that acupuncture attenuated the nociceptive behavior and the mechanical allodynia; these effects were blocked when ERK cascade was interrupted by the mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) inhibitor U0126 (.8 µg/µL). Based on these results, we suggest that ERK phosphorylation following acupuncture needling is a biochemical hallmark initiating the effect of acupuncture including analgesia. PERSPECTIVE: This article presents the novel evidence of the local molecular signaling in acupuncture analgesia by demonstrating that ERK activation in the skin layer contributes to the analgesic effect of acupuncture in a mouse pain model. This work improves our understanding of the scientific basis underlying acupuncture analgesia.

Integrative treatment modalities for stoke victims in Korea.

OBJECTIVES: To suggest and discuss an integrative medicine model for stroke patients, we introduce our experience in Korea, describe treatment modalities used for stroke in Korean medicine, and present safety data on integrative care. SUMMARY: For inpatients, integrative management is applied at the request of the primary physician with the consent of patients or their families. In the acute stage, neurologists or neurosurgeons take charge as the primary physicians. Korean medicine doctors cooperate as secondary physicians to the neurologists and neurosurgeons. After the acute stage, responsibilities are exchanged. The rehabilitation program is conducted under the supervision of rehabilitation medicine doctors. The most frequently used complementary and alternative medicine modalities are acupuncture (including manual acupuncture, electroacupuncture and intradermal acupuncture), moxibustion, herbal prescriptions, and acupuncture point injection. CONCLUSION: Based on our field experiences, we believe it is worthwhile to continue efforts to integrate complementary and alternative medicine and Western medicine.

Combined treatment with acupuncture reduces effective dose and alleviates adverse effect of L-dopa by normalizing Parkinson's disease-induced neurochemical imbalance.

This study first showed the behavioural benefits of novel combination therapy of L-dopa with acupuncture on Parkinson's disease, and its underlying mechanisms within basal ganglia. The previous study reported that acupuncture may improve the motor function of a Parkinson's disease (PD) mouse model by increasing the dopamine efflux and turnover ratio of dopamine. Hence, we hypothesised that combining L-dopa with acupuncture would have a behavioural benefit for those with PD. We performed unilateral injections of 6-OHDA into the striatum of C57Bl/6 mice to model hemi-Parkinsonian attributes. To test motor function and dyskinetic anomalies, we examined cylinder behaviour and abnormal involuntary movement (AIM), respectively. We found that (1) a 50% reduced dose of L-dopa (7.5 mg/kg) combined with acupuncture showed an improvement in motor function that was comparable to mice given the standard dose of L-dopa treatment (15 mg/kg) only, and that (2) the combination treatment (L-dopa +acupuncture) was significantly superior in reducing AIM scores when equivalent doses of L-dopa were used. The combination treatment also significantly reduces the abnormal increase of GABA contents in the substantia nigra compared to the standard L-dopa treatment. Furthermore, abnormal expression of FosB, the immediate early gene of L-dopa induced dyskinesia (LID), was mitigated in the striatum by the combination treatment. All of these results indicate that acupuncture enhances the benefits of L-dopa on motor function with reduced dose of L-dopa and alleviating LID by normalising neurochemical imbalance within the basal ganglia.

Skew-symmetric Random Effect Models with Application to a Preventive Cohort Study: Improving Outcomes in Low Back Pain Patients.

BACKGROUND: To investigate the respective contribution of various biologic and psychosocial factors, especially Health Related Quality of Life (HRQOL) as a main outcome, in the natural history of acute low back pain (LBP) and to evaluate the impact of this condition on HRQOL. METHODS: In a prospective cohort study For 24 weeks, 150 patients were assessed at an outpatient clinic in Korea consulting for low back and confirmed disc herniation duration at inclusion and treated with treatment package comprised of herbal medicines, acupuncture, bee venom acupuncture, and a Korean version of spinal manipulation (Chuna). Study participants were evaluated at baseline and every 4 weeks for 24 weeks. Low back intensity levels were measured on a visual analog scale (0-10), back function was evaluated with the Oswestry Disability Index (0-100), disability assessed by HRQOL assessed by the short form 36 health survey (0-100 in 8 different sub-categories). RESULTS: Out of 150 patients, 128 completed the 24 weeks of traditional therapy. Patients reported improvements SF-36 outcome measures. At the completion of the study, low back pain scores improved by a mean of 3.3 (95% CI = 2.8 to 3.8). According to the results of our modeling, low back intensity level, back function and BMI measures had significant effects on quality of life during study. Interpreting the coefficients of modeling, the impact of the decreasing acute LBP episode on HRQOL by VAS and ODI outcomes, was high and important. CONCLUSIONS: This study highlights the large contribution of integrative package therapy as an effective preventive method for improving LBP patient's HRQOL.

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.

Blinding measured: a systematic review of randomized controlled trials of acupuncture.

Background. There is no agreement among researchers on viable controls for acupuncture treatment, and the assessment of the effectiveness of blinding and its interpretation is rare. Purpose. To systematically assess the effectiveness of blinding (EOB) in reported acupuncture trials; to explore results of RCTs using a quantitative measure of EOB. Data Sources. A systematic review of published sham RCTs that assessed blinding. Study Selection. Five hundred and ninety studies were reviewed, and 54 studies (4783 subjects) were included. Data Extraction. The number of patients who guessed their treatment identity was extracted from each study. Variables with possible influence on blinding were identified. Data Synthesis. The blinding index was calculated for each study. Based on blinding indexes, studies were congregated into one of the nine blinding scenarios. Individual study characteristics were explored for potential association with EOB. Limitations. There is a possibility of publication or reporting bias. Conclusions. The most common scenario was that the subjects believed they received verum acupuncture regardless of the actual treatment received, and overall the subject blinding in the acupuncture studies was satisfactory, with 61% of study participants maintaining ideal blinding. Objectively calculated blinding data may offer meaningful and systematic ways to further interpret the findings of RCTs.

Blinding in clinical trials: a practical approach.

Blinding is important in the conduct of clinical trials, yet it generally receives less attention and effort than other trial components (e.g., randomization, compliance) that are rigorously treated in the design and/or analysis stages. Furthermore, although the word "blind" commonly appears in the titles of publications, its use is not always well justified. We are human beings, and our behavior or decisions can change depending on whether our eyes are open or closed. That is why virtually everyone in the clinical trial community, including subjects, investigators, treating practitioners, and outcome assessors, would agree that some form of blinding is needed to reach a fair and objective conclusion uninfluenced by knowledge of intervention assignment. Despite our best efforts, however, blinding may not always be successful. There is a considerable body of literature about blinding and the need to assess whether it has been properly implemented and maintained. By discussing how the trialist and the team may handle blinding-related issues in different stages of a clinical trial, this brief article intends to offer reasonable suggestions that could improve current practice, helping researchers deal confidently with blinding-related issues and research in a manner that meets rigorous standards, but is practical and flexible.

The current acceptance, accessibility and recognition of Chinese and Ayurvedic medicine in the United States in the public, governmental, and industrial sectors.

To assess the current level of acceptance in the United States of complementary and alternative medicine, recent research into the prevalence, acceptance, accessibility, and recognition of complementary and alternative therapies were reviewed. Several signs point to an increasing acceptance of complementary and alternative medicine in the United States; the use of complementary and alternative medicine is significantly increasing, many aspects of Chinese medicine and Ayurveda are becoming mainstream, practitioners in the United States are beginning to be licensed, and insurance companies are beginning to cover some complementary and alternative therapies. Remaining challenges to true acceptance include the restrictive Western mindset, the absence of published studies, a lack of consistent manufacturing processes and quality standards, and a fear of adulteration. Although the field still faces many challenges, alternative and complementary medicine, including Chinese medicine and Ayurvedic medicine, is becoming more accepted and accessible in the United States.

Exercise and Auricular Acupuncture for Chronic Low-back Pain: A Feasibility Randomized-controlled Trial.

OBJECTIVES: To evaluate the feasibility of a randomized-controlled trial (RCT) investigating the effects of adding auricular acupuncture (AA) to exercise for participants with chronic low-back pain (CLBP). METHODS: Participants with CLBP were recruited from primary care and a university population and were randomly allocated (n=51) to 1 of 2 groups: (1) "Exercise Alone (E)"-12-week program consisting of 6 weeks of supervised exercise followed by 6 weeks unsupervised exercise (n=27); or (2) "Exercise and AA (EAA)"-12-week exercise program and AA (n=24). Outcome measures were recorded at baseline, week 8, week 13, and 6 months. The primary outcome measure was the Oswestry Disability Questionnaire. RESULTS: Participants in the EAA group demonstrated a greater mean improvement of 10.7% points (95% confidence interval, -15.3,-5.7) (effect size=1.20) in the Oswestry Disability Questionnaire at 6 months compared with 6.7% points (95% confidence interval, -11.4,-1.9) in the E group (effect size=0.58). There was also a trend towards a greater mean improvement in quality of life, LBP intensity and bothersomeness, and fear-avoidance beliefs in the EAA group. The dropout rate for this trial was lower than anticipated (15% at 6 mo), adherence with exercise was similar (72% E; 65% EAA). Adverse effects for AA ranged from 1% to 14% of participants. DISCUSSION: Findings of this study showed that a main RCT is feasible and that 56 participants per group would need to be recruited, using multiple recruitment approaches. AA was safe and demonstrated additional benefits when combined with exercise for people with CLBP, which requires confirmation in a fully powered RCT.