Papers: 7 May 2022 - 13 May 2022

Dysmenorrhea is characterized by high rates of transition to chronic pain. In a previous study using structural equation modeling we demonstrated that several symptom domains associated with the emerging concept of nociplastic pain can be described using two symptom groups: generalized sensory sensitivity (GSS; composed of widespread pain, interceptive sensitivity, and environmental sensitivity) and SPACE (composed of unrefreshing Sleep, Pain, Affective disturbances, Cognitive issues, and reduced Energy). Here we perform a secondary cross-sectional analysis examining the same symptoms groups in a cohort of dysmenorrhea patients without a diagnosis of chronic pain. Our purpose is to determine if the same symptom patterns are apparent, and if they are associated with the presence and severity of comorbid pain. Participants were 201 women with dysmenorrhea. We replicated the hypothesized two-factor structure in this cohort (comparative fit index = .971, root mean square error of approximation =.055; 90% CI: .000, .097). GSS was associated with the severity of bladder, bowel, and overall pain in multivariable models including SPACE, patient age, and BMI (all β > .32, all p < .05). SPACE was associated with menstrual pain during NSAID use, while GSS was associated with the same in the absence of NSAID use (both p < .05). This two-factor model of symptoms appears to be replicable and valid in a cohort of women at risk for developing chronic pain conditions. These symptom groups are promising potential markers of future pain chronification and may point to patients in need of earlier or more aggressive intervention.

Delayed-onset of headache seems a specific feature of cerebrovascular events after COVID-19 vaccines.

The neural mechanisms underlying placebo analgesia have attracted considerable attention over the recent years. In contrast, little is known about the neural underpinnings of a nocebo-induced increase in pain. We previously showed that nocebo-induced hyperalgesia is accompanied by increased activity in the hippocampus that scaled with the perceived level of anxiety. As a key node of the neural circuitry of perceived threat and fear, the hippocampus has recently been proposed to coordinate defensive behaviour in a context-dependent manner. Such a role requires close interactions with other regions involved in the detection of and responses to threat. Here, we investigated the functional connectivity of the hippocampus during nocebo-induced hyperalgesia. Our results show an increase in functional connectivity between hippocampus and brain regions implicated in the processing of sensory-discriminative aspects of pain (posterior insula and primary somatosensory/motor cortex) as well as the periaqueductal gray (PAG). This nocebo-induced increase in connectivity scaled with an individual's increase in anxiety. Moreover, hippocampus connectivity with the amygdala was negatively correlated with the pain intensity reported during nocebo hyperalgesia relative to the placebo condition. Our findings suggest that the hippocampus links nocebo-induced anxiety to a heightened responsiveness to nociceptive input through changes in its crosstalk with pain-modulatory brain areas.

Second-order spinal cord excitatory neurons play a key role in spinal processing and transmission of pain signals to the brain. Exogenously-induced change in developmentally-imprinted excitatory neurotransmitter phenotype of these neurons to inhibitory has not yet been achieved. Here we use a subpial dorsal horn-targeted delivery of AAV (adeno-associated virus) vector(s) encoding GABA (gamma-Aminobutyric acid,) synthesizing-releasing inhibitory machinery in mice with neuropathic pain. Treated animals showed a progressive and complete reversal of neuropathic pain (tactile and brush-evoked pain behavior) which persisted for minimum 2.5 months post-treatment. The mechanism of this treatment effect results from the switch of excitatory to preferential inhibitory neurotransmitter phenotype in dorsal horn nociceptive neurons and a resulting increase in inhibitory activity in regional spinal circuitry after peripheral nociceptive stimulation. No detectable side effects (such as sedation, motor weakness or loss of normal sensation) were seen between 2-13 months post-treatment in naive adult mice, pigs and non-human primates. The use of this treatment approach may represent a potent and safe treatment modality in patients suffering from spinal cord- or peripheral nerve-injury induced neuropathic pain.

Neurons in the superficial dorsal horn that express the gastrin-releasing peptide receptor (GRPR) are strongly implicated in spinal itch pathways. However, a recent study reported that many of these correspond to vertical cells, a population of interneurons that are thought to transmit nociceptive information. In this study, we have used a GRPRCreERT2 mouse line to identify and target cells that possess Grpr mRNA. We find that the GRPR cells are highly concentrated in lamina I and the outer part of lamina II, that they are all glutamatergic, and that they account for ∼15% of the excitatory neurons in the superficial dorsal horn. We had previously identified 6 neurochemically distinct excitatory interneuron populations in this region based on neuropeptide expression and the GRPR cells are largely separate from these, although they show some overlap with cells that express substance P. Anatomical analysis revealed that the GRPR neurons are indeed vertical cells, and that their axons target each other, as well as arborising in regions that contain projection neurons: lamina I, the lateral spinal nucleus and the lateral part of lamina V. Surprisingly, given the proposed role of GRPR cells in itch, we found that most of the cells received monosynaptic input from Trpv1-expressing (nociceptive) afferents, that the great majority responded to noxious and pruritic stimuli, and that chemogenetically activating them resulted in pain- and itch-related behaviours. Together, these findings suggest that the GRPR cells are involved in spinal cord circuits that underlie both pain and itch.

Low back pain is a leading cause of disability worldwide. Intervertebral disc (IVD) degeneration is often associated with low back pain but is sometimes asymptomatic. IVD calcification is an often overlooked disc phenotype that might have considerable clinical impact. IVD calcification is not a rare finding in ageing or in degenerative and scoliotic spinal conditions, but is often ignored and under-reported. IVD calcification may lead to stiffer IVDs and altered segmental biomechanics, more severe IVD degeneration, inflammation and low back pain. Calcification is not restricted to the IVD but is also observed in the degeneration of other cartilaginous tissues, such as joint cartilage, and is involved in the tissue inflammatory process. Furthermore, IVD calcification may also affect the vertebral endplate, leading to Modic changes (non-neoplastic subchondral vertebral bone marrow lesions) and the generation of pain. Such effects in the spine might develop in similar ways to the development of subchondral marrow lesions of the knee, which are associated with osteoarthritis-related pain. We propose that IVD calcification is a phenotypic biomarker of clinically relevant disc degeneration and endplate changes. As IVD calcification has implications for the management and prognosis of degenerative spinal changes and could affect targeted therapeutics and regenerative approaches for the spine, awareness of IVD calcification should be raised in the spine community.

Pain perception involves multiple brain regions and networks. Understanding how these brain networks work together is fundamental for appreciating network-wise changes reported in patients with chronic pain disorders. Parcellating pain related networks and understanding their causal relationships is the first step to understand how painful information is processed, integrated, and modulated, and it requires direct manipulation of specific brain regions. Nonhuman primates (NHP) offer an ideal model system to achieve these goals because cortical and subcortical regions in the NHP brain are established based on a variety of different types of data collected in a way that is not feasible or, at least, extremely difficult in humans (i.e., histology data, tract-tracing, intracerebral recordings). In addition, different methodological techniques can also help characterize and further understand these brain cortical and subcortical regions over the course of development. Here we used a heat nociceptive stimulation that is proven to elicit activity of nociceptive neurons in the cortex to refine and parcellate the whole brain nociceptive functional networks, to identify key network hubs, and to characterize network-wise temporal dynamic signatures using high-resolution fMRI. We first functionally localized 24 cortical and subcortical regions that responded to heat nociceptive stimuli (somatosensory area 1/2, area 3a/3b, S2, posterior insula (pIns), anterior insula, area 7b, posterior parietal cortex, anterior cingulate cortex (ACC), prefrontal cortex, caudate, and mediodorsal (MD) and ventral posterior lateral (VPL) thalamic nuclei) and used them as seeds in resting state fMRI (rsfMRI) data analysis. We applied both hierarchical clustering and graph-theory analyses of the pairwise rsfMRI correlation metrics and identified five cortical and one subcortical sub-networks: strong resting state functional connectivity (rsFC) between ACC and prefrontal regions, parietal cortex and area 7b, S2 and posterior insula, areas 3a/3b and 1/2 within the S1 cortex, and thalamic MD and caudate nuclei. The rsFC strengths between cortical areas within each subnetwork were significantly stronger than those between subcortical regions. Regions within each sub-network also exhibited highly correlated temporal dynamics at rest, but the overall dynamic patterns varied drastically across sub-networks. Graph-theory analysis identified the MD nucleus as a hub that connects subcortical and cortical nociceptive sub-networks. The S2-pIns connection joins the sensory and affective/cognitive sub-networks.

Peripheral neuropathies that occur secondary to nerve injuries may be painful or painless, and including a low-grade inflammation and pro-inflammatory cytokines associated with both regeneration and damage of peripheral nerve cells and fibers. Currently, there are no validated methods that can distinguished between neuropathic pain and painless neuropathy. The aim of this study was to search for proinflammatory and anti-inflammatory proteins associated with pain and experimental pain sensitivity in subjects with surgeon-verified nerve injuries in the upper extremities.

Acutely, non-selective cannabinoid (CB) agonists have been shown to increase morphine antinociceptive effects, and we and others have also demonstrated that non-selective CB agonists attenuate morphine antinociceptive tolerance. Activation of cannabinoid CB2 receptors reverses allodynia and hyperalgesia in models of chronic pain, and co-administration of morphine with CB2 receptor selective agonists has been shown to be synergistic. CB2 receptor activation has also been shown to reduce morphine-induced hyperalgesia in rodents, an effect attributed to CB2 receptor modulation of inflammation. In the present set of experiments, we tested both the acute and chronic interactions between morphine and the CB2 receptor selective agonist O-1966 treatments on antinociception and antinociceptive tolerance in C57Bl6 mice. Co-administration of morphine and O-1966 was tested under three dosing regimens: simultaneous administration, morphine pre-treated with O-1966, and O-1966 pre-treated with morphine. The effects of O-1966 on mu-opioid receptor binding were determined using [3H]DAMGO and [S]GTPγS binding assays, and these interactions were further examined by FRET analysis linked to flow cytometry. Results yielded surprising evidence of interactions between the CB2 receptor selective agonist O-1966 and morphine that were dependent upon the order of administration. When O-1966 was administered prior to or simultaneous with morphine, morphine antinociception was attenuated and antinociceptive tolerance was exacerbated. When O-1966 was administered following morphine, morphine antinociception was not affected and antinociceptive tolerance was attenuated. The [S]GTPγS results suggest that O-1966 interrupts functional activity of morphine at the mu-opioid receptor, leading to decreased potency of morphine to produce acute thermal antinociceptive effects and potentiation of morphine antinociceptive tolerance. However, O-1966 administered after morphine blocked morphine hyperalgesia and led to an attenuation of morphine tolerance, perhaps due to well-documented anti-inflammatory effects of CB2 receptor agonism.

Neuroinflammation is critical in developing and maintaining neuropathic pain after spinal cord injury (SCI). The receptor-interacting protein kinase 3 (RIPK3) has been shown to promote inflammatory response by exerting its non-necroptotic functions. In this study, we explored the involvement of RIPK3 in neuropathic pain after SCI.

Central neuropathic pain is caused by a disease or lesion of the brain or spinal cord. It is difficult to predict which patients will develop central pain syndromes after a central nervous system injury, but depending on the etiology, lifetime prevalence may be greater than 50%. The resulting pain is often highly distressing and difficult to treat, with no specific treatment guidelines currently available. This narrative review discusses mechanisms contributing to central neuropathic pain, and focuses on pharmacological approaches for managing common central neuropathic pain conditions such as central post-stroke pain, spinal cord injury-related pain, and multiple sclerosis-related neuropathic pain. Tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and gabapentinoids have some evidence for efficacy in central neuropathic pain. Medications from other pharmacologic classes may also provide pain relief, but current evidence is limited. Certain non-pharmacologic approaches, neuromodulation in particular, may be helpful in refractory cases. Emerging data suggest that modulating the primary afferent input may open new horizons for the treatment of central neuropathic pain. For most patients, effective treatment will likely require a multimodal therapy approach.

G protein-coupled receptors (GPCRs) constitute the largest family of transmembrane receptors in eukaryotes. The adenosine A receptor (AAR) is a class A GPCR that is of interest as a therapeutic target particularly in the treatment of cardiovascular disease and neuropathic pain. Increased knowledge of the role AAR plays in mediating these pathophysiological processes will help realise the therapeutic potential of this receptor. There is a lack of enabling tools such as selective fluorescent probes to study AAR, therefore we designed a series of (benzimidazolyl)isoquinolinols conjugated to a fluorescent dye (31-35, 42-43). An improved procedure for the synthesis of isoquinolinols from tetrahydroisoquinolinols oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and atmospheric oxygen is reported. This synthetic method offers advantages over previous metal-based methods for the preparation of isoquinolinols and isoquinolines, which are important scaffolds found in many biologically active compounds and natural products. We report the first synthesis of the (benzimidazolyl)isoquinolinol compound class, however the fluorescent conjugates were not successful as AAR fluorescent ligands.

G protein-coupled receptors (GPCRs) are currently appreciated to be routed to diverse cellular platforms to generate both G protein-dependent and -independent signals. The latter has been best studied with respect to β-arrestin-associated receptor internalization and trafficking to signaling endosomes for extracellular signal-regulated kinase (ERK) activation. However, how GPCR structural and conformational variants regulate endosomal ERK signaling dynamics, which can be central in neural development, plasticity, and disease processes, is not well understood. Among class B GPCRs, the PACAP-selective PAC1 receptor is unique in the expression of variants that can contain intracellular loop 3 (ICL3) cassette inserts. The nervous system expresses preferentially the PAC1Null (no insert) and PAC1Hop (28-amino acid Hop insert) receptor variants. Our molecular modeling and signaling studies revealed that the PAC1Null and PAC1Hop receptor variants can associate with β-arrestin differentially, resulting in enhanced receptor internalization and ERK activation for the PAC1Hop variant. The study amplifies our understandings of GPCR intracellular loop structure/function relationships with the first example of how the duration of endosomal ERK activation can be guided by ICL3. The results provide a framework for how changes in GPCR variant expression can impact developmental and homeostatic processes and may be contributory to maladaptive neuroplasticity underlying chronic pain and stress-related disorders.

Low back pain (LBP) is the leading cause of disability in the low- and middle-income countries (LMICs), imposing substantial burden on individuals and health systems. The societal burden of LBP in LMICs challenges the United Nations' Sustainable Development Goals of eliminating poverty and improving health and well-being by pushing the people with the lowest socioeconomic position on the planet to greater poverty and more disability. This aims to (1) summarize the current state of LBP management in LMICs, (2) propose what best care for LBP in LMICs may look like, and (3) provide policy recommendations and a call to action. In this first paper, we summarize the extent of the problem: the prevalence, disability, and costs of LBP in LMICs. .

Chronic low back pain (LBP), neck pain (NP), and sleep quality (SQ) are genetically influenced. All three conditions frequently co-occur and shared genetic etiology on a pairwise base has been reported. However, to our knowledge no study has yet investigated if these three conditions are influenced by the same genetic and environmental factors and the extent and pattern of genetic overlap between them, hence the current research.

Pain is the most common nonmotor symptom of Parkinson's disease (PD) and is often undertreated. Deep brain stimulation (DBS) effectively mitigates the motor symptoms of this multisystem neurodegenerative disease; however, its therapeutic effect on nonmotor symptoms, especially pain, remains inconclusive. While there is a critical need to help this large PD patient population, guidelines for managing this significant disease burden are absent. Herein, the authors systematically reviewed the literature and conducted a meta-analysis to study the influence of traditional (subthalamic nucleus [STN] and globus pallidus internus [GPi]) DBS on chronic pain in patients with PD.

This literature review summarizes the role of plant-based foods and diet quality in osteoarthritis, particularly knee osteoarthritis, in observational studies and clinical trials published during 2015- 2020. The included studies have suggested favorable results on reducing the prevalence, pain, and cartilage changes related to osteoarthritis and inflammatory and oxidation markers such as inter- leukin-1, interleukin-6, tumor necrosis factor, and lipid peroxidation. Due to the lack of large lon- gitudinal cohorts to study whole foods or diets concerning knee osteoarthritis, findings from the cross-sectional studies or clinical trials require further validation, particularly in well-designed clinical trials and a more extended follow-up period. Potential mechanisms on the role of plant-based foods in body weight, inflammation, and microbiome were explored to explain their protective associations with osteoarthritis. However, most evidence examining the relationship between the microbiome and osteoarthritis joint pain is conducted in preclinical animal studies, and few observational studies show a positive association between Streptococcus species and local joint inflammation in the knee. Given the close links of plant-based foods on obesity, inflammation, and microbiome, data on the role of whole foods or diets in the change in knee osteoarthritis pain through the lens of microbial composition can provide more certainty regarding the utilization of microbiome as a potential thera- peutic target.

Transcranial ultrasound stimulation (TUS) is gaining traction as a safe and non-invasive technique in human studies. There has been a rapid increase in TUS human studies in recent years, with more than half of studies to date published after 2020. This rapid growth in the relevant body of literature necessitates comprehensive reviews to update clinicians and researchers.

Mechanical allodynia (pain caused by innocuous mechanical stimulation) is a hallmark symptom of neuropathic pain occurring following peripheral nerve injury (PNI). Using a transgenic mouse line, in which myelinated primary afferents, including Aβ fibers, express channelrhodopsin-2, we found that illumination of the plantar skin of mice following PNI produced an Aβ fiber-mediated pain-like withdrawal behavior and increased c-FOS neurons in the superficial spinal dorsal horn (SDH). These two responses were attenuated by chemogenetic silencing of primary sensory cortex (S1) neurons projecting directly to the SDH. These findings indicate that spinally projecting cortical S1 neurons contribute to Aβ fiber-derived neuropathic allodynia.

The nature and magnitude of nocebo responses in primary headache disorders are still unknown. To assess the distribution and possible predictors of nocebo responses in primary headache treatments, databases including PubMed, EMBASE, and Cochrane Library were searched from 1988 to 31 December 2020 for parallel-group, double-blind, randomised placebo-controlled trials (RCTs) of pharmacologic treatments of primary headaches. The nocebo responses were calculated using a random effects meta-analysis model. Subgroup and meta-regression analyses were performed to determine the associations of study design and demographic characteristics with nocebo responses. A total of 178 RCTs satisfied the inclusion criteria were included. Prophylactic treatments elicited stronger nocebo responses than acute treatments. The majority of nocebo adverse events (AEs) were mild to moderate in severity, with the nervous and digestive systems being the most commonly affected. There was a strong correlation between the active medication and control groups in terms of AEs, both quantitatively and qualitatively. Long treatment duration, a high proportion of subjects receiving active medications, multicenter design, North America, high body mass index (BMI), females, previous treatment experiences, and a high proportion of migraineurs with aura were all found to be significant positive predictors of nocebo responses, whereas the year of publication was found to be inversely related to them. Nocebo effects should be noticed for their contribution to discontinuation of or lack of adherence to active treatments. Clarifying these nocebo-related risk factors can aid in their clinical prevention and management. This article is protected by copyright. All rights reserved.

Chronic pain is one of the most detrimental symptoms exhibited by cancer patients, being an indication for opioid therapy in up to half of the patients' receiving chemotherapy and in 90% of advanced cases. Various successful non-pharmacological integrative therapy options have been explored and implemented to improve the quality of life in these patients. This review aims to highlight the mechanisms implicated; assessment tools used for cancer pain and summarize current evidence on non-pharmacological approaches in the treatment of chronic cancer pain.

Transcranial magnetic stimulation (TMS) is a promising treatment modality for psychiatric and neurological disorders. Repetitive TMS (rTMS) is widely used for the treatment of psychiatric and neurological diseases, such as depression, motor stroke, and neuropathic pain. However, the underlying mechanisms of rTMS-mediated neuronal modulation are not fully understood. In this respect, concurrent or simultaneous TMS-fMRI, in which TMS is applied during functional magnetic resonance imaging (fMRI), is a viable tool to gain insights, as it enables an investigation of the immediate effects of TMS. Concurrent application of TMS during neuroimaging usually causes severe artifacts due to magnetic field inhomogeneities induced by TMS. However, by carefully interleaving the TMS pulses with MR signal acquisition in the way that these are far enough apart, we can avoid any image distortions. While the very first feasibility studies date back to the 1990s, recent developments in coil hardware and acquisition techniques have boosted the number of TMS-fMRI applications. As such, a concurrent application requires expertise in both TMS and MRI mechanisms and sequencing, and the hurdle of initial technical set up and maintenance remains high. This review gives a comprehensive overview of concurrent TMS-fMRI techniques by collecting (1) basic information, (2) technical challenges and developments, (3) an overview of findings reported so far using concurrent TMS-fMRI, and (4) current limitations and our suggestions for improvement. By sharing this review, we hope to attract the interest of researchers from various backgrounds and create an educational knowledge base.

Inflammatory hyperalgesia represents a nociceptive phenotype that can become persistent in nature through dynamic protein modifications. However, a large gap in knowledge exists concerning how the integration of intracellular signaling molecules coordinates a persistent inflammatory phenotype. Herein, we demonstrate that Raf Kinase Anchoring Protein (RKIP) interrupts a vital canonical desensitization pathway to maintain bradykinin (BK) receptor activation in primary afferent neurons. Biochemical analyses of primary neuronal cultures indicate bradykinin-stimulated PKC phosphorylation of RKIP at Ser153. Furthermore, BK exposure increases G-protein Receptor Kinase 2 (GRK2) binding to RKIP, inhibiting pharmacological desensitization of the BK receptor. Additional studies found that molecular RKIP down-regulation increases BK receptor desensitization in real-time imaging of primary afferent neurons, identifying a key pathway integrator in the desensitization process that controls multiple GRK2-sensitive G-protein coupled receptors. Therefore, RKIP serves as an integral scaffolding protein that inhibits BK receptor desensitization.

Neuropathic pain (NP) is a frequent finding in patients diagnosed with spinal cord injuries (SCIs). To improve our understanding of the maladaptive changes taking place in the lumbar spinal cord that can lead to the development of NP and to find alternative options to treat this condition, we aimed to investigate the effects of voluntary exercise on NP after SCI and to elucidate its potential mechanisms.

Migraine results in an enormous burden on individuals and societies due to its high prevalence, significant disability, and considerable economic costs. Current treatment options for migraine remain inadequate, and the development of novel therapies is severely hindered by the incomplete understanding of the mechanisms responsible for the pain. The sensory innervation of the cranial meninges is now considered a key player in migraine headache genesis. Recent studies have significantly advanced our understanding of some of the processes that drive meningeal nociceptive neurons, which may be targeted therapeutically to abort or prevent migraine pain. In this review we will summarize our current understanding of the mechanisms that contribute to the genesis of the headache in one migraine subtype – migraine with aura. We will focus on animal studies that address the notion that cortical spreading depression is a critical process that drives meningeal nociception in migraine with aura, and discuss recent insights into some of the proposed underlying mechanisms.

A multisystem inflammatory condition occurring in children and adolescents with COVID-19 has become increasingly recognized and widely studied globally. This review aims to investigate and synthesize evolving evidence on its clinical characteristics, management, and outcomes in pediatric patients.

Hip fractures are debilitating in older adults because of their impact on quality of life. Opioids are associated with adverse effects in this population, so oral acetaminophen is commonly prescribed to minimize opioid use. Intravenous (iv) acetaminophen has been reported to have superior efficacy and bioavailability than oral acetaminophen. Nevertheless, its effect on postoperative outcomes in emergency hip fractures is unclear. This systematic review assessed the effect of iv acetaminophen on postoperative outcomes in older hip fracture patients.

Chronic postsurgical pain (CPSP) results from a cascade of events in the peripheral and central nervous systems following surgery. Several clinical predictors, including the prior pain state, premorbid psychological state (e.g., anxiety, catastrophizing), intraoperative surgical load (establishment of peripheral and central sensitization), and acute postoperative pain management, may contribute to the patient's risk of developing CPSP. However, research on the neurobiological and biobehavioral mechanisms contributing to pediatric CPSP and effective preemptive/treatment strategies are still lacking. Here we evaluate the perisurgical process by identifying key problems and propose potential solutions for the pre-, intra-, and postoperative pain states to both prevent and manage the transition of acute to chronic pain. We propose an eight-step process involving preemptive and preventative analgesia, behavioral interventions, and the use of biomarkers (brain-based, inflammatory, or genetic) to facilitate timely evaluation and treatment of premorbid psychological factors, ongoing surgical pain, and postoperative pain to provide an overall improved outcome. By achieving this, we can begin to establish personalized precision medicine for children and adolescents presenting to surgery and subsequent treatment selection.

This article comprehensively covers 3 major novel technologies and techniques in the management of chronic lower back pain. The first 2 procedures, percutaneous interspinous spacer implantation, and minimally invasive lumbar decompression have shown significant impact in the management of lumbar spinal stenosis (LSS), especially in patients who are not great surgical candidates or are otherwise not amenable to open spinal surgery. The wealth of data for these procedures continues to increase, with up to 4 to 6-year follow-up data recently being made available. A novel solution for vertebrogenic back pain is also discussed as follow-up data emphasizes the safety and sustainability of the procedure. This article also establishes a framework for evaluating novel technologies in interventional pain management.

This article provides a detailed description of peripheral joint radiofrequency ablation and its contemporary use in the treatment of chronic knee, hip, and shoulder pain. Special attention is given to anatomy and innervation of the joints discussed, technical approach, selection criteria, contraindications, and patient outcomes.

For patients with chronic pain or cancer-related pain, the most common indication for sympathetic block is to control visceral pain arising from malignancies or other alterations of the abdominal and pelvic viscera. When it is recalcitrant to conservative care, or if the patient is intolerant to pharmacotherapy, consideration of sympathetic blocks or neurolytic procedures is considered. Potential advantages of a neurolytic procedure, compared with spinal and epidural anesthetic infusions, include cost savings and avoidance of hardware. Interventional therapies that target afferent visceral innervation via the sympathetic ganglia offer effective and durable analgesia and improve multiple metrics of quality of life.

The sympathetic nervous system (SNS) is an integral component of the body's response to stress. Once activated, the SNS has broad-reaching effects on multiple organ systems that modulate pain, behavior, and mood. Blockade of the system can improve pain associated with multiple etiologies, including vascular, visceral, and neuropathic pain. Multiple techniques are available to block the SNS and provide options that improve analgesia and can be individualized to a particular patient's needs and disease state.

Intrathecal drug delivery systems are a well-established intervention for chronic pain. The localized delivery of analgesics allows for reduced side effect profiles and pain scores in patients with chronic pain. Given their proven benefits and the development of novel intrathecal medications, intrathecal drug delivery systems are being used earlier in chronic pain management treatment pathways. Success is reliant on proper patient selection and mitigating the risks of various adverse events stemming from the implantation procedure, medications, and the device itself. This article discusses patient selection criteria, medication selection, risks, complications, supporting data, and future directions of intrathecal drug delivery systems.

Myofascial pain and myofascial pain syndromes are among some of the most common acute and chronic pain conditions. Many interventional procedures can be performed in both an acute and chronic pain setting to address myofascial pain syndromes. Trigger point injections can be performed with or without imaging guidance such as fluoroscopy and ultrasound; however, the use of imaging in years past has been recommended to improve patient outcome and safety. Injections can be performed using no injectate (dry needling), or can involve the administration of local anesthetics, botulinum toxin, or corticosteroids.

Peripheral joint injections are a common interventional treatment of peripheral joint-mediated pain, including arthritis, tendinopathy, and bursitis that are not responsive to conservative management. Degenerative changes of articular joints are often related to these symptoms through chronic inflammatory changes, which typically arise due to repetitive trauma, autoimmune disease, or metabolic abnormalities. The primary diagnosis for degenerative disease in the peripheral joints is osteoarthritis but can also include rheumatoid arthritis, gout, and other less common etiologies. Chronic inflammatory damage to the articular surfaces and joint capsules can lead to pain and functional decline. As such, the use of peripheral joint injections after the failure of typical conservative treatment, including physical therapy and oral medications, is common. Although these injections are typically not curative in nature, their primary objective is to decrease pain to allow functional improvement concurrently with physical and pharmaceutical modalities. Common injectates used for peripheral joint injections include local anesthetic, corticosteroid, hyaluronic acid, platelet-rich plasma, and mesenchymal stromal cells.

The purpose of this study was to compare the serum inflammatory indicators and radiographic results of conventional manual total knee arthroplasty (CM-TKA) with those of MAKO-robotic assisted total knee arthroplasty (MA-TKA).