Placebo effects contribute to brief online mindfulness interventions for chronic pain: results from an online randomized sham-controlled trial.

ABSTRACT: Mindfulness apps are becoming popular treatments for chronic pain and mental health, despite mixed evidence supporting their efficacy. Furthermore, it is unclear whether improvements in pain are due to mindfulness-specific effects or placebo effects because no trials have compared mindfulness against a sham control. The objective of this study was to compare mindfulness against 2 sham conditions with differing proximity to mindfulness to characterize the relative contributions of mindfulness-specific and nonspecific processes on chronic pain. We assessed changes in pain intensity and unpleasantness and mindfulness-specific and nonspecific pain-related processes in 169 adults with chronic or recurrent pain randomized to receive a single 20-minute online session of mindfulness, specific sham mindfulness, general sham mindfulness, or audiobook control. Mindfulness was not superior to shams for reducing pain intensity or unpleasantness, and no differential engagement of theorized mindfulness-specific processes was observed. However, mindfulness and both shams reduced pain unpleasantness relative to audiobook control, with expectancy most strongly associated with this effect. Sham specificity had no influence on expectancy or credibility ratings, pain catastrophizing, or pain effects. These findings suggest that improvements in chronic pain unpleasantness following a single session of online-delivered mindfulness meditation may be driven by placebo effects. Nonspecific treatment effects including placebo expectancy and pain catastrophizing may drive immediate pain attenuation rather than theorized mindfulness-specific processes themselves. Further research is needed to understand whether mindfulness-specific effects emerge after longer durations of online training.

Outcome Expectancies, Effects, and Mechanisms of Brief Training in Mindfulness Meditation vs. Loving-Kindness Meditation vs a Control Condition for Pain Management: A Randomized Pilot Study.

This study investigated the analgesic effects of a single session of mindfulness meditation (MM) and loving-kindness meditation (LKM) relative to a control. A total of 100 adults with chronic or current problematic pain completed a survey and were randomized to a 20-minute MM, LKM, or audiobook control. Co-primary outcomes of pain intensity and unpleasantness and mediators of mindfulness and self-compassion were assessed pre- and posttraining. Expectancies were assessed pretraining. Pain type (chronic vs current problematic) was a covariate. Relative to the control, higher expectancies were reported for MM and LKM (P < .001). MM (d = 0.41, P = .032) and LKM (d = 0.38, P = .027) had medium effects on pain intensity, with greater decreases than control (d = 0.05, P = .768). All conditions had small effects on unpleasantness. Mindful observing increased more within MM (d = 0.52, P = .022) and the control (d = 0.50, P = .011) than LKM (d = 0.12, P = .50); self-compassion increased more in LKM (d = 0.36, P = .042) than MM (d = 0.27, P = .201) and the control (d = 0.22, P = .249). The mediation models were nonsignificant. Pain type was a nonsignificant covariate. Overall, MM and LKM were associated with positive expectancies and small-medium pain intensity reductions, which did not differ by pain type. Although MM and LKM were associated with changes in theorized mediators, these changes did not underlie improvement.

Dose-response Relationship of Reported Lifetime Meditation Practice with Mental Health and Wellbeing: a Cross-sectional Study.

Objectives: Meta-analyses of meditation studies have revealed mixed modest evidence of benefits across a range of outcomes. However, because this evidence-base is predominantly from brief interventions, it is unclear whether it accurately reflects how contemporary meditators practice or the dose-response relationship between amount of practice and outcome. This study sought to characterize how contemporary meditators practice, examine any possible dose-response relationships between historical practice and measures of psychological wellbeing, and explore which characteristics of practice most strongly predict favorable psychological outcomes. Methods: One thousand six hundred and sixty-eight meditators (M = 1095 h practice, SD = 2365) responded to advertisements in meditation practice communities and social media. We explored associations between demographics, meditation practice characteristics, and outcomes including positive and negative affect, psychological distress, and life satisfaction in a cross-sectional study design. Results: Historical meditation practice (accumulated lifetime hours) was significantly associated with favorable psychological outcomes (|r| ranging from .18 to .28). Model fit was optimized with a generalized additive model (average increase in R 2 = 2.22), indicating non-linear effects. The strength of association between practice time and outcomes was generally strongest for approximately the first 500 h, before plateauing. Several practice types including Vipassana (as taught by S.N. Goenka) and cultivating practices (e.g. compassion, lovingkindness) were more strongly predictive of favorable psychological outcomes. Conclusions: Benefits of meditation accrue over time in a non-linear manner, and show variation based on practice context. These results highlight the importance of understanding how the benefits of meditation accrue over longer time durations than typical standardized programs. Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-022-01977-6.

How do placebo effects contribute to mindfulness-based analgesia? Probing acute pain effects and interactions using a randomized balanced placebo design.

ABSTRACT: Recent sham-controlled studies suggest placebo effects contribute to acute pain relief after mindfulness interventions. However, the specific effects of mindfulness processes and their interaction with placebo effects remain unclear. This study aimed to characterize the role of mindfulness and placebo processes underlying mindfulness-based pain attenuation. Both treatment (focused attention mindfulness vs sham) and instruction (told mindfulness vs told sham) were manipulated in a balanced placebo design. Changes in acute heat pain were evaluated in 153 healthy adults randomized to receive 6 × 20 minutes of 1 of 4 treatment by instruction interventions or no treatment. Participants receiving any intervention demonstrated improved pain outcomes (unpleasantness, intensity, and tolerance) relative to those receiving no treatment. The instruction manipulation increased expectation for pain relief in those told mindfulness relative to those told sham, but there were no main effects or interactions of treatment or instruction on pain outcomes. However, irrespective of actual intervention received, the belief of receiving mindfulness predicted increased pain threshold and tolerance, with expectancy fully mediating the effect on pain tolerance. These findings suggest a lack of specific effects of mindfulness and instruction on acute pain. Nonetheless, participants' expectancies and beliefs about the treatment they received did predict pain relief. Together with the overall improvement after any intervention, these findings suggest that expectancy and belief may play a stronger role in attenuating acute pain in novices following brief mindfulness interventions than the actual mindfulness-specific processes or instructions delivered.

Mindfulness-Based Analgesia or Placebo Effect? The Development and Evaluation of a Sham Mindfulness Intervention for Acute Experimental Pain.

OBJECTIVE: Meta-analyses indicate that mindfulness meditation is efficacious for chronic and acute pain, but most available studies lack active control comparisons. This raises the possibility that placebo-related processes may account, at least in part, for mindfulness effects. The objective of this study was to develop a closely matched sham mindfulness condition to establish whether placebo effects contribute to mindfulness-based interventions for pain. METHODS: We developed and validated a closely matched sham mindfulness intervention then compared it with 6 × 20-minute sessions of focused-attention mindfulness and a no-treatment condition in 93 healthy volunteers undergoing acute experimental heat pain. RESULTS: The sham mindfulness intervention produced equivalent credibility ratings and expectations of improvement as the mindfulness intervention but did not influence mindfulness-related processes. In contrast, mindfulness increased "observing" relative to no treatment but not sham. Mindfulness (F(1,88) = 7.06, p = .009, ηp2 = 0.07) and sham (F(1,88) = 6.47, p = .012, ηp2 = 0.07) moderately increased pain tolerance relative to no treatment, with no difference between mindfulness and sham (F(1,88) = 0.01, p = .92, ηp2 < 0.001). No differences were found for pain threshold. Similarly, neither mindfulness nor sham reduced pain intensity or unpleasantness relative to no treatment, although mindfulness reduced pain unpleasantness relative to sham (F(1,88) = 5.03, p = .027, ηp2 = 0.05). CONCLUSIONS: These results suggest that placebo effects contribute to changes in pain tolerance after mindfulness training, with limited evidence of specific effects of mindfulness training on pain unpleasantness relative to sham, but not no treatment. To disentangle the specific analgesic effects of mindfulness from placebo-related processes, future research should prioritize developing and incorporating closely matched sham conditions.Trial Registration: Australian New Zealand Clinical Trials Registry (ACTRN12618001175268).

The efficacy of mindfulness-based interventions in acute pain: a systematic review and meta-analysis.

Recent meta-analyses have shown mindfulness-based interventions (MBIs) to be effective for chronic pain, but no pooled estimates of the effect of MBIs on acute pain are available. This meta-analysis was conducted to fill that gap. A literature search was conducted in 4 databases. Articles were eligible if they reported on randomized controlled trials of MBIs for people with acute pain and one of the following outcomes: pain severity, pain threshold, pain tolerance, or pain-related distress. Two authors independently extracted the data, assessed risk of bias, and provided GRADE ratings. Twenty-two studies were included. There was no evidence of an effect of MBIs on the primary outcome of pain severity in clinical {Hedges' g = 0.52; (95% confidence interval [CI] -0.241 to 1.280)} or experimental settings (Hedges' g = 0.04; 95% CI [-0.161 to 0.247]). There was a beneficial effect of MBIs on pain tolerance (Hedges' g = 0.68; 95% CI [0.157-1.282]) and pain threshold (Hedges' g = 0.72; 95% CI [0.210-1.154]) in experimental studies. There was no evidence of an effect of MBIs compared to control for pain-related distress in clinical (Hedges' g = 0.16; 95% CI [-0.018 to 0.419]) or experimental settings (Hedges' g = 0.44; 95% CI [-0.164 to 0.419]). GRADE assessment indicated that except for pain tolerance, the data were of low or very low quality. There is moderate evidence that MBIs are efficacious in increasing pain tolerance and weak evidence for pain threshold. However, there is an absence of good-quality evidence for the efficacy of MBIs for reducing the pain severity or pain-related distress in either clinical or experimental settings.

Bipartite syntaxin 1A interactions mediate CaV2.2 calcium channel regulation.

Functional interactions between syntaxin 1A and Ca(V)2 calcium channels are critical for fast neurotransmitter release in the mammalian brain, and coexpression of syntaxin 1A with these channels not only regulates channel availability, but also promotes G-protein inhibition. Both the syntaxin 1A C-terminal H3 domain, and N-terminal Ha domain have been shown to interact with the Ca(V)2.2 channel synprint region, suggesting a bipartite model of functional interaction, however the molecular determinants of this interaction have not been closely investigated. We used in vitro binding assays to assess interactions of syntaxin 1A truncation mutants with Ca(V)2.2 synprint and Ca(V)2.3 II-III linker regions. We identified two distinct interactions between the Ca(V)2.2 synprint region and syntaxin 1A: the first between C-terminal H3c domain of syntaxin 1A and residues 822-872 of Ca(V)2.2; and the second between the N-terminal 10 residues of the syntaxin 1A Ha region and residues 718-771 of Ca(V)2.2. The N-terminal syntaxin 1A fragment also interacted with the Ca(V)2.3 II-III linker. We then performed whole cell patch clamp recordings to test the effects of a putative interacting syntaxin 1A N-terminus peptide with Ca(V)2.2 and Ca(V)2.3 channels in a recombinant expression system. A YFP-tagged peptide corresponding to the N-terminal 10 residues of the syntaxin 1A Ha domain was sufficient to allosterically inhibit both Ca(V)2.2 and Ca(V)2.3 channel function but had no effect on G-protein mediated inhibition. Our results support a model of bipartite functional interactions between syntaxin 1A and Ca(V)2.2 channels and add accuracy to the two putative interacting domains, consistent with previous studies. Furthermore, we highlight the syntaxin 1A N-terminus as the minimal determinant for functional regulation of Ca(V)2.2 and Ca(V)2.3 channels.

Designing a thalamic somatosensory neural prosthesis: consistency and persistence of percepts evoked by electrical stimulation.

Intuitive somatosensory feedback is required for fine motor control. Here we explored whether thalamic electrical stimulation could provide the necessary durations and consistency of percepts for a human somatosensory neural prosthetic. Continuous and cycling high-frequency (185 Hz, 0.21 ms pulse duration charge balanced square wave) electrical pulses with the cycling patterns varying between 7% and 67% of duty cycle were applied in five patients with chronically implanted deep brain stimulators. Stimulation produced similar percepts to those elicited immediately after surgery. While consecutive continuous stimuli produced decreasing durations of sensation, the amplitude and type of percept did not change. Cycling stimulation with shorter duty cycles produced more persisting percepts. These features suggest that the thalamus could provide a site for stable and enduring sensations necessary for a long term somatosensory neural prosthesis.

Extensive arterial and venous thrombo-embolism with chemotherapy for testicular cancer: a case report.

Germ cell tumours tend to affect young adults and with advanced treatments achieve more than 90% cure rates. Over the years cisplatin has significantly improved the relapse free survival in these patients, hence forming an essential component of chemotherapy regimes. But, the thrombo-embolic complications suffered with cisplatin significantly affect the quality of life in these young patients.We describe a young adult who suffered a potentially fatal cerebral and pulmonary vascular insult on completing first cycle of cisplatin-based chemotherapy for a non-seminomatous germ cell tumour. Venous and arterial thrombo-embolism was the mechanism of injury and was promptly managed surgically and medically including neuro-rehabilitation.

Old proteins, developing roles: The regulation of calcium channels by synaptic proteins.

Coupling of presynaptic voltage-gated calcium channels to the synaptic release machinery is critical for neurotransmission. It was traditionally believed that anchoring calcium channels close to the calcium microdomain dependent release machinery was the main reason for the physical interactions between channels and synaptic proteins, however in recent years, it is becoming clear that these proteins additionally regulate channel activity, and such processes as channel targeting and alternative splicing, to orchestrate a much broader regulatory role in controlling calcium channel function, calcium influx and hence neurotransmission. Calcium signalling serves a multitude of cellular functions and therefore requires tight regulation. Specific, often calcium-dependent interactions between synaptic proteins and calcium channels appear to play a significant role in fine-tuning of the synaptic response over development. While it is clear that investigation of a few of the multitude of synaptic proteins will not provide a complete understanding of calcium channel regulation, consideration of the emerging mechanisms by which synaptic protein interactions might regulate calcium channel function is important in order to understand their possible contributions to synaptic transmission. Here, we review the current state of knowledge of the molecular mechanisms by which synaptic proteins regulate presynaptic calcium channel activity.

Novel splice variants of rat CaV2.1 that lack much of the synaptic protein interaction site are expressed in neuroendocrine cells.

Voltage-gated Ca(2+) channels are responsible for the activation of the Ca(2+) influx that triggers exocytotic secretion. The synaptic protein interaction (synprint) site found in the II-III loop of Ca(V)2.1 and Ca(V)2.2 mediates a physical association with synaptic proteins that may be crucial for fast neurotransmission and axonal targeting. We report here the use of nested PCR to identify two novel splice variants of rat Ca(V)2.1 that lack much of the synprint site. Furthermore, we compare immunofluorescence data derived from antibodies directed against sequences in the Ca(V)2.1 synprint site and carboxyl terminus to show that channel variants lacking a portion of the synprint site are expressed in two types of neuroendocrine cells. Immunofluorescence data also suggest that such variants are properly targeted to neuroendocrine terminals. When expressed in a mammalian cell line, both splice variants yielded Ca(2+) currents, but the variant containing the larger of the two deletions displayed a reduced current density and a marked shift in the voltage dependence of inactivation. These results have important implications for Ca(V)2.1 function and for the mechanisms of Ca(V)2.1 targeting in neurons and neuroendocrine cells.