Risk factors associated with poor pain outcomes following primary knee replacement surgery: Analysis of data from the clinical practice research datalink, hospital episode statistics and patient reported outcomes as part of the STAR research programme

Objective Identify risk factors for poor pain outcomes six months after primary knee replacement surgery. Methods Observational cohort study on patients receiving primary knee replacement from the UK Clinical Practice Research Datalink, Hospital Episode Statistics and Patient Reported Outcomes. A wide range of variables routinely collected in primary and secondary care were identified as potential predictors of worsening or only minor improvement in pain, based on the Oxford Knee Score pain subscale. Results are presented as relative risk ratios and adjusted risk differences (ARD) by fitting a generalized linear model with a binomial error structure and log link function. Results Information was available for 4,750 patients from 2009 to 2016, with a mean age of 69, of whom 56.1% were female. 10.4% of patients had poor pain outcomes. The strongest effects were seen for pre-operative factors: mild knee pain symptoms at the time of surgery (ARD 18.2% (95% Confidence Interval 13.6, 22.8), smoking 12.0% (95% CI:7.3, 16.6), living in the most deprived areas 5.6% (95% CI:2.3, 9.0) and obesity class II 6.3% (95% CI:3.0, 9.7). Important risk factors with more moderate effects included a history of previous knee arthroscopy surgery 4.6% (95% CI:2.5, 6.6), and use of opioids 3.4% (95% CI:1.4, 5.3) within three months after surgery. Those patients with worsening pain state change had more complications by 3 months (11.8% among those in a worse pain state vs. 2.7% with the same pain state). Conclusions We quantified the relative importance of individual risk factors including mild pre-operative pain, smoking, deprivation, obesity and opioid use in terms of the absolute proportions of patients achieving poor pain outcomes. These findings will support development of interventions to reduce the numbers of patients who have poor pain outcomes.

Occlusal Trauma Induces Neuroimmune Crosstalk for a Pain State

Temporomandibular joint (TMJ) disorder caused by occlusal trauma is one of the most controversial topics in dentistry. Experimental traumatic occlusion (ETO) induced by metal crowns cemented to mandibular first molars in rats causes a long-lasting nociceptive response. This study aimed to elucidate whether ETO generates an increase in inflammatory mediators in the TMJ. In addition, the impact of ETO on trigeminal ganglia, neurotransmitter release, and satellite glial cell (SGC) activation was investigated. ELISA revealed enhanced inflammatory mediators, including TNF-α, IL-1β, IL-6, CX3CL1, and ADAM-17 by Western blotting, in periarticular TMJ tissue after 28 d of ETO. In the trigeminal ganglia, ETO groups increased the release of the neurotransmitters substance P and glutamate. Overexpression of the AMPA receptor and upregulation of NMDA were observed in the 0.4- and 0.7-mm ETO groups, respectively, highlighting enhanced neuronal excitation. Increased IL-1β and COX-2 mRNA levels in the 0.7-mm ETO group confirmed trigeminal ganglia SGC activation. Immunofluorescence and electrophoresis of SGC revealed increased pERK expression in the 0.7-mm ETO group. ERK phosphorylation was shown to be nociceptive specific, with its upregulation occurring in cases of chronic inflammatory pain. Increased PKA mRNA levels were observed in the 0.4-mm ETO group, while CREB mRNA levels were upregulated for both ETO groups. Electrophoresis showed overexpression of sodium channel Nav 1.7 in the 0.7-mm ETO group, while immunofluorescence revealed that Nav 1.7 is expressed in sensory trigeminal ganglia cells. The results of this study suggest that occlusal trauma induces neuroimmune crosstalk, with synthesis of proinflammatory/pronociceptive mediators, which increases neuronal activity in trigeminal ganglia via the activation of an inflammatory response cascade to develop a persistent neuroinflammatory state that leads to central sensitization.

Fractalkine/CX3CR1 Pathway in Neuropathic Pain: An Update

Injuries to the nervous system can result in a debilitating neuropathic pain state that is often resistant to treatment with available analgesics, which are commonly associated with several side-effects. Growing pre-clinical and clinical evidence over the last two decades indicates that immune cell-mediated mechanisms both in the periphery and in the Central Nervous System (CNS) play significant roles in the establishment and maintenance of neuropathic pain. Specifically, following peripheral nerve injury, microglia, which are CNS resident immune cells, respond to the activity of the first pain synapse in the dorsal horn of spinal cord and also to neuronal activity in higher centres in the brain. This microglial response leads to the production and release of several proinflammatory mediators which contribute to neuronal sensitisation under neuropathic pain states. In this review, we collect evidence demonstrating the critical role played by the Fractalkine/CX3CR1 signalling pathway in neuron-to-microglia communication in neuropathic pain states and explore how strategies that include components of this pathway offer opportunities for innovative targets for neuropathic pain.

Anti-Neuropathic Pain Activity of A Cationic Palladium (II) Dithiocarbamate By Suppressing The Inflammatory Mediators in Paclitaxel-Induced Neuropathic Pain Model

Neuropathic pain is an obstinate chronic pain state which extremely worsens the quality of life of the suffered population. It is still intended as an intractable disease as existing therapies are not excellent in terms of efficacy and tolerability. Therefore, to search for novel drugs are crucial to acquire satisfactory treatments. The present study investigated the possible antiallodynic, antihyperalgesic and neuroprotective activities of (1,4-bis-(diphenylphosphino) butane) palladium (II)chloride monohydrate-(1) in Paclitaxel (PTX)-induced neuropathic pain model (Fig.10). Initially, 1 (5 and 10 mg/kg, b.w) was investigated for antinociceptive activities at behavioral level by performing mechanical and cold allodynia as well as thermal and tail immersion hyperalgesia. RT-PCR was performed to determine the suppressing effect of 1 on mRNA expression level of iNOS, COX-2 and proinflammatory cytokines (TNF-α, IL-1β, IL-6). In addition, antioxidant protein and enzymes (GSH, GST, Catalase), NO, MDA level and muscle activity were also determined. The results demonstrate that once daily dosing of 1 significantly repressed the behavioral pain responses dose dependently. Moreover, the mRNA gene expression of iNOS, COX-2 and inflammatory cytokines were reduced noticeably by 1. Furthermore, the treatment enhanced the level of antioxidant enzymes and lowered the level of MDA and NO production with no effect on motor activities of rats. These findings suggest the potential of 1 to attenuate neuropathic pain, neuroinflammation and neuroprotective effect. Thereupon, 1 might be a dynamic candidate for the therapeutic management of chronic neuropathic pain.

KCNQ Channels in the Mesolimbic Reward Circuit Regulate Nociception in Chronic Pain in Mice

Mesocorticolimbic dopaminergic (DA) neurons have been implicated in regulating nociception in chronic pain, yet the mechanisms are barely understood. Here, we found that chronic constructive injury (CCI) in mice increased the firing activity and decreased the KCNQ channel-mediated M-currents in ventral tegmental area (VTA) DA neurons projecting to the nucleus accumbens (NAc). Chemogenetic inhibition of the VTA-to-NAc DA neurons alleviated CCI-induced thermal nociception. Opposite changes in the firing activity and M-currents were recorded in VTA DA neurons projecting to the medial prefrontal cortex (mPFC) but did not affect nociception. In addition, intra-VTA injection of retigabine, a KCNQ opener, while reversing the changes of the VTA-to-NAc DA neurons, alleviated CCI-induced nociception, and this was abolished by injecting exogenous BDNF into the NAc. Taken together, these findings highlight a vital role of KCNQ channel-mediated modulation of mesolimbic DA activity in regulating thermal nociception in the chronic pain state.

Influences of Suvorexant and Mirtazapine on Chronic Pain-related Sleep Disorder in Neuropathic Pain Model Mice

Chronic pain and sleep disorders are independently associated with a reduction in the quality of life. They can be both a cause and consequence of each other; therefore, they should be treated simultaneously. However, optimal treatments for chronic pain-related sleep disorders are not well established. Here, we aimed to investigate the effects of suvorexant, a novel sleep drug, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, on pain-related sleep disorders in a preclinical neuropathic pain mouse model, which was produced by partial sciatic nerve ligation. We calculated the quantity, duration, and depth of sleep by analyzing the electroencephalogram. Voluntary activity was also evaluated by counting the number of wheel rotations with special cages. Daily administration of suvorexant and mirtazapine normalized the reduced rapid eye movement (REM) and non-REM sleep and improved the fragmented sleep, further regaining the depth of sleep at sleep onset in the chronic pain state. Suvorexant decreased voluntary activity, which was prolonged after the end of administration; however, mirtazapine did not decrease it. Both suvorexant and mirtazapine could be potential therapeutic agents for chronic pain-related sleep disorders.

Lysophophatidyl-choline 16:0 mediates persistent joint pain through Acid-Sensing Ion Channel 3: preclinical and clinical evidences

Rheumatic diseases are often associated to debilitating chronic joint pain, which remains difficult to treat and requires new therapeutic strategies. Here, we describe increased content of lysophosphatidyl-choline (LPC) 16:0 in the knee synovial fluids of two independent cohorts of patients with painful joint diseases. If LPC16:0 levels correlated with pain in patients with osteoarthritis (OA), they do not appear to be the hallmark of a particular joint disease. We found that intra-articular injections of LPC16:0 in mouse produce chronic pain and anxiety-like behaviors in both males and females with no apparent inflammation, peripheral nerve sprouting and damage, nor bone alterations. LPC16:0-induced persistent pain state is dependent on peripheral Acid-Sensing Ion Channel 3 (ASIC3), ultimately leading to central sensitization. LPC16:0 and ASIC3 thus appear as key players of chronic joint pain with potential implications in OA and possibly across others rheumatic diseases.

Dynamic Analysis of Human Brain in the Pain State by Electroencephalography

Objective Pain is an unpleasant sensation that is important in all therapeutic conditions. So far, some studies have focused on pain assessment and cognition through different tests and methods. Considering the occurrence of pain causes, along with the activation of a long network in brain regions, recognizing the dynamical changes of the brain in pain states is helpful for pain detection using the electroencephalogram (EEG) signal. Therefore, the present study addressed the above-mentioned issue by applying EEG at the time of inducing phasic pain. Results Phasic pain was produced using coldness and then dynamical features via EEG were analyzed by the Recurrence Quantification Analysis (RQA) method, and finally, the Rough neural network classifier was utilized for achieving accuracy regarding detecting and categorizing pain and non-pain states, which was 95.25\(\pm\)4%. The simulation results confirmed that cerebral behaviors are detectable during pain. In addition, the high accuracy of the classifier for evaluating the dynamical features of the brain during pain occurrence is one of the most merits of the proposed method. Eventually, pain detection can improve medical methods.

Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats

The loss of descending inhibitory control is thought critical to the development of chronic pain but what causes this loss in function is not well understood. We have investigated the dynamic contribution of prelimbic cortical neuronal projections to the periaqueductal grey (PrL-P) to the development of neuropathic pain in rats using combined opto- and chemogenetic approaches. We found PrL-P neurons to exert a tonic inhibitory control on thermal withdrawal thresholds in uninjured animals. Following nerve injury, ongoing activity in PrL-P neurons masked latent hypersensitivity and improved affective state. However, this function is lost as the development of sensory hypersensitivity emerges. Despite this loss of tonic control, opto-activation of PrL-P neurons at late post-injury timepoints could restore the anti-allodynic effects by inhibition of spinal nociceptive processing. We suggest that the loss of cortical drive to the descending pain modulatory system underpins the expression of neuropathic sensitisation after nerve injury.