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 Polyanalgesic Consensus Conference (PACC): Recommendations for Intrathecal Drug Delivery: Guidance for Improving Safety and Mitigating Risks.

INTRODUCTION: Intrathecal therapy is an important part of the pain treatment algorithm for chronic disease states. The use of this option is a viable treatment strategy, but it is inherent for pain physicians to understand risk assessment and mitigation. In this manuscript, we explore evidence and mitigating strategies to improve safety with intrathecal therapy. METHODS: A robust literature search was performed covering January 2011 to October 9, 2016, in PubMed, Embase, MEDLINE, Biomed Central, Google Scholar, Current Contents Connect, and International Pharmaceutical Abstracts. The information was cross-referenced and compiled for evidence, analysis, and consensus review, with the intent to offer weighted recommendations and consensus statements on safety for targeted intrathecal therapy delivery. RESULTS: The Polyanalgesic Consensus Conference has made several best practice recommendations to improve care and reduce morbidity and mortality associated with intrathecal therapy through all phases of management. The United States Prevention Service Task Force evidence level and consensus strength assessments are offered for each recommendation. CONCLUSION: Intrathecal therapy is a viable and relatively safe option for the treatment of cancer- and noncancer-related pain. Continued research and expert opinion are required to improve our current pharmacokinetic and pharmacodynamic model of intrathecal drug delivery, as this will undoubtedly improve safety and efficacy.

A systematic review of ketamine for complex regional pain syndrome.

OBJECTIVE: This systematic review aims to examine the available literature and to synthesize published data concerning the treatment of Complex Regional Pain Syndrome (CRPS) with ketamine. METHODS: The search was conducted utilizing the databases Medline, Embase and the Cochrane Central Registry of Controlled Trials. All relevant articles were systematically reviewed. RESULTS: The search yielded 262 articles, 45 of which met the inclusion/exclusion criteria. Of those included, 6 were reviews, 5 were randomized placebo-controlled trials, 13 were observational studies, and 21 were case reports. CONCLUSION: There is no high quality evidence available evaluating the efficacy of ketamine for CRPS and all manuscripts examined in this review were of moderate to low quality. Therefore, we conclude there is currently only weak evidence supporting the efficacy of ketamine for CRPS, yet there is clearly a rationale for definitive study.

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.

Refractory Chronic Pain Screening Tool (RCPST): a feasibility study to assess practicality and validity of identifying potential neurostimulation candidates.

OBJECTIVE: An international panel of pain specialists (anesthesiology, neurology, neurosurgery, and psychology) and research methodologists developed a screening tool to identify patients who may be suitable for spinal cord stimulation (SCS)--the Refractory Chronic Pain Screening Tool (RCPST) prototype. We describe a feasibility study to explore practicality and validity of this prototype. DESIGN: Consecutive outpatients were screened in two centers (United Kingdom and United States). Sixty chronic pain adults without satisfactory pain relief despite treatment were assessed using RCPST (by pain specialist without expertise in neurostimulation) and then evaluated by two pain specialists experienced in SCS implantation and management to determine whether the patient should be referred for SCS. To maintain blinding, the participating physicians did not inform each other or the patient of assessment outcome. Sensitivity and specificity of the RCPST prototype were calculated using implanters' judgment as "gold standard." RESULTS: The average age of patients was 47.7 years; 53% were female. Fifty-seven patients completed the study (one withdrew consent, two lost to follow-up). The pain specialists agreed the prototype was easy to use and took <10 minutes to complete. Implanter agreement was moderate (Kappa: 0.63, 95% confidence interval: 0.35-0.91). The prototype had low sensitivity (40%, 19-61%) and moderate specificity (78%, 65-92%). Using the same questionnaire with a modified decision algorithm, new prototypes were generated with range of high sensitivity (80-100%) and specificity (89-97%) values. CONCLUSIONS: The RCPST aims to identify patients that should be referred for consideration for neurostimulation. The final implant decision requires appropriate neurological diagnostic workup, psychological assessment, and trial stimulation. RCPST was considered practical for routine clinical practice and contained appropriate questions. Sensitivity needs to be improved. A future study should select and validate the ideal RCPST prototype.

Best practices for intrathecal drug delivery for pain.

OBJECTIVE: The objective of this study was to identify best practices and provide guidance to clinicians to ensure safety and optimize intrathecal drug delivery for chronic intractable pain. METHODS: Twelve experienced pain medicine practitioners-eight anesthesiologists, one neurosurgeon, one physiatrist, one clinical psychologist, and one advanced practice registered nurse-from the United States, Australia, and Europe gathered to identify and publish consensus on best practices in three areas related to safe intrathecal therapy for pain: safety and monitoring, patient and device management, and patient selection and trialing. CONCLUSIONS: Intrathecal drug delivery is a valuable alternative drug delivery system for many patients with severe chronic or end-of-life pain. While device-related complications (mostly with catheters) and surgical-site infections can occur, the main therapy-related safety issues associated with intrathecal drug delivery arise primarily with inadequate patient monitoring (e.g., respiratory depression), inflammatory mass (e.g., high doses and concentrations of opioids), wound healing, dosing errors (e.g., medication concentration and pump programming), pump fills or refills (e.g., pocket fills), and interaction with concomitant systemic medications (e.g., opioids and benzodiazepines). Many of the reported adverse events and complications of intrathecal drug delivery can be prevented by adequate clinician training, implementation of best practices, and experience. In adopting the therapy, patients must be apprised of its risks and benefits. Physicians and patients must partner to achieve both safety and effectiveness.

Medical cost impact of intrathecal drug delivery for noncancer pain.

INTRODUCTION: As healthcare budgets continue to contract, there is increased payer scrutiny on the use of implantable intrathecal drug-infusion devices. This study utilizes claims data to evaluate the economic effects of intrathecal drug delivery (IDD) based on health services utilization and costs of care before and after implantation. METHODS: We performed a retrospective database study involving 555 noncancer pain patients that received an IDD system implant within a 3-year service period (1/2006-1/2009). IDD patient costs were temporally aligned to implant month and repriced to a standardized, national pricing schedule over a 6-year episode cycle (3 years preimplant, implant month, and 3 years postimplant). Additionally, we made an actuarial projection of postimplant experience, in the absence of IDD intervention, simulating a conventional pain therapy (CPT) protocol by assuming the same slope in costs prior to implantation at standardized, national price levels. Cost projections were produced over a 30-year time horizon at various reimplantation rates. RESULTS: IDD therapy was less costly than the CPT protocol over our baseline implantation cycle. Costs in the month of IDD implantation, and in the year following, are cumulatively $17,317 more than the CPT protocol; however, IDD financial break-even occurs soon after the second year postimplant. The lifetime analysis indicates that IDD per patient per year savings is $3,111 compared with CPT. CONCLUSION: The authors found that patients receiving an implantable IDD system may experience reduced cumulative future medical costs relative to anticipated costs in the absence of receiving IDD. This finding complements published literature on the cost-effectiveness of IDD.

Polyanalgesic Consensus Conference--2012: recommendations to reduce morbidity and mortality in intrathecal drug delivery in the treatment of chronic pain.

INTRODUCTION: Targeted intrathecal drug infusion to treat moderate to severe chronic pain has become a standard part of treatment algorithms when more conservative options fail. This therapy is well established in the literature, has shown efficacy, and is an important tool for the treatment of both cancer and noncancer pain; however, it has become clear in recent years that intrathecal drug delivery is associated with risks for serious morbidity and mortality. METHODS: The Polyanalgesic Consensus Conference is a meeting of experienced implanting physicians who strive to improve care in those receiving implantable devices. Employing data generated through an extensive literature search combined with clinical experience, this work group formulated recommendations regarding awareness, education, and mitigation of the morbidity and mortality associated with intrathecal therapy to establish best practices for targeted intrathecal drug delivery systems. RESULTS: Best practices for improved patient care and outcomes with targeted intrathecal infusion are recommended to minimize the risk of morbidity and mortality. Areas of focus include respiratory depression, infection, granuloma, device-related complications, endocrinopathies, and human error. Specific guidance is given with each of these issues and the general use of the therapy. CONCLUSIONS: Targeted intrathecal drug delivery systems are associated with risks for morbidity and mortality that can be devastating. The panel has given guidance to treating physicians and healthcare providers to reduce the incidence of these problems and to improve outcomes when problems occur.

Polyanalgesic Consensus Conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel.

INTRODUCTION: The use of intrathecal (IT) infusion of analgesic medications to treat patients with chronic refractory pain has increased since its inception in the 1980s, and the need for clinical research in IT therapy is ongoing. The Polyanalgesic Consensus Conference (PACC) panel of experts convened in 2000, 2003, and 2007 to make recommendations on the rational use of IT analgesics based on preclinical and clinical literature and clinical experiences. METHODS: The PACC panel convened again in 2011 to update the standard of care for IT therapies to reflect current knowledge gleaned from literature and clinical experience. A thorough literature search was performed, and information from this search was provided to panel members. Analysis of published literature was coupled with the clinical experience of panel members to form recommendations regarding the use of IT analgesics to treat chronic pain. RESULTS: After a review of literature published from 2007 to 2011 and discussions of clinical experience, the panel created updated algorithms for the rational use of IT medications for the treatment of neuropathic pain and nociceptive pain. CONCLUSIONS: The advent of new algorithmic tracks for neuropathic and nociceptive pain is an important step in improving patient care. The panel encourages continued research and development, including the development of new drugs, devices, and safety recommendations to improve the care of patients with chronic pain.

Polyanalgesic Consensus Conference--2012: consensus on diagnosis, detection, and treatment of catheter-tip granulomas (inflammatory masses).

INTRODUCTION: Continuous intrathecal infusion of drugs to treat chronic pain and spasticity has become a standard part of the algorithm of care. The use of opioids has been associated with noninfectious inflammatory masses at the tip of the intrathecal catheter, which can result in neurologic complications. METHODS: The Polyanalgesic Consensus Conference is a meeting of a group of well-published and experienced practitioners; the purpose of the meeting is to update the standard of care for intrathecal therapies to reflect current knowledge gleaned from literature and clinical experience. An exhaustive literature search was performed, and information from this search was provided to panel members. Analysis of the published literature was coupled with the clinical experience of panel participants to form recommendations regarding intrathecal inflammatory masses or granulomas. RESULTS: The panel has made recommendations for the prevention, diagnosis, and management of intrathecal granulomas. CONCLUSION: The use of chronic infusions of intrathecal opioids is associated with the formation of inflammatory masses at the intrathecal catheter tip in a small minority of treated patients. Nonetheless, the appearance of these space-occupying lesions can lead to devastating neurologic sequelae. The prevention, early detection, and successful treatment of intraspinal granulomas are important considerations when offering intrathecal drug therapy to patients with chronic intractable pain.

Polyanalgesic Consensus Conference--2012: recommendations on trialing for intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel.

INTRODUCTION: Trialing for intrathecal pump placement is an essential part of the decision-making process in placing a permanent device. In both the United States and the international community, the proper method for trialing is ill defined. METHODS: The Polyanalgesic Consensus Conference (PACC) is a group of well-published experienced practitioners who meet to update the state of care for intrathecal therapies on the basis of current knowledge in the literature and clinical experience. Anexhaustive search is performed to create a base of information that the panel considers when making recommendations for best clinical practices. This literature, coupled with clinical experience, is the basis for recommendations and for identification of gaps in the base of knowledge regarding trialing for intrathecal pump placement. RESULTS: The panel has made recommendations for the proper methods of trialing for long-term intrathecal drug delivery. CONCLUSION: The use of intrathecal drug delivery is an important part of the treatment algorithm for moderate to severe chronic pain. It has become common practice to perform a temporary neuroaxial infusion before permanent device implantation. On the basis of current knowledge, the PACC has developed recommendations to improve care. The need to update these recommendations will be very important as new literature is published.

What does the mechanism of spinal cord stimulation tell us about complex regional pain syndrome?

Spinal cord stimulation (SCS) can have dramatic effects on painful, vascular, and motor symptoms of complex regional pain syndrome (CRPS), but its precise mechanism of action is unclear. Better understanding of the physiologic effects of SCS may improve understanding not only of this treatment modality but also of CRPS pathophysiology. Effects of SCS on pain perception are likely to occur through activation of inhibitory GABA-ergic and cholinergic spinal interneurons. Increased release of both neurotransmitters has been demonstrated following SCS in animal models of neuropathic pain, with accompanying reductions in pain behaviors. Effects of SCS on vascular symptoms of CRPS are thought to occur through two main mechanisms: antidromic activation of spinal afferent neurons and inhibition of sympathetic efferents. Cutaneous vasodilation following SCS in animal models has been shown to involve antidromic release of calcitonin gene-related peptide and possibly nitric oxide, from small-diameter sensory neurons expressing the transient receptor potential V1 (TRPV1) receptor. The involvement of sympathetic efferents in the effects of SCS has not been studied in animal models of neuropathic pain, but has been demonstrated in models of angina pectoris. In conclusion, SCS is of clinical benefit in CRPS, and although its mechanism of action merits further elucidation, what little we do know is informative and can partially explain some of the pathophysiology of CRPS.

Practice choices and challenges in the current intrathecal therapy environment: an online survey.

OBJECTIVE: The objective of this study was to evaluate current practice characteristics, treatment choices, clinical experiences, and economic concerns associated with intrathecal therapy. DESIGN: Health care professionals in the United States, who were known to actively use intrathecal therapy in their practices, were recruited to participate in an online survey; contact information was obtained via Internet searches, university Websites, association memberships, industry databases, and personal contacts. Survey responses were summarized descriptively. RESULTS: Of the 329 practitioners who were contacted, 87 participated in the survey. Most participants specialized in anesthesiology (77.0%), worked in a private practice or private hospital (74.7%), and had been practicing pain management for more than 10 years (64.4%). Morphine was the most frequently used opioid for the initiation of intrathecal therapy (80.7% of practitioners), and 81.9% had used ziconotide in their practice. Most practitioners (63.9%) had treated at least one patient who developed a granuloma, and 66.0% of those practitioners had a patient experience permanent or temporary neurological injury due to a granuloma. Fewer than half of practitioners were satisfied with reimbursement from private insurance companies (25.3%) or workers compensation (34.9%), and 90.5% believed reimbursement rates for filling, refilling, and programming patient pumps are not adequate to cover practice costs. The majority of practitioners (56.6%) use fewer pumps in their practices because of reimbursement issues. CONCLUSIONS: Intrathecal pain management practices continue to evolve as the options for treatment increase, and the body of applicable scientific literature grows; however, economic considerations can influence clinical decisions and may interfere with treatment choice and patient access to therapy.

Reassessment of evidence synthesis of occupational medicine practice guidelines for interventional pain management.

BACKGROUND: Appropriately developed practice guidelines present statements of best practice based on a thorough evaluation of the evidence from published studies on the outcomes of treatments, which include the application of multiple methods for collecting and evaluating evidence for a wide range of clinical interventions and disciplines. However, the guidelines are neither infallible, nor a substitute for clinical judgment. While the guideline development process is a complex phenomenon, conflict of interest in guideline development and inappropriate methodologies must be avoided. It has been alleged that the guidelines by the American College of Occupational and Environmental Medicine (ACOEM) prevent injured workers from receiving the majority of medically necessary and appropriate interventional pain management services. An independent critical appraisal of both chapters of the ACOEM guidelines showed startling findings with a conclusion that these guidelines may not be applied in patient care as they scored below 30% in the majority of evaluations utilizing multiple standardized criteria. OBJECTIVE: To reassess the evidence synthesis for the ACOEM guidelines for the low back pain and chronic pain chapters utilizing an expanded methodology, which includes the criteria included in the ACOEM guidelines with the addition of omitted literature and application of appropriate criteria. METHODS: For reassessment, randomized trials were utilized as it was in the preparation of the guidelines. In this process, quality of evidence was assessed and recommendations were made based on grading recommendations of Guyatt et al. The level of evidence was determined utilizing the quality of evidence criteria developed by the U.S. Preventive Services Task Force (USPSTF), as well as the outdated quality of evidence criteria utilized by ACOEM in the guideline preparation. Methodologic quality of each individual article was assessed utilizing the Agency for Healthcare Research and Quality (AHRQ) methodologic assessment criteria for diagnostic interventions and Cochrane methodologic quality assessment criteria for therapeutic interventions. RESULTS: The results of reassessment are vastly different from the conclusions derived by the ACOEM guidelines. The differences in strength of rating for the diagnosis of discogenic pain by provocation discography and facet joint pain by diagnostic facet joint nerve blocks is established with strong evidence. Therapeutic cervical and lumbar medial branch blocks and radiofrequency neurolysis, therapeutic thoracic medial branch blocks, cervical interlaminar epidural steroid injections, caudal epidural steroid injections, lumbar transforaminal epidural injections, percutaneous and endoscopic adhesiolysis, and spinal cord stimulation qualified for moderate to strong evidence. Additional insight is also provided for evidence rating for intradiscal electrothermal therapy (IDET), automated percutaneous disc decompression, and intrathecal implantables. CONCLUSION: The reassessment and reevaluation of the low back and chronic pain chapters of the ACOEM guidelines present results that are vastly different from the published and proposed guidelines. Contrary to ACOEM's conclusions of insufficient evidence for most interventional techniques, the results illustrate moderate to strong evidence for most diagnostic and therapeutic interventional techniques.

Review of occupational medicine practice guidelines for interventional pain management and potential implications.

In the modern day environment, workers' compensation costs continue to be a challenge, with a need to balance costs, benefits, and quality of medical care. The cost of workers' compensation care affects all stakeholders including workers, employers, providers, regulators, legislators, and insurers. Consequently, a continued commitment to quality, accessibility to care, and cost containment will help ensure that workers are afforded accessible, high quality, and cost-effective care. In 2004, workers' compensation programs in all 50 states, the District of Columbia, and federal programs in the United States combined received an income of $87.4 billion while paying out only $56 billion in medical and cash benefits with $31.4 billion or 37% in administrative expenses and profit. Occupational diseases represented only 8% of the workers' compensation claims and 29% of the cost. The American College of Occupational and Environmental Medicine (ACOEM) has published several guidelines; though widely adopted by WCPs, these guidelines evaluate the practice of medicine of multiple specialties without adequate expertise and expert input from the concerned specialties, including interventional pain management. An assessment of the ACOEM guidelines utilizing Appraisal of Guidelines for Research and Evaluation (AGREE) criteria, the criteria developed by the American Medical Association (AMA), the Institute of Medicine (IOM), and other significantly accepted criteria, consistently showed very low scores (< 30%) in most aspects of the these guidelines. The ACOEM recommendations do not appear to have been based on a careful review of the literature, overall quality of evidence, standard of care, or expert consensus. Based on the evaluation utilizing appropriate and current evidence-based medicine (EBM) principles, the evidence ratings for diagnostic techniques of lumbar discography; cervical, thoracic, and lumbar facet joint nerve blocks and sacroiliac joint nerve blocks; therapeutic cervical and lumbar medial branch blocks and radiofrequency neurolysis; cervical interlaminar epidural steroid injections, caudal epidural steroid injections, and lumbar transforaminal epidural injections; caudal percutaneous adhesiolysis; abd spinal cord stimulation were found to be moderate with strong recommendation applying for most patients in most circumstances. The evidence ratings for intradiscal electrothermal therapy (IDET), an automated percutaneous disc decompression and also deserve further scrutiny and analysis. In conclusion, these ACOEM guidelines for interventional pain management have no applicability in modern patient care due to lack of expertise by the developing organization (ACOEM), lack of utilization of appropriate and current EBM principles, and lack of significant involvement of experts in these techniques resulting in a lack of clinical relevance. Thus, they may result in reduced medical quality of care; may severely hinder access to appropriate, medically needed and essential medical care; and finally, they may increase costs for injured workers, third party payors, and the government by transferring the injured worker into a non-productive disability system.

Management of intrathecal catheter-tip inflammatory masses: an updated 2007 consensus statement from an expert panel.

Background. Expert panel of physicians and nonphysicians, all expert in intrathecal (IT) therapies, convened in the years 2000 and 2003 to make recommendations for the rational use of IT analgesics based on the preclinical and clinical literature known up to those times, presentations of the expert panel, discussions on current practice and standards, and the result of surveys of physicians using IT agents. An expert panel of physicians and convened in 2007 to review previous recommendations and to form recommendations for the rational use of IT agents as they pertain to new scientific and clinical information regarding the etiology, prevention and treatment for IT granuloma. Method. A review of preclinical and clinical literature from 2000 to 2006 was undertaken and disseminated to an expert panel of physicians. Focused discussions concerning the rational use of IT agents and its relationship to the etiology of, prevention of, and treatment of IT granuloma were held. Results. This report presents here new knowledge of the etiology of catheter tip granuloma and guidelines for its prevention and treatment.

Future directions for intrathecal pain management: a review and update from the interdisciplinary polyanalgesic consensus conference 2007.

Background. Expert panels of physicians and nonphysicians, all expert in intrathecal (IT) therapies, convened in the years 2000 and 2003 to make recommendations for the rational use of IT analgesics, based on the preclinical and clinical literature known up to those times, presentations of the expert panels, discussions on current practice and standards, and the result of surveys of physicians using IT agents. An expert panel of physicians and nonphysicians has convened in 2007 to update information known regarding IT therapies and to update information on new and novel opioid and nonopioid analgesic compounds that might show promise for IT use. Methods. A review of preclinical and clinical published relevant studies from 2000 to 2006 was undertaken and disseminated to a convened expert panel of physicians and nonphysicians to discuss new and novel analgesic agents for IT use. Results. The panelists identified several agents that were worthy of future studies for the clinical and rational use of IT agents that are presented in this article. Conclusions. A list of nonopioid IT analgesics, including gabapentin, adenosine, octreotide, the χ-conopeptide, Xen2174, the conopeptide, neurotensis 1 agonist, CGX-1160, the ω-conotoxin, AM-336, and physostigmine, were identified as worthy of future research by the panelists.