Antinociceptive Agents as General Anesthetic Adjuncts: Supra-additive and Infra-additive Interactions.

The hypothesis "General anesthesia consists of producing both loss of consciousness and the inhibition of noxious stimuli reaching the brain and causing arousal" was used as a basis for the review of published data on general anesthetic interactions with antinociceptive agents: opioids, α 2 adrenergic agonists, and systemic sodium channel blockers. This review is focused on a specific type of anesthetic interaction-the transformation of antinociceptive agents into general anesthetic adjuncts. The primary aim is to answer 2 questions. First, how does an antinociceptive agent transform the effect of an anesthetic in providing a certain component of anesthesia-hypnosis, immobility, or hemodynamic response to noxious stimulation? Second, does a combination of an anesthetic with an adjunct result in a simple summation of their respective effects or in a supra-additive or infra-additive interaction? The Medline database was searched for data describing the interactions of antinociceptive agents and general anesthetics. The following classes of antinociceptive agents were considered: opioids, α 2 adrenergic agonists, and systemic sodium channel blockers. Drugs used in combination with antinociceptive agents were general anesthetics and benzodiazepines. The following terms related to drug interactions were used: anesthetic interactions, synergy, antagonism, isobolographic analysis, response surface analysis, and fractional analysis. The interactions of antinociceptive agents with general anesthetics result in a decrease of general anesthetic requirements, which differ for each of the components of general anesthesia: hypnosis, immobility, and hemodynamic response to noxious stimulation. Most studies of the nature of anesthetic interactions are related to opioid-general anesthetic combinations, and their conclusions usually confirm supra-additivity.

Components of General Anesthesia: History of the Concept Transformation.

The concept that the state of general anesthesia consists of a number of components representing the distinct and desired central effects of general anesthetics was formulated when it was common to believe that all components of anesthesia have a lipid-centered mechanism of action. The transformation of this concept was associated with changes in our understanding of the mechanisms underlying general anesthetic action. First came the shift from a lipid- to a protein-centered mechanism of action, which opened the way to various molecular targets associated with general anesthesia. Then, it was found that different components of anesthesia may have completely different underlying mechanisms, such as blockade of movement in response to noxious stimulation by isoflurane centers at the spinal cord level, not at the brain, as is the case with other components. The chain of discoveries associated with newfound differences between components of anesthesia accompanied general progress toward a more comprehensive understanding of the mechanism of action of general anesthetics, including anesthetic binding sites, details of receptors and ion channels involved in neurotransmission, and the critical role of neuronal networks. There are several important consequences of our improved understanding. First, a single measurement of anesthetic depth (eg, minimum alveolar concentration index [MAC index]) might not be appropriate for the different component of anesthesia. Second, because the mechanism of action of the components varies, synergy for 1 component does not exclude an additive effect or even antagonism for another component.

Clinical studies that initiated the use of spinal opioids for the treatment of pain: A new approach to historical review.

Opioids administered into the spinal space by intrathecal or epidural routes can provide potent and prolonged selective analgesia. Compared to the systemic administration of opioids, spinal administration can bring about analgesia with fewer central and systemic adverse effects. For the past 40 years, spinal opioid analgesia has achieved great popularity in various fields of pain treatment. The aim of this work is to identify clinical studies that initiated the use of spinal opioids for the treatment of pain. To determine the historical role of each of the review's studies we used the combination of two factors: the study priority in terms of the time of its publication and the degree of its acknowl-edgement in the form of citation impact. The date of publication was regarded as the primary factor, but only if the count of citations indicated a sufficient acknowledgement by the other authors. The citation impact was assessed as the initial citation count - for period of five years after the year of article publication - and the total count. The selection of studies most important for the introduction of spinal opioids to clinical practice was based on two factors - the study priority in terms of the time of its publication and the degree of acknowledgement in the form of citation impact. The date of publication was regarded as the primary factor, but only if the citation count was indicative of sufficient acknowledgement by other authors. Analysis of the related data shows that the clinical studies initiating the use of spinal opioids for the treatment of pain belong to two groups of authors - Wang et al. and Behar et al. Both studies were published in 1979 and described delivery of morphine into the spinal space, although the techniques of administration were different: Wang et al. injected morphine intrathecally, Behar et al. administered morphine epidurally. The response to these studies was overwhelming -- close to a dozen reports on this topic were published in 1979 and more than a hundred - in 1980-1981. The total citation response to the Wang et al. article reached 699, and that to Behar et al. - 518. Two earlier records (1900-1901) of the use of intrathecal morphine, by Nicolae Racoviceanu-Pitesti and Otojiro Kitagawa, found no following in medical literature for more than three quarters of a century.

Progress in Analgesic Development: How to Assess its Real Merits?

BACKGROUND: Assessing analgesic drugs developed over preceding 50 years demonstrated that very intensive efforts directed at diverse molecular pain targets produced thousands of PubMed articles and the introduction of more than 50 new analgesics. Nevertheless, these analgesics did not have a sufficiently broad spectrum of action and level of effectiveness to demonstrably affect the use of opioids or nonsteroidal anti-inflammatory drugs for the treatment of pain. Analgesics in current are only modestly effective in chronic pain (at least with respect to neuropathic pain), and the widespread application of mu-opioid receptor agonists for this purpose culminated in the global "opioid crisis". The introduction of every new drug is regarded as an important success, at least initially. Assessing the merit of a new analgesic is extremely complicated. OBJECTIVE: The aim of this article is to describe an approach that combines very different categories of drug evaluation - multifactorial approach for the assessment of new analgesics. It is based on conclusiveness of clinical trials, novelty of a drug's molecular target, a drug's commercial appeal, and the interest in a drug reflected by scientometric indices. RESULTS: This approach was applied to analgesics developed in 1982-2016. It shows that although several new agents have completely novel mechanisms of action, all newly approved drugs, and drug candidates, demonstrated the same persistent problems: relatively low therapeutic advantage over previous treatment and narrow spectrum of use in different types of pain, compared to opioids or NSAIDs. CONCLUSION: The use of the suggested multifactorial approach to drug assessment may provide a better view of the whole spectrum of analgesics advantages and disadvantages.

High-Impact Clinical Studies That Fomented New Developments in Anesthesia: History of Achievements, 1966-2015.

The aim of this work is to identify the most influential initial clinical studies that fomented important developments in anesthesiology over the past 50 years. Studies fomenting new development can be selected using vastly different approaches and, therefore, might provide diverse outcomes. In the present work, two basic aspects of study assessments - the stage of development (eg, generation of idea, preclinical studies, clinical trials) and the method of selection (eg, committee vote, various types of citation analysis, method of finding the invention disclosure) - were chosen according to the following model. The stage of development: the initial clinical studies demonstrating the basic advantage of an innovation for providing anesthesia. The method: a combination of two factors - the study priority in terms of the time of its publication and the degree of its acknowledgement in the form of citation impact; the time of study publication was regarded as a primary factor, but only if the study's citation count was =/>20. The initial high-impact studies were selected for 16 drug-related topics (ketamine, isoflurane, etomidate, propofol, midazolam in anesthesia, vecuronium, alfentanil, atracurium, sevoflurane, sufentanil, rocuronium, desflurane, ropivacaine, remifentanil, dexmedetomidine in anesthesia, and sugammadex), and 9 technique-related topics (ultrasound-guided peripheral nerve block, capnography in anesthesia, target-controlled intravenous anesthesia, pulse oximetry in anesthesia, total intravenous anesthesia, transesophageal echocardiography in anesthesia, combined spinal-epidural anesthesia, and bispectral index). Twenty-five studies were designated the first high-impact studies (one for each topic); 16 are drug-related and 9 are technique-related. Half of the first high-impact studies had a citation count of =/>100, (range: 100 to 555). The citation count of the other half of high-impact studies did not reach the 100-citation threshold (range: 41 to 97). If a selected first high-impact study had a citation count <100, a next-on-timeline, additional study with citation count =/>100 was also selected; (range: 100 to 344). The present results show that an initial high-impact clinical study on a new development in anesthesiology can be determined and that related citations usually vary from one hundred to five hundred.

Academic Interest in Pain: Comparison of Four Specialties With Long-Standing Involvement in Pain Medicine.

PURPOSE: One of the most interesting signs of growth in a medical specialty is the addition of pain medicine as a clinical subspecialty to it. The aim of this study was to analyze publication-based academic interest in pain medicine among clinical specialties with long-standing involvement in pain management. METHODS: We assessed the activity within several specialties in the development of an academic foundation for pain medicine by measuring the frequency of the most common pain topics (1998-2017) in academic journals representing such specialties. The selection of materials for the analysis of publication-based academic interest associated with the development of pain medicine followed a three-step process: (1) Medical specialties, limited to those with accredited fellowship training in pain medicine for more than 20 years - anesthesiology, neurology, physiatry, and psychiatry; (2) Pain topics, based on the degree of topic association with the work of pain clinics - a total of 34 topics; (3) Specialty journals, mostly official journals of societies publishing articles representing all aspects of a specialty - four journals per specialty. Specialty-related academic interest was characterized in two dimensions: its breadth (the number of different topics of interest with distinctly high shares of publications) and its intensity (maximal number of publications on a particular topic). RESULTS: According to the number of topics with a distinctly high share of articles per topic (≥ 5%), the rank order of specialties was as follows (of 34 topics): anesthesiology (22), physiatry (20), neurology (10), and psychiatry (0). Regarding comparative intensity of interest, anesthesiology has prevailing interest in 16 topics (especially in postoperative pain and pharmacologic pain treatment), physiatry in 13 topics (especially in physical methods of pain therapy), and neurology in one topic (headache disorders). CONCLUSION: Publication-based academic interest in pain management was most intensive in two specialties, anesthesiology and physiatry, with anesthesiology being somewhat more multifaceted, especially in the methods of pain treatment.

Problems with Developments of Breakthrough Analgesics: Recent History via Scientometric Analysis.

This study evaluated 13 specific topics representing molecular targets for pain during the period 1982-2016. The evaluation was performed by measuring research efforts via a scientometric approach on one hand and by assessing successful outcomes of these efforts, as indicated by the development of FDA-approved analgesics, on the other. A number of new analgesics were developed during this period, some of them with a completely novel mechanism of action. However, the main problems with approved drugs, as well as drug candidates, are relatively low levels of clinical superiority in effectiveness and narrow spectrum of action in different types of pain, compared to opioids or NSAIDs. The most interesting feature of the scientometric analysis of the 13 analgesic discovery topics is the long-lasting growth in the number of articles. The total number of all PubMed articles persistently increased over each of many 5-year periods in every topic even without any success in the development of new analgesics. Scientometric indices of NIH-supported studies are not better at predicting successes in the discovery of new analgesics than indices applied to all publications without regard to the category of support. Thus, even the highly valued NIH-based funding system did not demonstrate a clear advantage for discovery efforts centered on pain-related molecular targets. The evaluated research efforts did not result in breakthrough analgesics that could demonstrably affect the current use of opioids or NSAIDs. Orthodox thinking-both in research and research funding-might be the main reason for the absence of breakthrough analgesics.

Academic Journals Assessed as Springboards for New Developments: A Study of Leading Anesthesia Journals Over Past 50 Years.

PURPOSE: The impact of academic journals on scientific activity can be measured using different approaches. The aim of this study was to assess the leading anesthesia journals as springboards for new developments in the field of anesthesia. METHODS: The selection of the topics for analysis was based on the degree of increase in the number of articles on a topic that was at the center of specialty interest during 1966-2015. The assessment of a journal's response to a new development was made by measuring the number of initial articles on a related topic. Six leading anesthesia journals were assessed collectively and individually as to whether their responses to new developments were prompt and prominent. RESULTS: The role of the leading specialty journals in presentation of 28 topics related to prominent new developments in anesthesia was found to depend on the nature of topics and the type of articles. Compared with all PubMed journals publishing articles associated with anesthesia in 1966-2015, the six leading anesthesia journals published 43% of drug-related research articles, 30% of technique-related research articles, and 16% of both drug- and technique-related review articles. Regarding initial publications (on new topics), this group of six journals contributed comparably more articles: from 43% to 84% of drug-related research articles, from 30% to 49% of technique-related research articles, from 16% to 33% of drug-related review articles, and from 16% to 25% of technique-related review articles. The approximate doubling of the shares demonstrates the dominance of this group of journals in the swiftness response to new anesthesia developments. The promptness of reaction to new developments in anesthesia of each of the six leading anesthesia journals was assessed (the combination of drug- and technique-related articles) based on the number of articles published among the first (first 5 plus next 30) on all 28 topics. The ranking order of four journals (with the highest number of all 1966-2015 articles) regarding early publications was (from high to low): Anesthesia & Analgesia, British Journal of Anaesthesia, Anesthesiology, and Anaesthesia. CONCLUSION: This study assesses six leading anesthesia journals for their function as springboards for new developments in anesthesia over the past 50 years. The dominance of leading journals in initial publications on 28 drug-related and technique-related topics was clearly demonstrated. The results also indicate the possibility of using promptness of response to new advances for quantitative assessment of this aspect of a journal's contribution to the specialty.

Recent History of Publication-Based Academic Interest in General Anesthetics.

PURPOSE: The aim of this study was to determine how interest in various general anesthetics among the authors of academic publications changed over the past 50 years. METHODS: Publication-based academic interest were analyzed using specific scientometric indices: popularity index (PI), top journal selectivity index (TJSI), and index of change (IC). Terms used for searches were the names of drugs belonging to two pharmacological classes of general anesthetics - inhaled and intravenous. Only those that had a PI value > 2.0 during at least one of the 10 five-year periods, from 1967 to 2016, were selected. RESULTS: The PI, an index of comparative popularity, reflects a consistent decline in academic interest over time in both classes of general anesthetics. Over the past 25 years, the PI of inhaled anesthetics decreased by 52 %, and that of intravenous anesthetics fell by 32%. At the same time, the PI of anesthesia management increased by 167%. Among individual anesthetics, the most impressive change was a profound decline in halothane's PI, from 22.9 in 1972-1976 to 0.5 in 2012-2016. The interest in halothane was gradually supplanted by that in new agents, initially by enflurane, followed by isoflurane and finally, sevoflurane. The next meaningful change was the gradual rise in sevoflurane's PI to surpass that of isoflurane. The most dramatic change among the PIs of intravenous anesthetics was associated with the introduction of propofol: an increase from 1.8 to its maximum of 13.6. CONCLUSIONS: The study revealed a constant decline over time in academic interest in the pharmacological basis of general anesthesia relative to all fields of anesthesia combined.

What Can Big Data on Academic Interest Reveal about a Drug? Reflections in Three Major US Databases.

The different stages of the life cycle of a drug - 'prenatal' stage, birth of a drug, rapid growth, maturity and stability, decline, and status before 'death' - are reflected in the three following databases: journal articles (PubMed-www.ncbi.nlm.nih.gov/pubmed); patents (US Patent Office-http://partfl1.uspto.gov/netahtml/PTO/search-adv.htlm); and approved drugs (FDA - www.accessdata.fda.gov/scripts/cder/drugsatfda/index/cfm). These databases are huge, from authoritative sources, correctly classified, and they properly link different datasets. Analysis of such data can uncover hidden patterns important for the assessment of drug status and may also yield some predictions regarding its future prospects. Drug-related, publication-based academic bibliographic records are especially numerous and support the development of various scientometric indices. In combination with information from other types of databases, they can outline various trends in pharmacology. Scientometric indices can be classified into those indicating a change in the status of a drug, and those assessing the chances for success, or even drug discontinuation. Here, we present big data analytics on publication-based academic interest in two segments: (i) description of scientometric indices and (ii) their applications for the assessment of the status of a drug.

Publication-Based Academic Interest in Drugs and Techniques for Treatment of Postoperative Pain, 1975-2015.

PURPOSE: The aim of this study was to determine how drugs and their administration techniques, introduced over the past 40 years and still popular now, influenced publication-based academic interest in the treatment of postoperative pain. METHODS: Specific scientometric indices-popularity index (PI), top journal selectivity index (TJSI), and index of change (IC)-were used. Of the 61 terms searched, only those that had a PI value ≥1.0 during the 2011-2015 period were selected. They include eight drugs-bupivacaine, fentanyl, ropivacaine, acetaminophen, tramadol, remifentanil, and dexamethasone-and five techniques-patient-controlled analgesia, epidural opioids, ultrasound-guided nerve blocks, continuous nerve blocks, and transversus abdominis plane block (presented according to their decreasing PI value in each category). RESULTS: Four of these drugs or techniques with the highest PI in 2011-2015 also held top positions even 20 years earlier: in 1991-1995, the PI for bupivacaine was 9.1; fentanyl, 6.6; patient-controlled analgesia, 10.4; and epidural opioids, 6.8. Since that time, their PI values slowly decreased, for the first three items by approximately 50% and much more than that (85%) with epidural opioids. Nevertheless, to this day, they continue to hold the highest degree of publication-based academic interest. The TJSI can be regarded as an index of expectations at the time of articles publication. With bupivacaine, fentanyl, patient-controlled analgesia, and epidural opioids, the TJSI exceeded the specific high threshold of 10.0 for a very long time. The TJSIs of acetaminophen, ketamine, and dexamethasone were increased with the advent of new expectations regarding the treatment of postoperative pain using these old agents. CONCLUSIONS: Two important developments related to ultrasound-guided nerve block and continuous nerve block demonstrated only a moderate degree of academic interest. In conclusion, even today, the greatest publication-based academic interest related to postoperative pain is associated with drugs and techniques introduced 40-50 years ago.

Assessing advances in regional anesthesia by their portrayals in meta-analyses: an alternative view on recent progress.

BACKGROUND: The aim of this study was to delineate research reflecting advances in regional/local anesthesia where recent clinical progress was clearly defined by meta-analysis. METHODS: We conducted a search to identify all articles with meta-analyses of randomized clinical trials related to the field of regional/local anesthesia. From 279 titles, after multiple exclusions, 16 meta-analyses on important clinical practice developments with high potential for a positive conclusion on the effectiveness of the treatment were left for the assessment. The assessment was performed in two steps. The first step was related to verification of proof-of-concept: the effect is statistically reliable (p-value, effect size, heterogeneity across different RCTs) and the risk of bias not too high. The second step was devoted to attempts to form an opinion on the real clinical benefits of a new development. RESULTS: The assessment revealed that seven recent developments passed the proof-of-concept step. At the same time, positive conclusion on real clinical benefits was reached only by one of these seven developments: ultrasound guidance for peripheral nerve blocks (at least with some of the blocks). Meaningful clinical improvements with other developments remains uncertain. The assessment of the relationships between analyzed advancements over the past 30 years and earlier similar developments indicated that their evolution was usually incremental. The most original advancement was found to be the introduction of the transversus abdominis plane block. CONCLUSION: The assessment of recent advances in regional/local anesthesia, based on the evaluation of related meta-analyses, revealed only incremental progress with mostly marginal benefits. The progress was the most notable with ultrasound guidance for some of peripheral nerve blocks.

Changes in Publication-Based Academic Interest in Local Anesthetics Over the Past 50 Years.

PURPOSE: To present the history of changes in academic interest in local anesthetics quantitatively. METHODS: The changes in publication-based academic interest in local anesthetics were assessed using information from the database of PubMed. The assessment was mostly based on the following indices: general popularity index (GPI), representing the proportion of articles on a drug relative to all articles in the field of regional anesthesia, and specific popularity index (SPI), representing the proportion of articles on a drug relative to all articles in one of the four forms of regional anesthesia: local anesthesia, spinal anesthesia, epidural anesthesia, and peripheral nerve blocks. RESULTS: The most important general feature of the changes in publication-based academic interest in local anesthetics for the past 50 years was the concentration of this interest on a very limited number of drugs. By 2010-2014, only three anesthetics demonstrated the GPI value above 4.0: bupivacaine (10.1), lidocaine (10.0), and ropivacaine (4.6). All other local anesthetics had GPI declining mostly to less than 1.0 (2010-2014). The rate of change in publication-based academic interest was very slow in both its increase and decline. The most profound change in publication-based academic interests was caused by the introduction of bupivacaine. During a 20-year period (from 1965-1969 to 1985-1989), bupivacaine's GPI increased from 1.3 to 12.9. CONCLUSION: A slowly developing concentration of publication-based academic interest on a very limited number of local anesthetics was the dominant feature related to this class of anesthetic agents.

Opioid prescriptions for pain and epidemic of overdose death: can the dramatic reduction in anesthesia mortality serve as an example?

The annual number of US deaths from prescription-opioid overdose quadrupled between 1999 and 2010 and in 2010 alone reached 16,651. Deaths from opioid overdose have now surpassed the historic death toll from another drug-related epidemic - anesthesia mortality. In 1954, Beecher and Todd published reliable data on anesthesia-related mortality in the US, estimating the annual number of deaths to be nearly 5,000. Presently anesthesia/anesthetics are reported as the underlying cause in approximately 34 deaths in the US annually. This spectacular decline in anesthesia-related mortality could serve as an example for attempts to curb the epidemic of opioid overdose death. The main reason that led to the dramatic decline in anesthesia-related mortality is the context in which anesthetics are used. It includes training of the anesthesia providers, the introduction of specific standards of patient safety, and anesthesia monitoring. I suggest that the introduction of a similar multifactorial proper context for the use of opioids in the treatment of chronic nonmalignant pain might be the same "game changer" it was for safety in anesthesia.

Decline in the Development of New Anesthetics.

The number of new anesthetics approved by the USA FDA over the past 30 years (1985-2014) is much smaller than during the preceding 30 years (1955-1984): four versus ten. Investigational anesthetics clinically tested since 1990 have been almost exclusively intravenous anesthetics (nine compounds), with only one now approved by the FDA. All nine agents represent modifications of anesthetics introduced approximately 40-50 years ago; none demonstrates a truly novel mechanism of action. The apparent drought of novel anesthetics is difficult to explain. While there may be multiple reasons, we believe that one is especially noteworthy: the dramatic improvement in anesthesia safety owing to the context in which anesthetics are administered, effectively decreasing the pressure to develop new drugs with better safety margins.