Recommendations for the development, implementation, and reporting of control interventions in efficacy and mechanistic trials of physical, psychological, and self-management therapies: the CoPPS Statement

Control interventions (often called “sham,” “placebo,” or “attention controls”) are essential for studying the efficacy or mechanism of physical, psychological, and self-management interventions in clinical trials. This article presents core recommendations for designing, conducting, and reporting control interventions to establish a quality standard in nonpharmacological intervention research. A framework of additional considerations supports researchers’ decision making in this context. We also provide a reporting checklist for control interventions to enhance research transparency, usefulness, and rigour

Magnetic resonance imaging as a biomarker in diabetic and HIV-associated peripheral neuropathy: A systematic review-based narrative

Background: Peripheral neuropathy can be caused by diabetes mellitus and HIV infection, and often leaves patients with treatment-resistant neuropathic pain. To better treat this condition, we need greater understanding of the pathogenesis, as well as objective biomarkers to predict treatment response. Magnetic resonance imaging (MRI) has a firm place as a biomarker for diseases of the central nervous system (CNS), but until recently has had little role for disease of the peripheral nervous system. Objectives: To review the current state-of-the-art of peripheral nerve MRI in diabetic and HIV symmetrical polyneuropathy. We used systematic literature search methods to identify all studies currently published, using this as a basis for a narrative review to discuss major findings in the literature. We also assessed risk of bias, as well as technical aspects of MRI and statistical analysis. Methods: Protocol was pre-registered on NIHR PROSPERO database. MEDLINE, Web of Science and EMBASE databases were searched from 1946 to 15th August 2020 for all studies investigating either diabetic or HIV neuropathy and MRI, focusing exclusively on studies investigating symmetrical polyneuropathy. The NIH quality assessment tool for observational and cross-sectional cohort studies was used for risk of bias assessment. Results: The search resulted in 18 papers eligible for review, 18 for diabetic neuropathy and 0 for HIV neuropathy. Risk of bias assessment demonstrated that studies generally lacked explicit sample size justifications, and some may be underpowered. Whilst most studies made efforts to balance groups for confounding variables (age, gender, BMI, disease duration), there was lack of consistency between studies. Overall, the literature provides convincing evidence that DPN is associated with larger nerve cross sectional area, T2-weighted hyperintense and hypointense lesions, evidence of nerve oedema on Dixon imaging, decreased fractional anisotropy and increased apparent diffusion coefficient compared with controls. Analysis to date is largely restricted to the sciatic nerve or its branches. Conclusions: There is emerging evidence that various structural MR metrics may be useful as biomarkers in diabetic polyneuropathy, and technique to other forms of peripheral neuropathy, including HIV neuropathy, would be of value

The association between pain-induced autonomic reactivity and descending pain control is mediated by the periaqueductal grey.

There is a strict interaction between the autonomic nervous system (ANS) and pain, which might involve descending pain modulatory mechanisms. The periaqueductal grey (PAG) is involved both in descending pain modulation and ANS, but its role in mediating this relationship has not yet been explored. Here, we sought to determine brain regions mediating ANS and descending pain control associations. Thirty participants underwent conditioned pain modulation (CPM) assessments, in which they rated painful pressure stimuli applied to their thumbnail, either alone or with a painful cold contralateral stimulation. Differences in pain ratings between ‘pressure-only’ and ‘pressure + cold’ stimuli provided a measure of descending pain control. In 18 of the 30 participants, structural scans and two functional MRI assessments, one pain-free and one during cold-pain were acquired. Heart rate variability (HRV) was simultaneously recorded. Normalised low-frequency HRV (LF-HRVnu) and the CPM score were negatively correlated; individuals with higher LF-HRVnu during pain reported reductions in pain during CPM. PAG-ventro-medial prefrontal cortex (vmPFC) and PAG-rostral ventromedial medulla (RVM) functional connectivity correlated negatively with the CPM. Importantly, PAG-vmPFC functional connectivity mediated the strength of the LF-HRVnu-CPM association. CPM response magnitude was also negatively correlated with vmPFC GM volume. Our multi-modal approach, using behavioural, physiological and MRI measures, provides important new evidence of interactions between ANS and descending pain mechanisms. ANS dysregulation and dysfunctional descending pain modulation are characteristics of chronic pain. We suggest that further investigation of body-brain interactions in chronic pain patients may catalyse the development of new treatments

Linking Pain Sensation to the Autonomic Nervous System: The Role of the Anterior Cingulate and Periaqueductal Gray Resting-State Networks.

There are bi-directional interactions between the autonomic nervous system (ANS) and pain. This is likely underpinned by a substantial overlap between brain areas of the central autonomic network and areas involved in pain processing and modulation. To date, however, relatively little is known about the neuronal substrates of the ANS-pain association. Here, we acquired resting state fMRI scans in 21 healthy subjects at rest and during tonic noxious cold stimulation. As indicators of autonomic function, we examined how heart rate variability (HRV) frequency measures were influenced by tonic noxious stimulation and how these variables related to participants' pain perception and to brain functional connectivity in regions known to play a role in both ANS regulation and pain perception, namely the right dorsal anterior cingulate cortex (dACC) and periaqueductal gray (PAG). Our findings support a role of the cardiac ANS in brain connectivity during pain, linking functional connections of the dACC and PAG with measurements of low frequency (LF)-HRV. In particular, we identified a three-way relationship between the ANS, cortical brain networks known to underpin pain processing, and participants' subjectively reported pain experiences. LF-HRV both at rest and during pain correlated with functional connectivity between the seed regions and other cortical areas including the right dorsolateral prefrontal cortex (dlPFC), left anterior insula (AI), and the precuneus. Our findings link cardiovascular autonomic parameters to brain activity changes involved in the elaboration of nociceptive information, thus beginning to elucidate underlying brain mechanisms associated with the reciprocal relationship between autonomic and pain-related systems

Blinding and Sham Control Methods in Trials of Physical, Psychological, and Self-Management Interventions for Pain (Article I): a Systematic Review and Description of Methods

Blinding is challenging in randomised controlled trials (RCTs) of physical, psychological, and self-management therapies (PPS) for pain, mainly due to their complex and participatory nature. To develop standards for the design, implementation, and reporting of control interventions in efficacy and mechanistic trials, a systematic overview of currently employed sham interventions and other blinding methods was required. Twelve databases were searched for placebo or sham controlled RCTs of PPS treatments in a clinical pain population. Screening and data extraction were performed in duplicate, and trial features, description of control methods and their similarity to the active intervention under investigation were extracted (protocol registration ID: CRD42020206590). The review included 198 unique control interventions, published between 2008 and December 2021. Most trials studied people with chronic pain, and more than half were manual therapy trials. The described control interventions ranged from clearly modelled based on the active treatment, to largely dissimilar control interventions. Similarity between control and active interventions was more frequent for certain aspects (e.g., duration and frequency of treatments) than others (e.g., physical treatment procedures and patient sensory experiences). We also provide an overview of additional, potentially useful methods to enhance blinding, as well as the reporting of processes involved in developing control interventions. A comprehensive picture of prevalent blinding methods is provided, including a detailed assessment of the resemblance between active and control interventions. These findings can inform future developments of control interventions in efficacy and mechanistic trials and best-practice recommendations

Research objectives and general considerations for pragmatic clinical trials of pain treatments: IMMPACT statement

Many questions regarding the clinical management of people experiencing pain and related health policy decision-making may best be answered by pragmatic controlled trials. To generate clinically relevant and widely applicable findings, such trials aim to reproduce elements of routine clinical care or are embedded within clinical workflows. In contrast with traditional efficacy trials, pragmatic trials are intended to address a broader set of external validity questions critical for stakeholders (clinicians, healthcare leaders, policymakers, insurers, and patients) in considering the adoption and use of evidence-based treatments in daily clinical care. This article summarizes methodological considerations for pragmatic trials, mainly concerning methods of fundamental importance to the internal validity of trials. The relationship between these methods and common pragmatic trials methods and goals is considered, recognizing that the resulting trial designs are highly dependent on the specific research question under investigation. The basis of this statement was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) systematic review of methods and a consensus meeting. The meeting was organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership. The consensus process was informed by expert presentations, panel and consensus discussions, and a preparatory systematic review. In the context of pragmatic trials of pain treatments, we present fundamental considerations for the planning phase of pragmatic trials, including the specification of trial objectives, the selection of adequate designs, and methods to enhance internal validity while maintaining the ability to answer pragmatic research questions

4 M's to make sense of evidence ::avoiding the propagation of mistakes, misinterpretation, misrepresentation and misinformation

Osteopaths are expected to keep up to date with research evidence relevant to their clinical practice and to integrate this knowledge with their own experience and their patients' values and preferences. One of the potential challenges when engaging with research is to make sense of it, to decide if it is trustworthy, and if it is applicable to the complex and context-sensitive nature of clinical practice and the care of individual people. Clinicians are increasingly exposed to (deliberate and undeliberate) misinformation and overstatements which propagate easily, including via social media. This masterclass aims to facilitate critical thinking and engagement in research for clinicians to make better-informed decisions with their patients. It was developed to support osteopaths facing these questions with the aim of empowering them to judge research themselves, detect common fallacies in the conduct and reporting of different research designs, and to increase researchers' accountability. Ultimately, we hope that by reading and considering the guidance and examples in this paper, clinicians will be better equipped to optimise the use of their (and their patients’) time when facing potential sources of evidence. Mistakes, misinterpretation, misrepresentation and misinformation are discussed for each of these methods/methodologies: case reports, clinical trials, qualitative research, and review