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Ryan S D’Souza,1 Yeng F Her,1 Nasir Hussain,2 Jay Karri,3 Michael E Schatman,4 Aaron K Calodney,5 Christopher Lam,6 Thomas Buchheit,7 Brennan J Boettcher,8 George C Chang Chien,9 Scott G Pritzlaff,10 Christopher Centeno,11 Shane A Shapiro,12 Johana Klasova,1 Jay S Grider,13 Ryan Hubbard,14 Eliana Ege,15 Shelby Johnson,8 Max H Epstein,16 Eva Kubrova,8 Mohamed Ehab Ramadan,17 Alexandra Michelle Moreira,18 Swarnima Vardhan,19 Yashar Eshraghi,20 Saba Javed,21 Newaj M Abdullah,22 Paul J Christo,17 Sudhir Diwan,23 Leslie C Hassett,24 Dawood Sayed,6 Timothy R Deer25 1Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA; 2Department of Anesthesiology, The Ohio State Wexner Medical Center, Columbus, OH, USA; 3Departments of Orthopedic Surgery and Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA; 4Department of Anesthesiology, Perioperative Care, & Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA; 5Precision Spine Care, Tyler, TX, USA; 6Department of Anesthesiology and Pain Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; 7Department of Anesthesiology, Duke University, Durham, NC, USA; 8Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA; 9Department of Regenerative Medicine, GCC Institute, Torrance, CA, USA; 10Department of Anesthesiology and Pain Medicine, University of California, Davis, Sacramento, CA, USA; 11Centeno-Schultz Clinic, Broomfield, CO, USA; 12Department of Orthopedic Surgery, Mayo Clinic, Jacksonville, FL, USA; 13Department of Anesthesiology, University of Kentucky College of Medicine, Lexington, KY, USA; 14Department of Sports Medicine, Anderson Orthopedic Clinic, Arlington, VA, USA; 15Department of Physical Medicine & Rehabilitation, Baylor College of Medicine, Houston, TX, USA; 16Department of Physical Medicine & Rehabilitation, Harvard Medical School, Boston, MA, USA; 17Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, MD, USA; 18Department of Physical Medicine & Rehabilitation, University of Miami/Jackson Memorial Hospital, Miami, FL, USA; 19Department of Internal Medicine, Yale New Haven Health – Bridgeport Hospital, Bridgeport, CT, USA; 20Department of Anesthesiology & Critical Care Medicine, Ochsner Health System, New Orleans, LA, USA; 21Department of Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 22Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA; 23Department of Pain Medicine, Advanced Spine on Park Avenue, New York City, NY, USA; 24Mayo Clinic Libraries, Mayo Clinic, Rochester, MN, USA; 25Department of Anesthesiology and Pain Medicine, West Virginia University School of Medicine, Charleston, WV, USACorrespondence: Ryan S D’Souza, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA, Tel +1-(507)-284-9696, Fax +1-(507)-266-7732, Email dsouza.ryan@mayo.eduPurpose: Injectable biologics have not only been described and developed to treat dermal wounds, cardiovascular disease, and cancer, but have also been reported to treat chronic pain conditions. Despite emerging evidence supporting regenerative medicine therapy for pain, many aspects remain controversial.Methods: The American Society of Pain and Neuroscience (ASPN) identified the educational need for an evidence-based guideline on regenerative medicine therapy for chronic pain. The executive board nominated experts spanning multiple specialties including anesthesiology, physical medicine and rehabilitation, and sports medicine based on expertise, publications, research, and clinical practice. A steering committee selected preliminary questions, which were reviewed and refined. Evidence was appraised using the United States Preventive Services Task Force (USPSTF) criteria for evidence level and degree of recommendation. Using a modified Delphi approach, consensus points were distributed to all collaborators and each collaborator voted on each point. If collaborators provided a decision of “disagree” or “abstain”, they were invited to provide a rationale in a non-blinded fashion to the committee chair, who incorporated the respective comments and distributed revised versions to the committee until consensus was achieved.Results: Sixteen questions were selected for guideline development. Questions that were addressed included type of injectable biologics and mechanism, evidence in treating chronic pain indications (eg, tendinopathy, muscular pathology, osteoarthritis, intervertebral disc disease, neuropathic pain), role in surgical augmentation, dosing, comparative efficacy between injectable biologics, peri-procedural practices to optimize therapeutic response and quality of injectate, federal regulations, and complications with mitigating strategies.Conclusion: In well-selected individuals with certain chronic pain indications, use of injectable biologics may provide superior analgesia, functionality, and/or quality of life compared to conventional medical management or placebo. Future high-quality randomized clinical trials are warranted with implementation of minimum reporting standards, standardization of preparation protocols, investigation of dose–response associations, and comparative analysis between different injectable biologics.Keywords: regenerative medicine, injectable biologics, platelet-rich plasma, mesenchymal stem cell, bone marrow aspirate concentrate, pain medicine

Vapor-deposited Co/Al nanolaminates having a net equiatomic stoichiometry exhibited rapid, high-temperature synthesis. When ignited locally, 7.5-μm-thick Co/Al foils were characterized by self-sustained propagating reactions with flame front speeds between ∼0.5 and 9 m/s. Speed was largely affected by bilayer thickness and premixed volume fraction, consistent with previous studies of other exothermic multilayers. Cobalt aluminide foils reacted by self-propagating synthesis developed a variety of rough surface morphologies characterized by a large amplitude (peak-to-valley ∼1.0 μm), multiperiod, wavelike structure. High-temperature reaction was also stimulated by rapid global heating. Tests revealed low ignition temperatures (Tig)∼240–460 °C compared with previous Co–Al powder reactant experiments. Ignition temperature was influenced by bilayer thickness. All foils ignited by global heating and those reacted in a self-propagating mode developed a single-phase B2 (CsCl-type) crystal structure. Thick Co/Al nanolaminates were used successfully to join a few different materials including metalized Al2O3 (by soldering) and polyetheretherketone (by direct attachment). [ABSTRACT FROM AUTHOR]

Despite being a recognized clinical entity for over 140 years, complex regional pain syndrome (CRPS) remains a difficult-to-treat condition. While there have been multiple therapies explored in the treatment of CRPS, NMDA antagonists such as ketamine continue to hold significant interest because of their potential ability to alter the central sensitization noted in chronic pain states. The objective of this review is to identify published literature for evidence of the efficacy and safety of ketamine in the treatment of CRPS. PubMed and the Cochrane Controlled Trials Register were searched (final search 26 May 2011) using the MeSH terms 'ketamine', 'complex regional pain syndrome', 'analgesia' and 'pain' in the English literature. The manuscript bibliographies were then reviewed to identify additional relevant papers. Observational trials were evaluated using the Agency for Healthcare Research and Quality criteria; randomized trials were evaluated using the methodological assessment of randomized clinical trials. The search methodology yielded three randomized, placebo-controlled trials, seven observational studies and nine case studies/reports. In aggregate, the data available reveal ketamine as a promising treatment for CRPS. The optimum dose, route and timing of administration remain to be determined. Randomized controlled trials are needed to establish the efficacy and safety of ketamine and to determine its long-term benefit in CRPS. [ABSTRACT FROM AUTHOR]

The interplay between deformation and microstructure evolution can be strong and is the basis of a large majority of thermomechanical processing techniques for metals. We present simulations of this interplay, using a sharp-interface front tracking model for grain growth and a finite-element polycrystal plasticity model of deformation that includes anisotropic linear elasticity. The two approaches are iteratively coupled, so that grain growth affects the deformation behavior, and vice versa. Analyses of both purely elastic and of elastic-plastic materials are presented through coupled simulations of static loading of model polycrystalline micro- structures. In the elastic case, stored elastic energies can reach relatively high values, and the mechanical driving force can locally exceed the curvature driving force, causing boundaries to assume noncompact (rippled) shapes. These large driving forces also serve to accelerate the grain growth process. In the elastic-plastic case, under relatively low strains, plasticity provides a stress relief mechanism that prohibits the generation of large stored elastic energies; thus, substantial deviations from compact interface morphologies were not observed, and growth kinetics did not accelerate substantially. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of chemotherapy for cancer, and has limited effective treatment options. Autologous conditioned serum (ACS) is an effective biologic therapy used by intra-articular injection for patients with osteoarthritis. However, ACS has not been systematically tested in the treatment of peripheral neuropathies such as CIPN. It has been generally assumed that the analgesic effect of this biologic therapy results from augmented concentrations of anti-inflammatory cytokines and growth factors. Here we report that a single intrathecal injection of human conditioned serum (hCS) produced long-lasting inhibition of paclitaxel chemotherapy-induced neuropathic pain (mechanical allodynia) in mice, without causing motor impairment. Strikingly, the analgesic effect of hCS in our experiments was maintained even 8 weeks after the treatment, compared with non-conditioned human serum (hNCS). Furthermore, the hCS transfer-induced pain relief in mice was fully recapitulated by rat or mouse CS transfer to mice of both sexes, indicating cross-species and cross-sex effectiveness. Mechanistically, CS treatment blocked the chemotherapy-induced glial reaction in the spinal cord and improved nerve conduction. Compared to NCS, CS contained significantly higher concentrations of anti-inflammatory and pro-resolving mediators, including IL-1Ra, TIMP-1, TGF-β1, and resolvins D1/D2. Intrathecal injection of anti-TGF-β1 and anti-Il-1Ra antibody transiently reversed the analgesic action of CS. Nanoparticle tracking analysis revealed that rat conditioned serum contained a significantly greater number of exosomes than NCS. Importantly, the removal of exosomes by high-speed centrifugation largely diminished the CS-produced pain relief, suggesting a critical involvement of small vesicles (exosomes) in the beneficial effects of CS. Together, our findings demonstrate that intrathecal CS produces a remarkable resolution of neuropathic pain mediated through a combination of small vesicles/exosomes and neuroimmune/neuroglial modulation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Authors TB, YH, AB, SB, JX, YM, RG, TH, and RRJ have no competing financial interest in this study. Authors JR and PW are employed by Orthogen AG., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The epidural blood patch (EBP) is one of the most effective treatments for intracranial hypotension. Anesthesiologists are familiar with performing EBPs for the treatment of dural puncture-associated intracranial hypotension following spinal anesthesia, complicated epidural analgesia, and diagnostic lumbar puncture. Increasingly, EBPs are used to treat patients with spontaneous intracranial hypotension. However, the treatment of these non-iatrogenic conditions presents new therapeutic challenges. The purpose of this narrative review is to discuss both procedural and diagnostic considerations of EBP for the various presentations of intracranial hypotension and allow the clinician to tailor treatment for the patient, especially in the setting of diagnostic dilemmas. After discussing EBP history and relevant anatomy, we review mechanisms of action and clinical indications for this intervention. The contraindications, complications, and treatment alternatives to the blood patch are examined in detail. Finally, objective methods to evaluate the effectiveness of the EBP, such as MRI or Doppler ultrasound, are presented as novel methods that may improve future diagnostic accuracy and treatment success., (Copyright © 2022 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

Regenerative pain medicine, which seeks to harness the body's own reparative capacity, is rapidly emerging as a field within pain medicine and orthopedics. It is increasingly appreciated that common analgesic mechanisms for these treatments depend on neuroimmune modulation. In this Review, we discuss recent progress in mechanistic understanding of nociceptive sensitization in chronic pain with a focus on neuroimmune modulation. We also examine the spectrum of regenerative outcomes, including preclinical and clinical outcomes. We further distinguish the analgesic mechanisms of regenerative therapies from those of cellular replacement, creating a conceptual and mechanistic framework to evaluate future research on regenerative medicine.

Objective: To determine if the perioperative administration of valproic acid reduces the incidence of chronic pain three months after amputation or revision surgery., Design: Multicenter, randomized, double-blind, placebo-controlled trial., Setting: Academic, military, and veteran medical centers., Subjects: One hundred twenty-eight patients undergoing amputation or amputation revision surgery at Duke University Hospital, Walter Reed National Military Medical Center, or the Durham Veterans Affairs Medical Center for either medical disease or trauma., Methods: Patients were randomized to placebo or valproic acid for the duration of hospitalization and treated with multimodal analgesic care, including regional anesthetic blockade. Primary outcome was the proportion of patients with chronic pain at three months (average numeric pain score intensity of 3/10 or greater). Secondary outcomes included functional trajectories (assessed with the Brief Pain Inventory short form and the Defense and Veterans Pain Rating Scale)., Results: The overall rate of chronic pain was 68.2% in the 107 patients who completed the end point assessment. There was no significant effect of perioperative valproic acid administration, with a rate of 65.45% (N = 36) in the treatment group and a rate of 71.15% (N = 37) in the placebo group. Overall, pain scores decreased from baseline to follow-up (median = -2 on the numeric pain scale). Patients additionally experienced improvements in self-perceived function., Conclusions: The rate of chronic pain after amputation surgery is not significantly improved with the perioperative administration of valproic acid. In this cohort treated with multimodal perioperative analgesia and regional anesthetic blockade, we observed improvements in both pain severity and function., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Factors contributing to development of complex regional pain syndrome (CRPS) are not fully understood. This study examined possible epigenetic mechanisms that may contribute to CRPS after traumatic injury. DNA methylation profiles were compared between individuals developing CRPS (n = 9) and those developing non-CRPS neuropathic pain (n = 38) after undergoing amputation following military trauma. Linear Models for Microarray (LIMMA) analyses revealed 48 differentially methylated cytosine-phosphate-guanine dinucleotide (CpG) sites between groups (unadjusted P's < 0.005), with the top gene COL11A1 meeting Bonferroni-adjusted P < 0.05. The second largest differential methylation was observed for the HLA-DRB6 gene, an immune-related gene linked previously to CRPS in a small gene expression study. For all but 7 of the significant CpG sites, the CRPS group was hypomethylated. Numerous functional Gene Ontology-Biological Process categories were significantly enriched (false discovery rate-adjusted q value <0.15), including multiple immune-related categories (eg, activation of immune response, immune system development, regulation of immune system processes, and antigen processing and presentation). Differentially methylated genes were more highly connected in human protein-protein networks than expected by chance (P < 0.05), supporting the biological relevance of the findings. Results were validated in an independent sample linking a DNA biobank with electronic health records (n = 126 CRPS phenotype, n = 19,768 non-CRPS chronic pain phenotype). Analyses using PrediXcan methodology indicated differences in the genetically determined component of gene expression in 7 of 48 genes identified in methylation analyses (P's < 0.02). Results suggest that immune- and inflammatory-related factors might confer risk of developing CRPS after traumatic injury. Validation findings demonstrate the potential of using electronic health records linked to DNA for genomic studies of CRPS.

Background: The Opioid Safety Initiative decreased high-dose prescriptions across the Veterans Health Administration. This study sought to examine the impact of this intervention (i.e., the Opioid Safety Initiative) on pain scores and opioid prescriptions in patients undergoing total knee arthroplasty., Methods: This was an ecological study of group-level data among 700 to 850 patients per month over 72 consecutive months (January 2010 to December 2015). The authors examined characteristics of cohorts treated before versus after rollout of the Opioid Safety Initiative (October 2013). Each month, the authors aggregated at the group-level the differences between mean postoperative and preoperative pain scores for each patient (averaged over 6-month periods), and measured proportions of patients (per 1,000) with opioid (and nonopioid) prescriptions for more than 3 months in 6-month periods, preoperatively and postoperatively. The authors compared postintervention trends versus trends forecasted based on preintervention measures., Results: After the Opioid Safety Initiative, patients were slightly older and sicker, but had lower mortality rates (postintervention n = 28,509 vs. preintervention n = 31,547). Postoperative pain scores were slightly higher and the decrease in opioid use was statistically significant, i.e., 871 (95% CI, 474 to 1,268) fewer patients with chronic postoperative prescriptions. In time series analyses, mean postoperative minus preoperative pain scores had increased from 0.65 to 0.81, by 0.16 points (95% CI, 0.05 to 0.27). Proportions of patients with chronic postoperative and chronic preoperative opioid prescriptions had declined by 20% (n = 3,355 vs. expected n = 4,226) and by 13% (n = 5,861 vs. expected n = 6,724), respectively. Nonopioid analgesia had increased. Sensitivity analyses confirmed all findings., Conclusions: A system-wide initiative combining guideline dissemination with audit and feedback was effective in significantly decreasing opioid prescriptions in populations undergoing total knee arthroplasty, while minimally impacting pain scores.

Background and Objectives: Pain scores are routinely reported in clinical practice, and we wanted to examine whether this routinely measured, patient-reported variable provides prognostic information, especially with regard to chronic opioid use, after taking preoperative and perioperative variables into account in a preoperative opioid user population., Methods: In 32,874 preoperative opioid users undergoing primary total knee arthroplasty at Veterans Affairs hospitals between 2010 and 2015, we compared preoperative and perioperative characteristics in patients reporting lower versus higher acute pain (scores ≤4/10 vs >4/10 averaged over days 1-3). We calculated the propensity for lower acute pain based on all available data. After 1:1 propensity score matching, to identify similar patients differing only in acute pain, we contrasted rates of chronic significant opioid use (mean >30 mg/d in morphine equivalents) beyond postoperative month 3, discharge prescriptions, and changes in postoperative versus preoperative dose categories. Sensitivity analysis examined associations with dose escalation., Results: Rates of chronic significant opioid use (21% overall) differed in patients with lower versus higher acute pain (36% vs 64% of the overall cohort). After propensity matching (total n = 20,926 patients) and adjusting for all significant factors, lower acute pain was associated with less chronic significant opioid use (rates 12% vs 16%), smaller discharge prescriptions (ie, supply <30 days and daily oral morphine equivalent <30 mg/d), and more reduction in dose, all P < 0.001. In sensitivity analysis, dose escalation was 15% less likely with lower acute pain (odds ratio, 0.85; 95% confidence interval, 0.80-0.91)., Conclusions: Acute pain predicts chronic opioid use. Prospective studies of efforts to reduce acute pain, in terms of long-term effects, are needed.

Introduction: Certain common medications are associated with an elevated risk of fracture and recent data suggests that medications can also increase nonunion risk. Medication use is a modifiable nonunion risk factor, but it is unknown whether risk accrues solely to chronic medication use or whether there is also risk inherent to acute use., Methods: Multivariate logistic regression was used in an inception cohort to calculate odds ratios (OR) for fracture nonunion associated with medication use, in context with other risk factors demonstrated to influence nonunion. Patient-level health claims for medical and drug expenses were compiled from a payer database. Patients were included if they had a fracture coded in 2011, with continuous enrollment for 1 month prior to and 12 months after fracture. The database contained demographic descriptors, treatment procedures per CPT codes, co-morbidities per ICD-9 codes, and prescriptions per National Drug Codes. Chronic medication use was defined as ≥30 days of prescription prior to fracture with ≥1 day afterward; acute use was any other prescription., Results: Most non-analgesic medications were safe in acute or chronic use, but risk of nonunion was elevated for a wide range of analgesics. Overall, 45,085 fractures (14.6% of fractures) affected patients using chronic opioids. Nonunion OR was elevated for acute and chronic use of Schedule 2 opioids including acetaminophen/oxycodone, hydromorphone, oxycodone, and acetaminophen/hydrocodone bitartrate, as well as Schedule 3-5 opioids including tramadol (all, p < 0.0001). The highest ORs were associated with chronic administration of Schedule 2 opioids., Discussion: Most medications do not increase nonunion risk, but acute and chronic use of NSAIDs or opioids was associated with impaired fracture healing. There is particular risk in prescribing opioid analgesics for fracture, though literature suggests that roughly half of opioid-naïve patients receive such a prescription., Conclusions: Patients evaluated in this study were not a random sample of Americans; they may approximate a random sample of the Emergency Department population in the United States. Thus, trauma patients may represent a population enriched for nonunion risk factors. Opioids impair recovery from injury; if they also predispose to injury, the ongoing opioid epidemic could presage an increase in nonunion prevalence., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Epigenetic mechanisms are increasingly implicated in chronic pain pathology. In this study, we demonstrate that the novel epigenetic mark 5-hydroxymethylcytosine (5hmC) is present in dorsal root ganglia (DRG) neurons and glia, and its levels increase following nerve injury. Furthermore, we show that the 5hmC-generating Ten-eleven translocation 1-3 (TET1-3) proteins are expressed in a cell-type specific manner in the DRG, with Tet3 displaying differential upregulation after injury, suggesting a potential role in neuropathic pain.