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 non-pharmacological 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.

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.

Diabetic neuropathy (DN) is a common complication of diabetes that is becoming an increasing concern as the prevalence of diabetes rapidly rises. There are several types of DN, but the most prevalent and studied type is distal symmetrical polyneuropathy, which is the focus of this review and is simply referred to as DN. It can lead to a wide range of sensorimotor and psychosocial symptoms and is a major risk factor for diabetic foot ulceration and Charcot neuropathic osteoarthropathy, which are associated with high rates of lower limb amputation and mortality. The prevention and management of DN are thus critical, and clinical guidelines recommend several strategies for these based on the best available evidence. This article aims to provide a narrative review of DN prevention and management strategies by discussing these guidelines and the evidence that supports them. First, the epidemiology and diverse clinical manifestations of DN are summarized. Then, prevention strategies such as glycemic control, lifestyle modifications and footcare are discussed, as well as the importance of early diagnosis. Finally, neuropathic pain management strategies and promising novel therapies under investigation such as neuromodulation devices and nutraceuticals are reviewed.

Background: Cervicogenic headache is a secondary headache, and manual therapy is one of the most common treatment choices for this and other types of headache. Nonetheless, recent guidelines on the management of cervicogenic headache underlined the lack of trials comparing manual and exercise therapy to sham or no-treatment controls. The main objective of this systematic review and meta-analysis was to assess the effectiveness of different forms of manual and exercise therapy in people living with cervicogenic headache, when compared to other treatments, sham, or no treatment controls. Methods: Following the PRISMA guidelines, the literature search was conducted until January 2022 on MEDLINE, CENTRAL, DOAJ, and PEDro. Randomized controlled trials assessing the effects of manual or exercise therapy on patients with cervicogenic headache with headache intensity or frequency as primary outcome measures were included. Study selection, data extraction and Risk of Bias (RoB) assessment were done in duplicate. GRADE was used to assess the quality of the evidence. Results: Twenty studies were included in the review, with a total of 1439 patients. Common interventions were spinal manipulation, trigger point therapy, spinal mobilization, scapulo-thoracic and cranio-cervical exercises. Meta-analysis was only possible for six manual therapy trials with sham comparators. Data pooling showed moderate-to-large effects in favour of manual therapy for headache frequency and intensity at short-term, small-to-moderate for disability at short-term, small-to-moderate for headache intensity and small for headache frequency at long-term. A sensitivity meta-analysis of low-RoB trials showed small effects in favor of manual therapy in reducing headache intensity, frequency and disability at short and long-term. Both trials included in the sensitivity meta-analysis studied spinal manipulation as the intervention of interest. GRADE assessment showed moderate quality of evidence. Conclusion: The evidence suggests that manual and exercise therapy may reduce headache intensity, frequency and disability at short and long-term in people living with cervicogenic headache, but the overall RoB in most included trials was high. However, a sensitivity meta-analysis on low-RoB trials showed moderate-quality evidence supporting the use of spinal manipulation compared to sham interventions. More high-quality trials are necessary to make stronger recommendations, ideally based on methodological recommendations that enhance comparability between studies. Trial registration The protocol for this meta-analysis was pre-registered on PROSPERO under the registration number CRD42021249277.

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. image Key points: Heart rate variability (HRV) is associated with descending pain modulation as measured by the conditioned pain modulation protocol (CPM). There is an association between CPM scores and the functional connectivity between the periaqueductal grey (PAG) and ventro‐medial prefrontal cortex (vmPFC). CPM scores are also associated with vmPFC grey matter volume. The strength of functional connectivity between the PAG and vmPFC mediates the association between HRV and CPM. Our data provide new evidence of interactions between the autonomic nervous system and descending pain mechanisms.