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.

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.

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.

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.

Local anesthetic blockade of peripheral nerves for treatment of neuralgias: systematic analysis.

BACKGROUND: Nerve blocks with local anesthetics have been used in the diagnosis and treatment of neuralgias. Usually these blocks were administered in combination with corticosteroids and other drugs that can be effective by themselves. Although lasting benefits from nerve blocks in neuralgias have long been described, definitive evidence is lacking. We had the following objectives in this systematic review: to analyze the evidence behind the practice of peripheral nerve blockade with local anesthetics in patients with neuralgias and radicular pain syndromes; to assess the duration of pain relief after conduction block resolution; and to evaluate the effectiveness of the treatment of these syndromes with a series of blocks. METHODS: We searched Medline, Embase, narrative reviews, and book chapters. Only articles published in English were collected. The list of 3347 identified articles was reduced to 39 articles that were read entirely, 12 of which met inclusion criteria. RESULTS: Twelve included articles were analyzed. Each can be classified as a single case report or case series; there were no controlled studies among them. Nine reports assessed a single block outcome; all recorded pain relief beyond the duration of conduction blockade. Those 9 reports represented a total of 69 patients, 30 of whom had complete pain relief and 10 had relief ≥50%. Seven reports with the assessment of continuous pain ≥1 week after a single block reported complete or profound pain relief in 11 of 17 patients. All 3 reports with the assessment of a series of blocks in a large number of patients (total of 270) reported overall positive results. CONCLUSION: Because all reviewed articles were only single case reports or case series, no reliable conclusion could be drawn concerning the effectiveness of nerve blocks with local anesthetics in neuralgia. However, 2 features of the analyzed reports-the large magnitude of the effect and the high consistency of the reported outcome-indicate that future research efforts are warranted.

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.

The development of new analgesics over the past 50 years: a lack of real breakthrough drugs.

Fifty-nine drugs identified as analgesics were introduced from 1960 to 2009 and remain in use. Seven can be regarded as having novel molecular targets; however, only one, sumatriptan, was sufficiently effective to motivate the introduction of many similar drugs acting at the same target (triptans). Publication productivity in the area of pain grew exponentially during this period. Pain-related publications on morphine were dominant among other analgesics. Very intensive research efforts directed at diverse molecular targets related to pain mechanisms produced thousands of publications, but those efforts have not yet yielded new analgesics with sufficient effectiveness to change the share of publications on opioids or nonsteroidal antiinflammatory drugs. Morphine and aspirin, introduced for the treatment of pain more than a century ago, continue to dominate biomedical publications despite their limited effectiveness in many areas (e.g., neuropathic pain) and multiple serious adverse effects. The present assessment reveals the lack of real breakthroughs in analgesic drug development despite intense research efforts. Possible factors contributing to the apparent drought of novel analgesics are discussed.

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.

Patient-controlled-analgesia analgesimetry and its problems.

In addition to providing pain relief, patient-controlled-analgesia (PCA) is also extensively used in clinical research for the assay of analgesic effectiveness of new drugs and methods of pain treatment. The main outcome measure of PCA analgesimetry is the difference in opioid requirements between the control (placebo) group and the new drug (or treatment) group. The following potential problems of PCA analgesimetry are analyzed: 1) weak correlation between pain intensity and opioid consumption, 2) interference of nonanalgesic effects of opioids, 3) role of acute tolerance to the analgesic effect of opioids, 4) problems of the patient's training, 5) interaction between main outcome measures, and 6) sample size and negative outcome problems. Knowledge of the pitfalls of PCA analgesimetry should decrease the risk of errors in its use.

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.

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.

Persistent changes in spinal cord gene expression after recovery from inflammatory hyperalgesia: a preliminary study on pain memory.

BACKGROUND: Previous studies found that rats subjected to carrageenan injection develop hyperalgesia, and despite complete recovery in several days, they continue to have an enhanced hyperalgesic response to a new noxious challenge for more than 28d. The study's aim was to identify candidate genes that have a role in the formation of the long-term hyperalgesia-related imprint in the spinal cord. This objective was undertaken with the understanding that the long-lasting imprint of acute pain in the central nervous system may contribute to the transition of acute pain to chronicity. RESULTS: To analyze changes in gene expression when carrageenan-induced hyperalgesia has disappeared but propensity for the enhanced hyperalgesic response is still present, we determined the gene expression profile using oligo microarray in the lumbar part of the spinal cord in three groups of rats: 28d after carrageenan injection, 24h after injection (the peak of inflammation), and with no injection (control group). Out of 17,000 annotated genes, 356 were found to be differentially expressed compared with the control group at 28d, and 329 at 24h after carrageenan injection (both groups at p < 0.01). Among differentially expressed genes, 67 (39 in 28d group) were identified as being part of pain-related pathways, altered in different models of pain, or interacting with proteins involved in pain-related pathways. Using gene ontology (GO) classification, we have identified 3 functional classes deserving attention for possible association with pain memory: They are related to cell-to-cell interaction, synaptogenesis, and neurogenesis. CONCLUSION: Despite recovery from inflammatory hyperalgesia, persistent changes in spinal cord gene expression may underlie the propensity for the enhanced hyperalgesic response. We suggest that lasting changes in expression of genes involved in the formation of new synapses and neurogenesis may contribute to the transition of acute pain to chronicity.

Vanilloid-induced conduction analgesia: selective, dose-dependent, long-lasting, with a low level of potential neurotoxicity.

Vanilloid agonists (capsaicin, resiniferatoxin, [RTX]) applied to the peripheral nerves provide conduction blockade. In contrast to the analgesic component of conduction anesthesia produced by local anesthetics, vanilloid agonists provide conduction analgesia not associated with suppression of motor or sensory functions not related to pain. Vanilloid agonists provide conduction analgesia selectively because their effect on the nerve trunks is limited to C- and ADelta-fibers. RTX is much more potent than capsaicin and has a wider therapeutic window. In rat experiments, perineural RTX produced a long-lasting thermal and mechanical hypoalgesia with a very wide separation between effective concentrations (from 0.00003% to 0.001%) providing an effect lasting from several hours to several weeks. A nerve block with RTX prevented the development of thermal and mechanical hyperalgesia as well as pain behavior in a model of incisional pain. RTX-induced conduction blockade has an inherent drawback of TRPV1 agonists, the initial excitation (pain); therefore, a local anesthetic should be injected to prevent it. When RTX was applied to the rat's sciatic nerve in doses necessary to provide conduction analgesia, the frequency of unmyelinated fiber degeneration was more than an order of magnitude lower than that with the therapeutic concentration of lidocaine. These promising results should be confirmed by experiments in species other than rodents (pigs, sheep). Taken together, the data indicate possible clinical applicability of vanilloid-induced conduction analgesia.

A high concentration of resiniferatoxin inhibits ion channel function in clonal neuroendocrine cells.

BACKGROUND: Resiniferatoxin (RTX) is a potent agonist of the transient receptor potential vanilloid 1 channel (TRPV1) found in peripheral nociceptors. RTX causes cellular excitation first, followed by a long-lasting refractory state, which has suggested its therapeutic use for pain control. RTX's effect could result from specific actions on TRPV1 channels, but might also arise from previously reported TRPV1-independent effects. We have tested whether exposure to RTX compromises ion channels in a TRPV1-independent manner. METHODS: Clonal rat anterior pituitary (GH(3)) cells, loaded with the Ca(+2)-sensitive fluorescent dye (fluo-4), were stimulated with the Na(+) channel activator veratridine (VTD) or directly depolarized by 60 mM K(+) solution. The physiological effects of exposure to RTX were evaluated by stimulated increases of fluorescence from raised intracellular [Ca(2+)]. RESULTS: The presence of 10 microM RTX acutely reduced the median fluorescence changes by VTD and 60 mM K(+) to 45% and 50%, respectively (P = 0.018 and 0.043). Prolonged exposure (24 h) of cells to 10 microM RTX, followed by a 2 h washout, reduced the median fluorescence changes by VTD and 60 mM K(+) to 5.6% and 42% of control changes, respectively (P = 0.027 and 0.011). Cell responses to VTD partially recovered, to 42% of control, after incubation in RTX-free medium for 24 h. CONCLUSION: RTX at 10 microM directly and acutely inhibited voltage-dependent Ca(2+) channels, in a TRPV1-independent manner. Prolonged exposure (24 h) to 10 microM RTX inhibited voltage-dependent Na(+) channels in addition to the Ca(2+) channels, in at least a partially reversible manner.