The Polyanalgesic Consensus Conference (PACC)®: Intrathecal Drug Delivery Guidance on Safety and Therapy Optimization When Treating Chronic Noncancer Pain.

INTRODUCTION: The International Neuromodulation Society convened a multispecialty group of physicians and scientists based on expertise with international representation to establish evidence-based guidance on intrathecal drug delivery in treating chronic pain. This Polyanalgesic Consensus Conference (PACC)® project, created more than two decades ago, intends to provide evidence-based guidance for important safety and efficacy issues surrounding intrathecal drug delivery and its impact on the practice of neuromodulation. MATERIALS AND METHODS: Authors were chosen on the basis of their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from 2017 (when PACC® last published guidelines) to the present. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on the strength of evidence or consensus when evidence is scant. RESULTS: The PACC® examined the published literature and established evidence- and consensus-based recommendations to guide best practices. Additional guidance will occur as new evidence is developed in future iterations of this process. CONCLUSIONS: The PACC® recommends best practices regarding intrathecal drug delivery to improve safety and efficacy. The evidence- and consensus-based recommendations should be used as a guide to assist decision-making when clinically appropriate.

A Review of the Factors and Outcomes of Institutional Interdisciplinary Neuromodulation Committees: A Multicenter Experience.

INTRODUCTION: Neuromodulation represents one of the more advanced tools in the armamentarium of pain physicians. To optimize neuromodulation patient selection and management, an institutional interdisciplinary neuromodulation committee was created at each of two academic medical centers (University of California Davis [UCD] and Stanford University). The committee aims to collaboratively optimize neuromodulation candidates, to assess and minimize medical and psychologic risks, and to select the best device given a patient's pain condition. In this study, we present the methods and outcome data of the Neuromodulation Committee at the two institutions. MATERIALS AND METHODS: After institutional review board approval, we included all adult patients who were evaluated by the Neuromodulation Committee between 2017 and 2020 at two academic pain clinics. Patients with insufficient data were excluded from the study. A retrospective chart review was completed on 385 UCD and Stanford University patient committee reviews. Data collected from the chart review included demographics (age, sex), committee meeting results (proceed with trial/implant or decline), trial success, and implant rate. RESULTS: Of the 385 patients screened, the committees recommended proceeding with an implantable device (peripheral and neuraxial) in 337 patients (87.5%). Of the 278 patients recommended for neuraxial neuromodulation, 131 underwent trials with percutaneous leads (47.1%). Trials were successful (causing a ≥50% reduction in self-reported pain or improved function) in 108 patients (82.4%). The institutions completed 87 implants of 131 trials, representing a trial-to-permanent ratio of 66.4%. CONCLUSIONS: The Neuromodulation Committee aims to identify optimal patients for neuromodulation, address procedural challenges, decrease adverse events, provide educational context for trainees, and improve patient-related outcomes. Patients who were recommended for neuromodulation and subsequently underwent intervention had high trial success rates for dorsal root ganglion stimulation and spinal cord stimulation. The findings indicate that such an approach can lead to neuromodulation success, especially at academic centers, by combining the expertise of both medical and psychologic professionals.

Pain Education and Knowledge (PEAK) Consensus Guidelines for Neuromodulation: A Proposal for Standardization in Fellowship and Training Programs.

The need to be competent in neuromodulation is and should be a prerequisite prior to completing a fellowship in interventional pain medicine. Unfortunately, many programs lack acceptable candidates for these advanced therapies, and fellows may not receive adequate exposure to neuromodulation procedures. The American Society of Pain and Neuroscience (ASPN) desires to create a consensus of experts to set a minimum standard of competence for neurostimulation procedures, including spinal cord stimulation (SCS), dorsal root ganglion stimulation (DRG-S), and peripheral nerve stimulation (PNS). The executive board of ASPN accepted nominations for colleagues with excellence in the subject matter of neuromodulation and physician education. This diverse group used peer-reviewed literature and, based on grading of evidence and expert opinion, developed critical consensus guides for training that all accredited fellowship programs should adopt. For each consensus point, transparency and recusal were used to eliminate bias, and an author was nominated for evidence grading oversight and bias control. Pain Education and Knowledge (PEAK) Consensus Guidelines for Neuromodulation sets a standard for neuromodulation training in pain fellowship training programs. The consensus panel has determined several recommendations to improve care in the United States for patients undergoing neuromodulation. As neuromodulation training in the United States has evolved dramatically, these therapies have become ubiquitous in pain medicine. Unfortunately, fellowship programs and the Accreditation Council for Graduate Medical Education (ACGME) pain program requirements have not progressed training to match the demands of modern advancements. PEAK sets a new standard for fellowship training and presents thirteen practice areas vital for physician competence in neuromodulation.

Birds of a Feather Redux: Defining Ways to Stimulate the Peripheral Nervous System.

Peripheral nerve stimulation (PNS) has become an essential component in the pain management plan for individuals suffering from peripheral nerve-mediated pain. The recent surge in interest in PNS can be attributed to the advancements in imaging techniques and the availability of minimally invasive stimulation systems along with a deeper grasp of PNS physiology. These advancements have made PNS more accessible to clinicians and patients alike. However, it is important to note that PNS requires a different set of technical requirements and skills compared to other pain management procedures. The work, knowledge, and surgical and interventional skillset required for PNS are in a class of their own. This article aims to educate and clarify the differences between procedures that may have similar names but are vastly different in terms of technology, expertise, and skill sets necessary for their safe implementation. Some of the procedures that this article will cover include indirect peripheral nerve field stimulation (PNfS), indirect percutaneous electrical nerve stimulation (PENS), PENS-Field Stimulation (PENFS), and transcutaneous electrical nerve stimulation (TENS). By understanding the differences between these procedures, patients and health-care providers can make informed decisions about the best approach for managing pain.

Application of multidisciplinary team conference for neuromodulation candidates facilitates patient selection and optimization.

Introduction: Psychological evaluation is required by insurance companies in the United States prior to proceeding with a spinal cord stimulation or a dorsal root ganglion stimulation trial. Since January 2017, we implemented a Multidisciplinary Team Conference for Neuromodulation in our center to facilitate the collaboration between pain physicians and psychologists and to optimize screening of neuromodulation candidates. This study aims to report the impact of this team conference on improvement of neuromodulation outcome in our center. Methods: Appropriateness of neuromodulation were discussed in the team conference after initial visit with the pain specialist and psychological evaluation. For this study, we prospectively and retrospectively collected data on neuromodulation candidates who went through the team conference and those who did not as controls. Results: We discussed 461 patients in the team conference sessions from January 2017 to July 2023. Out of these, a spinal cord stimulator or a dorsal root ganglion stimulator trial was performed in 164 patients with 80.5% (132 cases) trial success rate leading to 140 implants. Out of these implants, 26 (18.6%) explanted and 21 (15%) required revision in 41 (29.3%) patients. We performed neuraxial neuromodulation trial for 70 patients without going through the team conference from January 2016 to July 2023 with a trial success rate of 45.7% (32 cases). In this group, 7 (21.9%) and 6 (18.8%) patients underwent explant and revision. The differences between the groups were statistically significant for trial success rate (odds ratio of 4.9 with p-value of <0.01) but not for explant (odds ratio of 0.8 with p-value of 0.627) or revision (odds ratio of 0.8 with p-value of 0.595). Conclusion: Implementing Multidisciplinary Team Conference increased trial success rate in our center. Team conference provides therapeutic benefit for patients, and also provides the opportunity for an educational discussion for trainees.

Considerations in permanent implantation of peripheral nerve stimulation (PNS) for chronic neuropathic pain: An international cross-sectional survey of implanters.

AIM: Novel minimally invasive short-term and long-term peripheral nerve stimulation (PNS) systems have revolutionized targeted treatment of chronic neuropathic pain. We present an international survey of PNS-implanting pain physicians to assess what factors they consider when offering permanent PNS. METHODS: This cross-sectional study consisted of a survey (Qualtrics) that was distributed to PNS-implanting physicians in a device supplier's entire email database on November 13, 2020, with 3 weeks of response time. Physicians' contact information in the form of their email addresses had been previously collected by the supplier upon device distribution with permission to use survey responses for research. RESULTS: Of 2032 database physicians, 40 physicians representing 37 institutions responded to the survey. The most common application of PNS was mononeuropathic pain (57%). The most frequently targeted nerve was the suprascapular nerve (29%). 14% of physicians reported 81-100% of their implants were dual-lead. The representative physicians ranged broadly in their most frequently targeted nerves. Although mononeuropathic pain was the most common indication for PNS, there was still varied response regarding other indications such as CRPS and post-surgical chronic pain. CONCLUSION: In context of a low response rate, identifying such factors can help update the prevailing treatment algorithm for interventional therapies, assist pain physicians in better identifying which patients are the best candidates for PNS, and inform future clinical trial design on PNS efficacy.

The Neurostimulation Appropriateness Consensus Committee (NACC): Recommendations on Best Practices for Cervical Neurostimulation.

INTRODUCTION: The International Neuromodulation Society convened a multispecialty group of physicians based on expertise with international representation to establish evidence-based guidance on the use of neurostimulation in the cervical region to improve outcomes. This Neurostimulation Appropriateness Consensus Committee (NACC) project intends to provide evidence-based guidance for an often-overlooked area of neurostimulation practice. MATERIALS AND METHODS: Authors were chosen based upon their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from 2017 (when NACC last published guidelines) to the present. Identified studies were graded using the US Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on the strength of evidence or consensus when evidence was scant. RESULTS: The NACC examined the published literature and established evidence- and consensus-based recommendations to guide best practices. Additional guidance will occur as new evidence is developed in future iterations of this process. CONCLUSIONS: The NACC recommends best practices regarding the use of cervical neuromodulation to improve safety and efficacy. The evidence- and consensus-based recommendations should be utilized as a guide to assist decision making when clinically appropriate.

Emphysematous Cholecystitis Secondary to Fusobacterium nucleatum.

Fusobacterium nucleatum may be implicated in cases of emphysematous cholecystitis (EC) and carries a high mortality risk, especially in individuals with heart disease, renal insufficiency, and underlying malignancy. Fusobacterium infections are rarely detected in the setting of cholecystitis possibly due to the difficulty with properly culturing the bacteria. We describe a case of a patient with EC in whom blood cultures were positive for growth of F. nucleatum in one of two samples. The patient was treated with empiric antibiotic therapy consisting of metronidazole and cefepime. In patients with EC and negative cultures, it is possible that they may have an undetected infection with fusobacteria, which carries a high mortality risk. As such, clinicians should maintain a high degree of suspicion of obligate anaerobic infection in patients who have negative blood culture for growth in the setting of EC and consider continuation of adequate antimicrobial coverage.

Stanford Pragmatiec Effectiveness Comparison (SPEC) protocol: Comparing long-term effectiveness of high-frequency and burst spinal cord stimulation in real-world application.

OBJECTIVES: High-frequency and burst stimulation are newer waveforms that have demonstrated promise compared to traditional tonic spinal cord stimulation (SCS), but more studies are needed to compare their effectiveness. We report the study methods for an ongoing, single center, pragmatic randomized clinical trial to compare the effectiveness of high-frequency and burst SCS in patients with chronic back and/or leg pain. MATERIALS AND METHODS: Participants who are candidates for spinal cord stimulation are enrolled and screened. Participants will be randomly assigned using point-of-care randomization to receive either high-frequency or burst SCS. Data collection will be through Stanford Pain Management Center's learning healthcare system: CHOIR. CHOIR surveys include National Institutes of Health Patient Reported Outcomes Measurement Information System item banks, a body map, questions about pain intensity, pain catastrophizing scale, and questions about patients' pain experience and healthcare utilization. Participants will complete online surveys at baseline and then 1, 3, 6, 12, 18, 24 and 36 months after their device implant. All participants will use our routine process of trial and implant. Reported adverse events are monitored throughout the study. Our primary outcome is change from baseline in pain intensity at 12 months. RESULTS: We hypothesize that high-frequency SCS is more effective than burst SCS in improving pain, physical function and pain interference in participants with chronic low back and/or leg pain. CONCLUSIONS: The pragmatic nature of our proposed trial enables us to recruit a larger participant cohort faster and to follow up these participants longer than currently published clinical trials.

Synthesis and Structure-Activity Relationships of Inhibitors That Target the C-Terminal MEEVD on Heat Shock Protein 90.

Herein, we describe the synthesis and structure-activity relationships of cyclic peptides designed to target heat shock protein 90 (Hsp90). Generating 19 compounds and evaluating their binding affinity reveals that increasing electrostatic interactions allows the compounds to bind more effectively with Hsp90 compared to the lead structure. Exchanging specific residues for lysine improves binding affinity for Hsp90, indicating some residues are not critical for interacting with the target, whereas others are essential. Replacing l- for d-amino acids produced compounds with decreased binding affinity compared to the parent structure, confirming the importance of conformation and identifying key residues most important for binding. Thus, a specific conformation and electrostatic interactions are required in order for these inhibitors to bind to Hsp90.

Linear self-assembly formation between gold nanoparticles and aminoglycoside antibiotics.

Ribostamycin is a broad-spectrum aminoglycoside antibiotic with a molecular weight of 454.5 g/mol. Under neutral pH conditions, ribostamycin is highly positive charged because it carries multiple amino groups in its structure. Negatively charged citrate ligand capped-gold nanoparticles (AuNPs) have been studied extensively for their interactions with a wide range of biomolecules including proteins, carbohydrates, and small drug compounds. These studies are aimed at developing new therapeutics and diagnostics by exploiting the unique properties of gold nanoparticles. Under this general aim, we studied the interaction between ribostamycin and AuNPs. Using a suite of analytical techniques including dynamic light scattering (DLS), UV-vis absorption spectroscopy, and dark field optical microscope imaging (DFM), we analyzed the mixture products of AuNPs with various sizes and ribostamycin under different concentrations. Our study revealed for the first time that ribostamycin has a tendency to self-assemble into linear oligomers at increased concentrations (above 250-500 µM). Such self-assembled oligomers then interact with negatively charged AuNPs to produce rod-like AuNP assemblies. Similar findings were observed from another structurally related aminoglycoside antibiotic, amikacin. It is technically challenging to detect and characterize oligomer formation of small molecules. It is especially challenging when the interactions that are holding the oligomers are not very strong. Through their interaction with gold nanoparticles that have exceptionally strong light scattering properties, we were able to observe the self-assembling of ribostamycin and amikacin in solution using various spectroscopic and microscopic techniques. This concentration-dependent self-assembling behavior of ribostamycin and amikacin may have direct relevance to the antibiotic effect of ribostamycin, amikacin and other structurally similar antibiotics.

The Polyanalgesic Consensus Conference (PACC): Recommendations on Intrathecal Drug Infusion Systems Best Practices and Guidelines.

INTRODUCTION: Pain treatment is best performed when a patient-centric, safety-based philosophy is used to determine an algorithmic process to guide care. Since 2007, the International Neuromodulation Society has organized a group of experts to evaluate evidence and create a Polyanalgesic Consensus Conference (PACC) to guide practice. METHODS: The current PACC update was designed to address the deficiencies and innovations emerging since the previous PACC publication of 2012. An extensive literature search identified publications between January 15, 2007 and November 22, 2015 and authors contributed additional relevant sources. After reviewing the literature, the panel convened to determine evidence levels and degrees of recommendations for intrathecal therapy. This meeting served as the basis for consensus development, which was ranked as strong, moderate or weak. Algorithms were developed for intrathecal medication choices to treat nociceptive and neuropathic pain for patients with cancer, terminal illness, and noncancer pain, with either localized or diffuse pain. RESULTS: The PACC has developed an algorithmic process for several aspects of intrathecal drug delivery to promote safe and efficacious evidence-based care. Consensus opinion, based on expertise, was used to fill gaps in evidence. Thirty-one consensus points emerged from the panel considerations. CONCLUSION: New algorithms and guidance have been established to improve care with the use of intrathecal drug delivery.

The appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: the Neuromodulation Appropriateness Consensus Committee.

INTRODUCTION: The Neuromodulation Appropriateness Consensus Committee (NACC) of the International Neuromodulation Society (INS) evaluated evidence regarding the safety and efficacy of neurostimulation to treat chronic pain, chronic critical limb ischemia, and refractory angina and recommended appropriate clinical applications. METHODS: The NACC used literature reviews, expert opinion, clinical experience, and individual research. Authors consulted the Practice Parameters for the Use of Spinal Cord Stimulation in the Treatment of Neuropathic Pain (2006), systematic reviews (1984 to 2013), and prospective and randomized controlled trials (2005 to 2013) identified through PubMed, EMBASE, and Google Scholar. RESULTS: Neurostimulation is relatively safe because of its minimally invasive and reversible characteristics. Comparison with medical management is difficult, as patients considered for neurostimulation have failed conservative management. Unlike alternative therapies, neurostimulation is not associated with medication-related side effects and has enduring effect. Device-related complications are not uncommon; however, the incidence is becoming less frequent as technology progresses and surgical skills improve. Randomized controlled studies support the efficacy of spinal cord stimulation in treating failed back surgery syndrome and complex regional pain syndrome. Similar studies of neurostimulation for peripheral neuropathic pain, postamputation pain, postherpetic neuralgia, and other causes of nerve injury are needed. International guidelines recommend spinal cord stimulation to treat refractory angina; other indications, such as congestive heart failure, are being investigated. CONCLUSIONS: Appropriate neurostimulation is safe and effective in some chronic pain conditions. Technological refinements and clinical evidence will continue to expand its use. The NACC seeks to facilitate the efficacy and safety of neurostimulation.

The appropriate use of neurostimulation: avoidance and treatment of complications of neurostimulation therapies for the treatment of chronic pain. Neuromodulation Appropriateness Consensus Committee.

INTRODUCTION: The International Neuromodulation Society (INS) has determined that there is a need for guidance regarding safety and risk reduction for implantable neurostimulation devices. The INS convened an international committee of experts in the field to explore the evidence and clinical experience regarding safety, risks, and steps to risk reduction to improve outcomes. METHODS: The Neuromodulation Appropriateness Consensus Committee (NACC) reviewed the world literature in English by searching MEDLINE, PubMed, and Google Scholar to evaluate the evidence for ways to reduce risks of neurostimulation therapies. This evidence, obtained from the relevant literature, and clinical experience obtained from the convened consensus panel were used to make final recommendations on improving safety and reducing risks. RESULTS: The NACC determined that the ability to reduce risk associated with the use of neurostimulation devices is a valuable goal and possible with best practice. The NACC has recommended several practice modifications that will lead to improved care. The NACC also sets out the minimum training standards necessary to become an implanting physician. CONCLUSIONS: The NACC has identified the possibility of improving patient care and safety through practice modification. We recommend that all implanting physicians review this guidance and consider adapting their practice accordingly.

The appropriate use of neurostimulation: new and evolving neurostimulation therapies and applicable treatment for chronic pain and selected disease states. Neuromodulation Appropriateness Consensus Committee.

INTRODUCTION: The International Neuromodulation Society (INS) has determined that there is a need to provide an expert consensus that defines the appropriate use of neuromodulation technologies for appropriate patients. The Neuromodulation Appropriateness Consensus Committee (NACC) was formed to give guidance to current practice and insight into future developments. METHODS: The INS executive board selected members of the international scientific community to analyze scientific evidence for current and future innovations and to use clinical experience to fill in any gaps in information. The NACC used PubMed and Google Scholar to obtain current evidence in the field and used clinical and research experience to give a more complete picture of the innovations in the field. RESULTS: The NACC has determined that currently approved neurostimulation techniques and technologies have expanded our ability to treat patients in a more effective and specific fashion. Despite these advances, the NACC has identified several additional promising technologies and potential applications for neurostimulation that could move this field forward and expand the applicability of neuromodulation. CONCLUSIONS: The NACC concludes that the field of neurostimulation is an evolving and rapidly changing one that will lead to improved patient access, safety, and outcomes.