PAIN®最新文献

Abstract: Menopausal and postmenopausal women, characterized by a significant reduction in ovarian hormones, have a high prevalence of chronic pain with great pain intensity. However, the underlying mechanism of hyperalgesia induced by ovarian hormone withdrawal remains poorly understood. Here, we report that decreases in the activity and excitability of GABAergic neurons in the dorsal raphe nucleus (DRN) are associated with hyperalgesia induced by ovariectomy in mice. Supplementation with 17β-estradiol, but not progesterone, is sufficient to increase the mechanical pain threshold in ovariectomized (OVX) mice and the excitability of DRN GABAergic (DRNGABA) neurons. Moreover, activation of the DRNGABA neurons projecting to the lateral parabrachial nucleus was critical for alleviating hyperalgesia in OVX mice. These findings show the essential role of DRNGABA neurons and their modulation by estrogen in regulating hyperalgesia induced by ovarian hormone withdrawal, providing therapeutic basis for the treatment of chronic pain in physiological or surgical menopausal women.

Abstract: Restless legs syndrome/Willis-Ekbom disease (RLS/WED) causes a strong urge to move legs while resting. Restless legs syndrome/WED is an often-inherited disease occurring in 3% to 10% of adult populations, increasing with age. Severity varies from mild disturbance of sleep to painful restless legs and arms, loss of sleep, fatigue, and risk of suicide. Dopaminergic drugs relieve symptoms, but cause augmentation, ie, initially helpful but later increase the burden of symptoms. Oral gabapentinoids and opioids are often added, but opioid tolerance and adverse effects are common. With the high prevalence and incomplete help from oral drugs, significant unmet needs exist for effective therapy for severe RLS/WED. Ongoing spinal intrathecal infusion of low-dose morphine is effective, but not generally recognized, as only 12 cases have been published since 2002. We report 7 patients suffering from severe RLS/WED, who had no relief from oral dopaminergic, gabapentinoid, or opioid drugs; they all had excellent relief during ongoing spinal intrathecal infusion of morphine at only 1 to 5 μg/h, ongoing for 1 to 21 years without need of higher doses of morphine.. We suggest that morphine may be transported with the cerebrospinal fluid reaching and readjusting malfunctioning dopamine neuronal systems in the brain and spinal cord. The effects last only as long as the infusion continues. A patient with RLS/WED and persistent genital arousal disorder (PGAD) was relieved of both RLS/WED and PGAD symptoms. These case reports suggest that intrathecal infusion of low-dose morphine is an effective treatment of severe RLS.

Abstract: This is the first study to empirically determine the potential for data-driven personalization in the context of chronic primary pain (CPP). Effect sizes of psychological treatments for individuals with CPP are small to moderate on average. Aiming for better treatment outcomes for the individual patient, the call to personalize CPP treatment increased over time. However, empirical evidence that personalization of psychological treatments can optimize treatment outcomes in CPP is needed. This study seeks to estimate heterogeneity of treatment effect for cognitive behavioral therapy (CBT) as the psychological treatment approach for CPP with the greatest evidence base. For this purpose, a Bayesian variance ratio meta-regression is conducted using updated data from 2 recently published meta-analyses with randomized controlled trials comparing CBT delivered face-to-face to treatment-as-usual or waiting list controls. Heterogeneity in patients with CPP would be reflected by a larger overall variance in the post-treatment score compared with the control group. We found first evidence for an individual treatment effect in CBT compared with the control group. The estimate for the intercept was 0.06, indicating a 6% higher variance of end point values in the intervention groups. However, this result warrants careful consideration. Further research is needed to shed light on the heterogeneity of psychological treatment studies and thus to uncover the full potential of data-driven personalized psychotherapy for patients with CPP.A Bayesian variance ratio meta-regression indicates empirical evidence that data-driven personalized psychotherapy for patients with chronic primary pain could increase effects of cognitive behavioral therapy.

Abstract: Facial expressions of pain play an important role in pain diagnostics and social interactions. Given the prominent impact of sex on various aspects of pain, it is not surprising that sex differences have also been explored regarding facial expressions of pain; however, with inconclusive findings. We aim to further investigate sex differences in facial expressions of pain by using a large, combined sample to maximize statistical power. Data from 7 previous studies of our group were merged, combining in total the data of 392 participants (male: 192, female: 200). All participants received phasic heat pain, with intensities being tailored to the individual pain threshold. Pain intensity ratings were assessed, and facial responses were manually analyzed using the Facial Action Coding. To compare facial and subjective responses between sexes, linear mixed-effects models were used, with study ID as a random effect. We found significant sex differences in facial responses, with females showing elevated facial responses to pain, although they received lower physical heat intensities (women had lower pain thresholds). In contrast, pain intensity ratings did not differ between sexes. Additionally, facial and subjective responses to pain were significantly associated across sexes, with females showing slightly stronger associations. Although variations in facial expressions of pain are very large even within each sex, our findings demonstrate that women facially communicate pain more intensively and with a better match to their subjective experience compared with men. This indicates that women might be better in using facial communication of pain in an intensity-discriminative manner.

Abstract: Stigma is common in people experiencing chronic pain and there are indications that it may adversely affect pain outcomes. However, to date, there is no systematic review exploring the impact of stigma on chronic pain-related outcomes. This systematic review and meta-analysis aimed to examine the association between stigma and key chronic pain outcomes and differences in stigma between pain conditions. Seven databases were searched for studies reporting a measure of association between stigma and at least one pain outcome in adults with chronic pain. Studies were screened by 2 independent researchers. Nineteen studies met eligibility criteria and data were extracted, quality-assessed, and narratively synthesised and meta-analysed where possible. Meta-analyses of bivariate cross-sectional correlations demonstrated significant positive correlations between stigma and pain intensity, disability, and depression, with small to moderate effects. Data from 2 prospective studies and those only reporting multivariate analyses that were not included in meta-analyses further supported these findings. There was some evidence that individuals who experience pain conditions with less clear pathophysiology may report greater stigma, although more research is needed. The review highlights that there is a growing number of studies on stigma in the pain field showing an adverse association between stigma and chronic pain outcomes.

Abstract: Our aim was to investigate relative contributions of central and peripheral mechanisms to knee osteoarthritis (OA) diagnosis and their independent causal association with knee OA. We performed longitudinal analysis using data from UK-Biobank participants. Knee OA was defined using International Classification of Diseases manual 10 codes from participants' hospital records. Central mechanisms were proxied using multisite chronic pain (MCP) and peripheral mechanisms using body mass index (BMI). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated, and proportional risk contribution (PRC) was estimated from receiver-operator-characteristic (ROC) analysis. To estimate the causal effects, we performed 2-sample multivariable Mendelian Randomisation (MR) analysis. We selected genetic instruments from the largest Genome Wide Association Study of BMI (N = 806,834) and MCP (N = 387,649) and estimated the instruments genetic associations with knee OA in the largest available dataset (62,497 cases and 333,557 control subjects). The multivariable MR was performed using modified inverse-variance weighting methods. Of the 203,410 participants, 6% developed knee OA. Both MCP (OR 1.23, 95% CI; 1.21-1.24) and BMI (1.10, 95% CI; 1.10-1.11) were associated with knee OA diagnosis. The PRC was 6.9% (95% CI; 6.7%-7.1%) for MCP and 21.9% (95% CI; 21.4%-22.5%) for BMI; the combined PRC was 38.8% (95% CI; 37.9%-39.8%). Body mass index and MCP had independent causal effects on knee OA (OR 1.76 [95% CI, 1.64-1.88] and 1.83 [95% CI, 1.54-2.16] per unit change, respectively). In conclusion, peripheral risk factors (eg, BMI) contribute more to the development of knee OA than central risk factors (eg, MCP). Peripheral and central factors are independently causal on knee OA.

Abstract: Despite being widely assumed, the worsening impact of unpredictability on pain perception remains unclear because of conflicting empirical evidence, and a lack of systematic integration of past research findings. To fill this gap, we conducted a systematic review and meta-analysis focusing on the effect of unpredictability on pain perception. We also conducted meta-regression analyses to examine the moderating effect of several moderators associated with pain and unpredictability: stimulus duration, calibrated stimulus pain intensity, pain intensity expectation, controllability, anticipation delay, state and trait negative affectivity, sex/gender and age of the participants, type of unpredictability (intensity, onset, duration, location), and method of pain induction (thermal, electrical, mechanical pressure, mechanical distention). We included 73 experimental studies with adult volunteers manipulating the (un)predictability of painful stimuli and measuring perceived pain intensity and pain unpleasantness in predictable and unpredictable contexts. Because there are insufficient studies with patients, we focused on healthy volunteers. Our results did not reveal any effect of unpredictability on pain perception. However, several significant moderators were found, ie, targeted stimulus pain intensity, expected pain intensity, and state negative affectivity. Trait negative affectivity and uncontrollability showed no significant effect, presumably because of the low number of included studies. Thus, further investigation is necessary to clearly determine their role in unpredictable pain perception.

Abstract: Secreted microRNAs (miRNAs) have been detected in various body fluids including the cerebrospinal fluid, yet their direct role in regulating synaptic transmission remains uncertain. We found that intrathecal injection of low dose of let-7b (1 μg) induced short-term (<24 hours) mechanical allodynia and heat hyperalgesia, a response that is compromised in Tlr7-/- or Trpa1-/- mice. Ex vivo and in vivo calcium imaging in GCaMP6-report mice revealed increased calcium signal in spinal cord afferent terminals and doral root ganglion/dorsal root ganglia neurons following spinal perfusion and intraplantar injection of let-7b. Patch-clamp recordings also demonstrated enhanced excitatory synaptic transmission (miniature excitatory postsynaptic currents [EPSCs]) in spinal nociceptive neurons following let-7b perfusion or optogenetic activation of axonal terminals. The elevation in spinal calcium signaling and EPSCs was dependent on the presence of toll-like receptor-7 (TLR7) and transient receptor potential ion channel subtype A1 (TRPA1). In addition, endogenous let-7b is enriched in spinal cord synaptosome, and peripheral inflammation increased let-7b in doral root ganglion/dorsal root ganglia neurons, spinal cord tissue, and the cerebrospinal fluid. Notably, let-7b antagomir inhibited inflammatory pain and inflammation-induced synaptic plasticity (EPSC increase), suggesting an endogenous role of let-7b in regulating pain and synaptic transmission. Furthermore, intrathecal injection of let-7b, at a higher dose (10 μg), induced persistent mechanical allodynia for >2 weeks, which was abolished in Tlr7-/- mice. The high dose of let-7b also induced microgliosis in the spinal cord. Of interest, intrathecal minocycline only inhibited let-7b-induced mechanical allodynia in male but not female mice. Our findings indicate that the secreted microRNA let-7b has the capacity to provoke pain through both neuronal and glial signaling, thereby establishing miRNA as an emerging neuromodulator.

Abstract: Neuropathic pain is a type of chronic pain that entails severe prolonged sensory dysfunctions caused by a lesion of the somatosensory system. Many of those suffering from the condition do not experience significant improvement with existing medications, resulting in various side effects. In this study, Sprague-Dawley male rats were used, and long-term deep brain stimulation of the ventrolateral periaqueductal gray was conducted in a rat model of spared nerve injury. We found that 5-Hz deep brain stimulation effectively modulated mechanical allodynia and induced neuronal activation in the rostral ventromedial medulla, restoring impaired descending serotonergic system. At the spinal level, glial cells were still activated but only the 5-HT1a receptor in the spinal cord was activated, implying its inhibitory role in mechanical allodynia. This study found that peripheral neuropathy caused dysfunction in the descending serotonergic system, and prolonged stimulation of ventrolateral periaqueductal gray can modulate the pathway in an efficient manner. This work would provide new opportunities for the development of targeted and effective treatments for this debilitating disease, possibly giving us lower chances of side effects from repeated high-frequency stimulation or long-term use of medication.